Mark Genovese

All Publications

• A double-blind, placebo-controlled, randomized withdrawal trial of sarilumab for the treatment of glucocorticoid-dependent sarcoidosis. Rheumatology (Oxford, England) Baker, M. C., Horomanski, A., Wang, Y., Yuhan, L., Parsafar, S., Fairchild, R., Mooney, J. J., Raj, R., Witteles, R., Genovese, M. C. 2023

  Abstract

  Effective steroid-sparing therapies for the treatment of sarcoidosis are lacking; interleukin-6 (IL-6) antagonists may reduce sarcoidosis disease activity. This study assessed the safety and efficacy of the IL-6 receptor antagonist, sarilumab, in subjects with glucocorticoid-dependent sarcoidosis.This phase II, double-blind, placebo-controlled, randomized withdrawal trial enrolled 15 subjects with biopsy-proven sarcoidosis at Stanford University from November 2019 to September 2022. In Period 1, subjects were treated with open-label sarilumab 200mg subcutaneously every two weeks for 16 weeks, with predefined tapering of prednisone. Subjects who completed Period 1 without a sarcoidosis flare entered Period 2 and were randomized to continue sarilumab or to receive matching placebo for 12 weeks. Endpoints included flare-free survival, as well as changes in pulmonary function tests, chest imaging, patient reported outcomes, and laboratory values.Fifteen subjects were enrolled in the study (median age 57 years, 80% male, 73.3% White), and 10 subjects successfully completed Period 1. During Period 1, 4 of 15 subjects (26.7%) discontinued due to worsening of their sarcoidosis, and CT chest imaging worsened in 5 of 15 subjects (35.7%). During Period 2, 0 of 2 subjects in the sarilumab group and 1 of 8 subjects (12.5%) in the placebo group had a flare. Treatment with sarilumab 200 mg was generally well tolerated in subjects with sarcoidosis.In this double-blind, placebo-controlled, randomized withdrawal trial, a meaningful signal for improvement in subjects with sarcoidosis treated with sarilumab was not observed. Given the small numbers in this study, no definitive conclusions can be drawn.ClinicalTrials.gov Identifier: NCT04008069.

  View details for DOI 10.1093/rheumatology/kead373

  View details for PubMedID 37471590

• A Randomized, Double-Blind, Sham-Controlled, Clinical Trial of Auricular Vagus Nerve Stimulation for the Treatment of Active Rheumatoid Arthritis. Arthritis & rheumatology (Hoboken, N.J.) Baker, M. C., Kavanagh, S., Cohen, S., Matsumoto, A. K., Dikranian, A., Tesser, J., Kivitz, A., Alataris, K., Genovese, M. C. 2023

  Abstract

  Preliminary evidence suggests that vagus nerve stimulation (VNS) may have some benefit in patients with rheumatoid arthritis (RA), however prior studies have been small and/or uncontrolled; this study aimed to address that gap.This randomized, double-blind, sham-controlled trial enrolled patients aged 18-75 years with active RA who had failed conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and were naïve to biologic and/or targeted synthetic DMARDs. All patients received an auricular vagus nerve stimulator and were randomized 1:1 to active stimulation or sham. The primary endpoint was the proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at week 12. Secondary endpoints included mean changes in disease activity score of 28 joints with C-reactive protein (DAS28-CRP) and Health Assessment Questionnaire-Disability Index (HAQ-DI).A total of 113 patients (mean age 54 years; 82% female) enrolled, and 101 patients (89.4%) completed week 12. ACR20 response at week 12 was 25.0% for active stimulation vs 26.9% for sham (difference vs sham [95% CI]: -1.9 [-18.8-14.9], p=0.823). The least square mean (SE) change in DAS28-CRP was -0.95 (0.16) for active stimulation and -0.66 (0.16) for sham (p=0.201); in HAQ-DI it was -0.19 (0.06) for active stimulation and -0.02 (0.06) for sham (p=0.044). Adverse events occurred in 17 patients (15%); all were mild or moderate.Auricular VNS did not meaningfully improve RA disease activity. If VNS with other modalities is pursued in the future for the treatment of RA, larger, controlled studies will be needed to understand its utility. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/art.42637

  View details for PubMedID 37390360

• A plain language summary of what clinical studies can tell us about the safety of evobrutinib - a potential treatment for multiple sclerosis. Neurodegenerative disease management Montalban, X., Wallace, D., Genovese, M. C., Tomic, D., Parsons-Rich, D., Bolay, C. L., Kao, A. H., Guehring, H. 2023

  Abstract

  WHAT IS THIS SUMMARY ABOUT?: This summary explains the findings from a recent investigation that combined the results of over 1000 people from three clinical studies to understand the safety of evobrutinib. Evobrutinib is an oral medication (taken by mouth), being researched as a potential treatment for multiple sclerosis (MS). This medication was also investigated in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Over 1000 people have taken evobrutinib as part of three separate phase 2 clinical studies. These studies looked at how much of the drug should be taken, how safe the drug is, and how well it might work for treating a certain medical condition.WHAT WERE THE RESULTS?: Evobrutinib was well-tolerated by participants in all three studies. The number of side effects reported by participants taking the medication was very similar to those reported by participants taking the placebo (a 'dummy' treatment without a real drug). The most common side effects in clinical studies were urinary tract infections, headache, swelling of the nose and throat, diarrhoea and blood markers of potential liver damage (these returned to normal once the treatment was stopped).WHAT DO THE RESULTS MEAN?: The safety data from all three clinical studies are encouraging and can be used to inform further research into using evobrutinib in MS. Clinical Trial Registration: NCT02975349 (multiple sclerosis), NCT03233230 (rheumatoid arthritis), NCT02975336 (systemic lupus erythematosus) (ClinicalTrials.gov).

  View details for DOI 10.2217/nmt-2023-0003

  View details for PubMedID 37345645

• Characterisation of the safety profile of evobrutinib in over 1000 patients from phase II clinical trials in multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus: an integrated safety analysis. Journal of neurology, neurosurgery, and psychiatry Montalban, X., Wallace, D., Genovese, M. C., Tomic, D., Parsons-Rich, D., Le Bolay, C., Kao, A. H., Guehring, H. 2022

  Abstract

  OBJECTIVE: Analyse the integrated safety profile of evobrutinib, a Bruton's tyrosine kinase inhibitor (BTKi), using pooled data from multiple sclerosis (MS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) trials.METHODS: Phase II, randomised, double-blind, placebo-controlled trial data were analysed (N=1083; MS: n=213, 48 weeks (W); RA: n=390, 12W; SLE: n=480, 52W). The analysis included all patients who received ≥1dose of evobrutinib (25mg or 75mg once daily, or 50mg or 75mgtwice daily) or placebo. Descriptive statistics and exposure-adjusted incidence rates (EAIR) were used to report treatment-emergent adverse events (TEAEs).RESULTS: Data from 1083 patients were pooled: evobrutinib, n=861; placebo, n=271 (sum >1083due to MS trial design: n=49 received both placebo (W0-24) and evobrutinib 25mg (W25-48)); median follow-up time (pt-years): evobrutinib, 0.501; placebo, 0.463. Across indications, the proportion of patients with TEAEs and the EAIR were similar for evobrutinib and placebo (66.2% (247.6 events/100 pt-years) vs 62.4% (261.4 events/100 pt-years)). By indication, the EAIR (events/100 pt-years) of TEAEs for evobrutinib versus placebo were: MS: 119.7 vs 148.3; RA: 331.8 vs 306.8; SLE: 343.0 vs 302.1. Two fatal events occurred (in SLE). The serious infections EAIR was 2.7 and 2.1 events/100 pt-years for evobrutinib and placebo. For previously reported BTKi-class effects, the EAIR of transient elevated alanine aminotransferase/aspartate aminotransferase TEAEs (events/100 pt-years) with evobrutinib versus placebo was 4.8 vs 2.8/3.5 vs 0.7, respectively. IgG levels were similar in evobrutinib/placebo-treated patients.CONCLUSIONS: This is the first BTKi-integrated safety analysis that includes patients with MS. Overall, evobrutinib treatment (all doses) was generally well tolerated across indications.TRIAL REGISTRATION NUMBERS: NCT02975349, NCT03233230, NCT02975336.

  View details for DOI 10.1136/jnnp-2022-328799

  View details for PubMedID 36418156

• A phase 2 randomized controlled trial of the Janus Kinase (JAK) inhibitor filgotinib in patients with noninfectious uveitis Srivastava, S. K., Watkins, T., Quan Dong Nguyen, Sharma, S., Scales, D., Dacey, M., Shah, R. E., Chu, D., Grewal, D. S., Faia, L., Suhler, E. B., Genovese, M., Guo, Y., Barchuk, W., Dick, A. D., Rosenbaum, J. T. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2022

  View details for Web of Science ID 000844437001059

• The Incidence, Prevalence, and Associated Costs of Anemia, Malignancy, Venous Thromboembolism, Major Adverse Cardiovascular Events, and Infections in Rheumatoid Arthritis Patients by Treatment History in the United States. ACR open rheumatology Dore, R. K., Antonova, J. N., Burudpakdee, C., Chang, L., Gorritz, M., Genovese, M. C. 2021

  Abstract

  OBJECTIVE: Comorbidities in rheumatoid arthritis (RA) can influence treatment selection, impact treatment persistency, and increase health care costs. This study assessed the magnitude of comorbidity burden via epidemiology (incidence and prevalence) and associated costs of select comorbidities in RA patients: anemia, malignancy, venous thromboembolism (VTE), major adverse cardiovascular events (MACE), and infections, stratified by history of disease-modifying antirheumatic drug (DMARD) exposure.METHODS: From the IQVIA PharMetrics Plus database, we selected adult patients with RA (2 or more RA diagnostic codes at least 30days apart) at initiation of a new DMARD (DMARD-naive), after the first conventional synthetic DMARD (csDMARD) or after the first biologic DMARD (bDMARD). We assessed pre-index prevalence (percentage) and on-treatment incidence (per 100 patient-years [P100PY]) of the aforementioned comorbidities. For patients with versus without incident conditions, we compared total all-cause health care costs as unadjusted and adjusted for baseline characteristics and health care costs.RESULTS: Prior to initiating a new treatment, among DMARD-naive patients (N=28,201), csDMARD switchers (N=7,816), or bDMARD switchers (N=4,656), the overall prevalence ranged from 14.1% to 16.2% (anemia), from 1.3% to 5.2% (malignancy, evaluated in csDMARD and bDMARD switchers), from 1.5% to 2.1% (VTE), from 1.8% to 2.9% (MACE), and from 66.6% to 76.1% (infections). Once on index treatment, overall incidence (P100PY) among the cohorts ranged from 6.9 to 8.9 (anemia), from 2.0 to 2.3 (malignancy), from 0.7 to 0.9 (VTE), from 1.6 to 2.0 (MACE), and from 77.4 to 87.7 (infections). The incident comorbidities (except herpes zoster) were associated with increased adjusted health care costs.CONCLUSION: Anemia, malignancy, VTE, MACE, and infections affect patients with RA at all stages of their treatment journey and are associated with increased health care costs.

  View details for DOI 10.1002/acr2.11376

  View details for PubMedID 34792867

• Corrigendum to: Safety of ixekizumab in adult patients with plaque psoriasis, psoriatic arthritis and axial spondyloarthritis: data from 21 clinical trials. Rheumatology (Oxford, England) Genovese, M. C., Mysler, E., Tomita, T., Papp, K. A., Salvarani, C., Schwartzman, S., Gallo, G., Patel, H., Lisse, J. R., Kronbergs, A., Leage, S. L., Adams, D. H., Xu, W., Marzo-Ortega, H., Lebwohl, M. G. 2021

  View details for DOI 10.1093/rheumatology/keab566

  View details for PubMedID 34549772

• Twenty-four-week Follow-up of a Randomized Controlled First-in-Human Trial of the Safety and Efficacy of Neurostimulation with a Miniaturized Vagus Nerve Stimulation Device in Patients with Multidrug-Refractory Rheumatoid Arthritis Gaylis, N., Genovese, M., Sikes, D., Kivitz, A., Horowitz, D., Peterfy, C., Levine, Y., Chernoff, D. WILEY. 2021: 3561-3563

  View details for Web of Science ID 000744545207022

• Olokizumab, a monoclonal antibody against interleukin 6, in combination with methotrexate in patients with rheumatoid arthritis inadequately controlled by methotrexate: efficacy and safety results of a randomised controlled phase III study. Annals of the rheumatic diseases Nasonov, E., Fatenejad, S., Feist, E., Ivanova, M., Korneva, E., Krechikova, D. G., Maslyanskiy, A. L., Samsonov, M., Stoilov, R., Zonova, E. V., Genovese, M. 2021

  Abstract

  OBJECTIVE: To evaluate the efficacy and safety of olokizumab (OKZ) in patients with active rheumatoid arthritis despite treatment with methotrexate (MTX).METHODS: In this 24-week multicentre, placebo-controlled, double-blind study, patients were randomised 1:1:1 to receive subcutaneously administered OKZ 64mg once every 2 weeks, OKZ 64mg once every 4 weeks, or placebo plus MTX. The primary efficacy endpoint was the proportion of patients achieving an American College of Rheumatology 20% (ACR20) response at week 12. The secondary efficacy endpoints included percentage of subjects achieving Disease Activity Score 28-joint count based on C reactive protein <3.2, Health Assessment Questionnaire Disability Index at week 12, ACR50 response and Clinical Disease Activity Index ≤2.8 at week 24. Safety and immunogenicity were assessed throughout the study.RESULTS: A total of 428 patients were randomised. ACR20 responses were more frequent with OKZ every 2 weeks (63.6%) and OKZ every 4 weeks (70.4%) than placebo (25.9%) (p<0.0001 for both comparisons). There were significant differences in all secondary efficacy endpoints between OKZ-treated arms and placebo. Treatment-emergent serious adverse events (TESAEs) were reported by more patients in the OKZ groups compared with placebo. Infections were the most common TESAEs. No subjects developed neutralising antidrug antibodies.CONCLUSIONS: Treatment with OKZ was associated with significant improvement in signs, symptoms and physical function of rheumatoid arthritis without discernible differences between the two regimens. Safety was as expected for this class of agents. Low immunogenicity was observed. Trial registration number NCT02760368.

  View details for DOI 10.1136/annrheumdis-2021-219876

  View details for PubMedID 34344706

• Targeting GM-CSF in rheumatological conditions: risk of PAP Reply LANCET RHEUMATOLOGY Genovese, M. C., Buckley, C. D., Saurigny, D., Schett, G., Davy, K., Gupta, A., Smith, J. E., Patel, J., Tak, P. P. 2021; 3 (7): E473-E474

  View details for Web of Science ID 000667298900009

• Safety Profiles of Ixekizumab versus Adalimumab: 52-Week Results from a Head-to-Head Comparison in Patients With Active Psoriatic Arthritis Mease, P., Smolen, J., Kavanaugh, A., Nash, P., Gallo, G., Liu-Leage, S., Sapin, C., Genovese, M., Bessette, L. J RHEUMATOL PUBL CO. 2021: 1167

  View details for Web of Science ID 000680554800184

• Corrigendum to 'TNF-alpha Inhibition for the Treatment of Cardiac Sarcoidosis' Seminars in Arthritis and Rheumatism. 2020 Jun;50(3):546-552. Seminars in arthritis and rheumatism Baker, M. C., Sheth, K., Witteles, R., Genovese, M. C., Shoor, S., Simard, J. F. 2021

  View details for DOI 10.1016/j.semarthrit.2021.05.009

  View details for PubMedID 34172273

• Long-term safety and efficacy of sarilumab over 5 years in patients with rheumatoid arthritis refractory to TNF inhibitors. Rheumatology (Oxford, England) Fleischmann, R., Genovese, M. C., Maslova, K., Leher, H., Praestgaard, A., Burmester, G. R. 2021

  Abstract

  OBJECTIVE: To evaluate long-term safety and efficacy of sarilumab over 5 years in patients with RA refractory to TNF inhibitors (TNFi).METHODS: Patients in the 24-week randomized controlled trial (RCT) TARGET (NCT01709578) whoreceived double-blind placebo or sarilumab 150 or 200mg every 2 weeks (q2w), plus conventionalsynthetic DMARDs (csDMARDs), were eligible to receive open-label sarilumab 200mg q2w pluscsDMARDs in the open-label extension (OLE), EXTEND (NCT01146652). OLE dose reduction to 150mg q2w was permitted per investigators' judgement or protocol-mandated safety concerns. Safety and efficacy were assessed through treatment-emergent adverse events (AEs), laboratoryabnormalities and clinical disease activity scores. All statistics are descriptive.RESULTS: Of 546 patients, 454 (83%) were treated with sarilumab in the OLE. Cumulative observation period was 1654.8 patient-years (PY; n = 521); 268 patients (51%) had ≥4 years' exposure. Incidencerates per 100 PY of AEs, AEs leading to discontinuation, infection and serious infection were 160.4, 8.1, 57.8 and 3.9, respectively. Neutropenia was the most common AE (15.3 per 100 PY). Absoluteneutrophil count <1000 cells/mm3 (Grade 3/4 neutropenia) was observed in 74 patients (14.2%) and normalized on treatment in 48. Clinical efficacy was sustained through 5 years' follow-up. Efficacy was similar for patients with 1 and >1 TNFi failure, and between patients who either remained on 200mg or reduced to 150mg.CONCLUSION: In patients with RA refractory to TNFi, sarilumab's long-term term safety profile was consistent with previous clinical studies and post-marketing reports. Efficacy was sustained over 5years.

  View details for DOI 10.1093/rheumatology/keab355

  View details for PubMedID 33871596

• Non-invasive vagus nerve stimulation for rheumatoid arthritis: a proof-of-concept study LANCET RHEUMATOLOGY Marsal, S., Corominas, H., Jose de Agustin, J., Perez-Garcia, C., Lopez-Lasanta, M., Borrell, H., Reina, D., Sanmarti, R., Narvaez, J., Franco-Jarava, C., Peterfy, C., Antonio Narvaez, J., Sharma, V., Alataris, K., Genovese, M. C., Baker, M. C. 2021; 3 (4): E262-E269

  View details for DOI 10.1016/S2665-9913(20)30425-2

  View details for Web of Science ID 000644477400012

• EFFICACY AND SAFETY OF UPADACITINIB IN PATIENTS WITH ACTIVE PSA AND INADEQUATE RESPONSE TO BIOLOGIC DMARDS (SELECT-PSA-2): A DOUBLE-BLIND, RANDOMISED CONTROLLED PHASE III TRIAL Genovese, M. C., Lertratanakul, A., Anderson, J., Papp, K., Tillett, W., van den Bosch, F., Tsuji, S., Dokoupilova, E., Keiserman, M., Wang, X., Zhong, S., Zueger, P., Pangan, A., Mease, P. OXFORD UNIV PRESS. 2021: 90

  View details for DOI 10.1093/rheumatology/keab247.166

  View details for Web of Science ID 000667796000199

• Safety and Efficacy of Filgotinib: Up to 4-Year Results From an Open-Label Extension Study of Phase 2 Rheumatoid Arthritis Programs. The Journal of rheumatology Kavanaugh, A., Westhovens, R. R., Winthrop, K. L., Lee, S. J., Tan, Y., An, D., Ye, L., Sundy, J. S., Besuyen, R., Meuleners, L., Stanislavchuk, M., Spindler, A. J., Greenwald, M., Alten, R., Genovese, M. C. 2021

  Abstract

  OBJECTIVE: The long-term safety and efficacy of filgotinib (from phase 2 studies), with or without methotrexate (MTX), for the treatment of patients with rheumatoid arthritis was assessed in DARWIN 3, a long-term, open-label extension study (NCT02065700).METHODS: Eligible patients completing the 24-week DARWIN 1 (filgotinib + MTX) and DARWIN 2 (filgotinib monotherapy) studies entered DARWIN 3, where they received filgotinib 200 mg/day, except for 15 men who received filgotinib 100 mg/day. Safety analyses were performed using the safety analysis set and exposure-adjusted incidence rate (EAIR) of treatment-emergent adverse events (TEAEs) was calculated. Efficacy was assessed from baseline in the parent studies.RESULTS: Of 790 patients completing the phase 2 parent studies, 739 enrolled in the study. Through April 2019, 59.5% of patients had received ≥4 years of study drug. Mean (SD) exposure to filgotinib was 3.55 (1.57) years in the filgotinib + MTX group and 3.38 (1.59) years in the filgotinib monotherapy group. EAIR per 100 patient years of exposure (PYE) for TEAEs was 24.6 in the filgotinib + MTX group and 25.8 in the filgotinib monotherapy group, and for serious TEAEs, the EAIR was 3.1 and 4.3, respectively. ACR20/50/70 responses among patients remaining in the study could be maintained through 4 years, with 89.3%/69.6%/49.1% of filgotinib + MTX group and 91.8%/69.4%/44.4% of monotherapy group maintaining ACR20/50/70 responses based on observed data.CONCLUSION: Filgotinib was well tolerated with a 4-year safety profile comparable to that of the parent trials, both in patients receiving combination therapy with MTX or as monotherapy.

  View details for DOI 10.3899/jrheum.201183

  View details for PubMedID 33526618

• Long-term safety and efficacy of olokizumab in patients with rheumatoid arthritis and inadequate response to tumor necrosis factor inhibitor therapy in phase II studies. European journal of rheumatology Genovese, M. C., Durez, P., Fleischmann, R., Tanaka, Y., Furst, D., Yamanaka, H., Korneva, E., Vasyutin, I., Takeuchi, T. 2021

  Abstract

  This study aimed to evaluate the long-term safety and efficacy of olokizumab (OKZ), an anti-interleukin (IL)-6 monoclonal antibody, in patients with rheumatoid arthritis (RA) and inadequate response to tumor necrosis factor-alpha inhibitors.Eligible patients completed study RA0056, which tested several doses of OKZ, placebo (PBO), and tocilizumab (TCZ) plus methotrexate (MTX) in Western countries, and RA0083 included several doses of OKZ and PBO plus MTX in Asian countries. Both studies were followed by open-label extension (OLE) studies with OKZ 120 mg every 2 weeks, RA0057 and RA0089, respectively. Safety assessments were reported up to 124 weeks in RA0057 and 92 weeks in RA0089. Efficacy assessments were reported up to week 60 in RA0057 and week 52 in RA0089. No formal statistical hypothesis testing was performed, and missing data were not imputed.A total of 190 patients in RA0057 and 103 patients in RA0089 received OKZ with median treatment duration of 14.1 and 10.1 months, respectively. Serious adverse events (SAEs) were reported in 44 patients (23.2%, 32.7 events per 100 patient-years [PY]) in RA0057 and in 13 patients (12.6%, 23.6 events per 100 PY) in RA0089. Among treatment-emergent adverse events (TEAEs), including SAEs, infections were the most common events. TEAEs leading to withdrawal were reported in 33 (17.4%) patients in RA0057 and in 7 (6.8%) patients in RA0089. Disease activity score 28-joint count on the basis of C-reactive protein level, clinical disease activity index, and simplified disease activity index, as well as the American College of Rheumatology 20%, 50%, and 70% response rates were maintained during the OLE studies, including in those who switched from PBO or TCZ. Improvements in patient-reported outcomes were maintained in OLEs as well.In the 2 long-term studies, OKZ treatment demonstrated a safety profile expected for IL-6 blocking agents without new safety signals and led to sustained improvements in RA symptoms, physical function, and quality of life.

  View details for DOI 10.5152/eurjrheum.2021.19207

  View details for PubMedID 34101570

• 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis & rheumatology (Hoboken, N.J.) Fraenkel, L., Bathon, J. M., England, B. R., St Clair, E. W., Arayssi, T., Carandang, K., Deane, K. D., Genovese, M., Huston, K. K., Kerr, G., Kremer, J., Nakamura, M. C., Russell, L. A., Singh, J. A., Smith, B. J., Sparks, J. A., Venkatachalam, S., Weinblatt, M. E., Al-Gibbawi, M., Baker, J. F., Barbour, K. E., Barton, J. L., Cappelli, L., Chamseddine, F., George, M., Johnson, S. R., Kahale, L., Karam, B. S., Khamis, A. M., Navarro-Millán, I., Mirza, R., Schwab, P., Singh, N., Turgunbaev, M., Turner, A. S., Yaacoub, S., Akl, E. A. 2021

  Abstract

  To develop updated guidelines for the pharmacologic management of rheumatoid arthritis.We developed clinically relevant population, intervention, comparator, and outcomes (PICO) questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the certainty of evidence. A voting panel comprising clinicians and patients achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations.The guideline addresses treatment with disease-modifying antirheumatic drugs (DMARDs), including conventional synthetic DMARDs, biologic DMARDs, and targeted synthetic DMARDs, use of glucocorticoids, and use of DMARDs in certain high-risk populations (i.e., those with liver disease, heart failure, lymphoproliferative disorders, previous serious infections, and nontuberculous mycobacterial lung disease). The guideline includes 44 recommendations (7 strong and 37 conditional).This clinical practice guideline is intended to serve as a tool to support clinician and patient decision-making. Recommendations are not prescriptive, and individual treatment decisions should be made through a shared decision-making process based on patients' values, goals, preferences, and comorbidities.

  View details for DOI 10.1002/art.41752

  View details for PubMedID 34101376

• 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis care & research Fraenkel, L., Bathon, J. M., England, B. R., St Clair, E. W., Arayssi, T., Carandang, K., Deane, K. D., Genovese, M., Huston, K. K., Kerr, G., Kremer, J., Nakamura, M. C., Russell, L. A., Singh, J. A., Smith, B. J., Sparks, J. A., Venkatachalam, S., Weinblatt, M. E., Al-Gibbawi, M., Baker, J. F., Barbour, K. E., Barton, J. L., Cappelli, L., Chamseddine, F., George, M., Johnson, S. R., Kahale, L., Karam, B. S., Khamis, A. M., Navarro-Millán, I., Mirza, R., Schwab, P., Singh, N., Turgunbaev, M., Turner, A. S., Yaacoub, S., Akl, E. A. 2021

  Abstract

  To develop updated guidelines for the pharmacologic management of rheumatoid arthritis.We developed clinically relevant population, intervention, comparator, and outcomes (PICO) questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to rate the certainty of evidence. A voting panel comprising clinicians and patients achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations.The guideline addresses treatment with disease-modifying antirheumatic drugs (DMARDs), including conventional synthetic DMARDs, biologic DMARDs, and targeted synthetic DMARDs, use of glucocorticoids, and use of DMARDs in certain high-risk populations (i.e., those with liver disease, heart failure, lymphoproliferative disorders, previous serious infections, and nontuberculous mycobacterial lung disease). The guideline includes 44 recommendations (7 strong and 37 conditional).This clinical practice guideline is intended to serve as a tool to support clinician and patient decision-making. Recommendations are not prescriptive, and individual treatment decisions should be made through a shared decision-making process based on patients' values, goals, preferences, and comorbidities.

  View details for DOI 10.1002/acr.24596

  View details for PubMedID 34101387

• Vagus nerve stimulation in rheumatoid arthritis Reply LANCET RHEUMATOLOGY Genovese, M. C., Levine, Y. A., Chernoff, D. 2021; 3 (1): E14–E15

  View details for Web of Science ID 000608435700015

• Diminished cytokine-induced Jak/STAT signaling is associated with rheumatoid arthritis and disease activity. PloS one Ptacek, J. n., Hawtin, R. E., Sun, D. n., Louie, B. n., Evensen, E. n., Mittleman, B. B., Cesano, A. n., Cavet, G. n., Bingham, C. O., Cofield, S. S., Curtis, J. R., Danila, M. I., Raman, C. n., Furie, R. A., Genovese, M. C., Robinson, W. H., Levesque, M. C., Moreland, L. W., Nigrovic, P. A., Shadick, N. A., O'Dell, J. R., Thiele, G. M., Clair, E. W., Striebich, C. C., Hale, M. B., Khalili, H. n., Batliwalla, F. n., Aranow, C. n., Mackay, M. n., Diamond, B. n., Nolan, G. P., Gregersen, P. K., Bridges, S. L. 2021; 16 (1): e0244187

  Abstract

  Rheumatoid arthritis (RA) is a systemic and incurable autoimmune disease characterized by chronic inflammation in synovial lining of joints. To identify the signaling pathways involved in RA, its disease activity, and treatment response, we adapted a systems immunology approach to simultaneously quantify 42 signaling nodes in 21 immune cell subsets (e.g., IFNα→p-STAT5 in B cells) in peripheral blood mononuclear cells (PBMC) from 194 patients with longstanding RA (including 98 patients before and after treatment), and 41 healthy controls (HC). We found multiple differences between patients with RA compared to HC, predominantly in cytokine-induced Jak/STAT signaling in many immune cell subsets, suggesting pathways that may be associated with susceptibility to RA. We also found that high RA disease activity, compared to low disease activity, was associated with decreased (e.g., IFNα→p-STAT5, IL-10→p-STAT1) or increased (e.g., IL-6→STAT3) response to stimuli in multiple cell subsets. Finally, we compared signaling in patients with established, refractory RA before and six months after initiation of methotrexate (MTX) or TNF inhibitors (TNFi). We noted significant changes from pre-treatment to post-treatment in IFNα→p-STAT5 signaling and IL-10→p-STAT1 signaling in multiple cell subsets; these changes brought the aberrant RA signaling profiles toward those of HC. This large, comprehensive functional signaling pathway study provides novel insights into the pathogenesis of RA and shows the potential of quantification of cytokine-induced signaling as a biomarker of disease activity or treatment response.

  View details for DOI 10.1371/journal.pone.0244187

  View details for PubMedID 33444321

• Efficacy and safety of filgotinib in Japanese patients with refractory rheumatoid arthritis: Subgroup analyses of a global phase 3 study (FINCH 2) MODERN RHEUMATOLOGY Takeuchi, T., Matsubara, T., Atsumi, T., Amano, K., Ishiguro, N., Sugiyama, E., Yamaoka, K., Genovese, M. C., Kalunian, K., Walker, D., Gottenberg, J., de Vlam, K., Bartok, B., Pechonkina, A., Kondo, A., Gao, J., Guo, Y., Tasset, C., Sundy, J. S., Tanaka, Y. 2020: 1–16

  Abstract

  To evaluate efficacy and safety of filgotinib in Japanese RA patients who have failed or were intolerant to one or more biologic disease-modifying antirheumatic drugs (bDMARD) from the global FINCH 2 study (NCT02873936).This subgroup analysis was performed using the predefined statistical analyses. The FINCH 2 study is a randomized, double-blind, placebo-controlled, Phase 3 study in adult RA patients with inadequate response to bDMARDs. The randomized patients were treated with once-daily filgotinib 200 mg, filgotinib 100 mg or placebo on a background of csDMARDs for 24 weeks.Of 449 patients enrolled in the overall population, 40 patients were enrolled from Japan. In the Japanese population, the American College of Rheumatology 20% response rates at week 12 (primary endpoint) were 83.3% and 53.3% for filgotinib, 200 mg and 100 mg, respectively, vs 30.8% for placebo. Filgotinib was well tolerated, similar to the overall population.Both doses of once-daily filgotinib 200 mg and filgotinib 100 mg were effective, and generally well-tolerated in Japanese patients with active refractory RA.

  View details for DOI 10.1080/14397595.2020.1859675

  View details for Web of Science ID 000608504000001

  View details for PubMedID 33274687

• MRI of the joint and evaluation of the granulocyte-macrophage colony-stimulating factor-CCL17 axis in patients with rheumatoid arthritis receiving otilimab: a phase 2a randomised mechanistic study LANCET RHEUMATOLOGY Genovese, M. C., Berkowitz, M., Conaghan, P. G., Peterfy, C., Davy, K., Fisheleva, E., Gupta, A., Inman, D., Janiczek, R., Layton, M., Mitchell, N., Patel, J., Roberts, A., Saurigny, D., Smith, J. E., Williamson, R., Tak, P. P. 2020; 2 (11): E666–E676

  View details for DOI 10.1016/S2665-9913(20)30224-1

  View details for Web of Science ID 000582523300021

• Efficacy and Safety of Neihulizumab (AbGn-168H) in Patients with Active Psoriatic Arthritis: 24-week Results from a Phase II Open Label Study Cohen, S., Fiechtner, J., Mease, P., Kaine, J., Kavanaugh, A., Cheng, Y., Chou, C., Cheng, T., Lin, S., Genovese, M. WILEY. 2020

  View details for Web of Science ID 000587568502132

• A Subgroup Analysis of Low Disease Activity and Remission from Phase 3 Study of Filgotinib in Patients with Inadequate Response to Biologic DMARDs Gottenberg, J., Buch, M., Caporali, R., Wright, G., Takeuchi, T., Kalunian, K., Pechonkina, A., Guo, Y., Rao, S., Tan, Y., Besuyen, R., Genovese, M. WILEY. 2020

  View details for Web of Science ID 000587568500217

• Long-Term Safety and Effectiveness of Upadacitinib or Adalimumab in Patients with Rheumatoid Arthritis: Results at 72 Weeks Fleischmann, R., Song, I., Enejosa, J., Mysler, E., Bessette, L., Durez, P., Ostor, A., Swierkot, J., Song, Y., Genovese, M. WILEY. 2020

  View details for Web of Science ID 000587568500213

• Efficacy and Safety of Upadacitinib in Patients with Active Psoriatic Arthritis and Inadequate Response to Biologic Disease-Modifying Anti-Rheumatic Drugs: A Double-Blind, Randomized Controlled Phase 3 Trial Genovese, M., Lertratanakul, A., Anderson, J. K., Papp, K., Tillett, W., Van den Bosch, F., Tsuji, S., Dokoupilova, E., Keiserman, M., Wang, X., Zhong, S., Zueger, P., Pangan, A., Mease, P. WILEY. 2020

  View details for Web of Science ID 000587568501015

• A Phase IIb, Randomized, Double-blind Study in Patients with Rheumatoid Arthritis Evaluating the Safety and Efficacy of Evobrutinib Compared with Placebo in Patients with an Inadequate Response to Methotrexate Peterfy, C., Buch, M., Choy, E., Schett, G., Parsons-Rich, D., Patel, A., Zima, Y., Le Bolay, C., Genovese, M. WILEY. 2020

  View details for Web of Science ID 000587568506263

• Non-invasive Vagus Nerve Stimulation Improves Signs and Symptoms of Rheumatoid Arthritis: Results of a Pilot Study Marsal, S., Corominas, H., De Agustin De Oro, J., Perez Garcia, C., Lopez Lasanta, M., Borrell, H., Reina, D., Sanmarti, R., Javier Narvaez, F., Franco-Jarava, C., Peterfy, C., Antonio Narvaez, J., Sharma, V., Alataris, K., Genovese, M., Baker, M. WILEY. 2020

  View details for Web of Science ID 000587568506246

• Safety and efficacy of neurostimulation with a miniaturised vagus nerve stimulation device in patients with multidrug-refractory rheumatoid arthritis: a two-stage multicentre, randomised pilot study LANCET RHEUMATOLOGY Genovese, M. C., Gaylis, N. B., Sikes, D., Kivitz, A., Horowitz, D., Peterfy, C., Glass, E., Levine, Y. A., Chernoff, D. 2020; 2 (9): E527–E538

  View details for DOI 10.1016/S2665-9913(20)30172-7

  View details for Web of Science ID 000580060100019

• Immunogenicity of an adalimumab biosimilar, FKB327, and its reference product in patients with rheumatoid arthritis. International journal of rheumatic diseases Alten, R., Markland, C., Boyce, M., Kawakami, K., Muniz, R., Genovese, M. C. 2020

  Abstract

  AIM: This study, FKB327-003, is a phase 3, open-label extension (OLE) study comparing the long-term immunogenicity of an adalimumab biosimilar, FKB327 (F), with the reference product (RP).METHODS: In the OLE, patients completing 24weeks of an initial randomized, double-blind (DB) study (Period 1) with clinical response and no safety concerns were rerandomized to F or RP, so that two-thirds of patients remained on the same treatment and one-third switched to the alternate treatment for weeks 24 through 54 (OLE weeks 0-30; Period 2), then all received F through week 100 (OLE week 76; Period 3). Treatment sequences were F-F-F (no switch), RP-F-F and RP-RP-F (single switch), and F-RP-F (double switch). Patients who entered the OLE study were evaluated for immunogenicity across switching sequences.RESULTS: The proportion of patients with positive antidrug antibody (ADA) status at the end of Period 1 was 61.7% and 60.0% for F and RP, respectively. The proportion of patients with positive ADA status did not increase throughout Period 1, and was similar for F and RP at all time points. At the end of Period 3, the proportion of patients with positive ADA status was lower in all treatment sequences, at 51.1%, 54.4%, 48.1%, and 42.5% for F-F-F, F-RP-F, RP-F-F, and RP-RP-F, respectively.CONCLUSION: The RP and F showed comparable immunogenicity characteristics after long-term administration. Development of ADAs with the RP and F was similar, and was not impacted by switching and double switching between F and RP treatment.

  View details for DOI 10.1111/1756-185X.13951

  View details for PubMedID 32852139

• Infections in baricitinib clinical trials for patients with active rheumatoid arthritis. Annals of the rheumatic diseases Winthrop, K. L., Harigai, M., Genovese, M. C., Lindsey, S., Takeuchi, T., Fleischmann, R., Bradley, J. D., Byers, N. L., Hyslop, D. L., Issa, M., Nishikawa, A., Rooney, T. P., Witt, S., Dickson, C. L., Smolen, J. S., Dougados, M. 2020

  Abstract

  OBJECTIVES: To evaluate the incidence of infection in patients with active rheumatoid arthritis (RA) treated with baricitinib, an oral selective Janus kinase (JAK)1 and JAK2 inhibitor.METHODS: Infections are summarised from an integrated database (8 phase 3/2/1b clinical trials and 1 long-term extension (LTE)) with data to 1 April 2017. The 'all-bari-RA' analysis set included patients who received any baricitinib dose. Placebo comparison was based on six studies with 4mg and placebo to week 24, including four trials with 2mg (placebo-controlled set). Dose-response assessment was based on four studies with 2mg and 4mg, including LTE data (2-4 mg extended set).RESULTS: There were 3492 patients who received baricitinib for 7860 patient-years (PY) of exposure (median 2.6 years, maximum 6.1 years). Treatment-emergent infections were higher for baricitinib versus placebo (exposure-adjusted incidence rate (IR)/100 PY: placebo 75.9, 2mg 84.0 (p not significant), 4mg 88.4 (p≤0.001)). The IR of serious infection was similar for baricitinib versus placebo and stable over time (all-bari-RA IR 3.0/100 PY). There were 11 cases of tuberculosis (all-bari-RA IR 0.1/100 PY); all occurred with 4mg in endemic regions. Herpes zoster (HZ) IR/100 PY was higher for baricitinib versus placebo (placebo 1.0, 2mg 3.1 (p not significant), 4mg 4.3 (p≤0.01)); rates remained elevated and stable over time (all-bari-RA 3.3). Opportunistic infections, including multidermatomal HZ, were infrequent in the baricitinib programme (all-bari-RA IR 0.5/100 PY).CONCLUSIONS: Increased rates of treatment-emergent infections including HZ were observed in patients with RA treated with baricitinib, consistent with baricitinib's immunomodulatory mode of action.

  View details for DOI 10.1136/annrheumdis-2019-216852

  View details for PubMedID 32788396

• SAFETY PROFILE OF BARICITINIB FOR THE TREATMENT OF RHEUMATOID ARTHRITIS UP TO 7 YEARS: AN UPDATED INTEGRATED SAFETY ANALYSIS Hall, S., Genovese, M. C., Smolen, J. S., Takeuchi, T., Burmester, G., Brinker, D., Rooney, T. P., Zhong, J., Mo, D., Saifan, C., Cardoso, A., Issa, M., Wu, W., Winthrop, K. L. WILEY. 2020: 16

  View details for Web of Science ID 000553988700039

• Pooled Safety Analyses from Phase 3 Studies of Filgotinib in Patients with Rheumatoid Arthritis Keystone, E., Winthrop, K., Genovese, M., Combe, B., Tanaka, Y., Kivitz, A., Matzkies, F., Bartok, B., Ye, L., Guo, Y., Tasset, C., Sundy, J., Westhovens, R., Rigby, W., Burmester, G. J RHEUMATOL PUBL CO. 2020: 1108

  View details for Web of Science ID 000578896800213

• Impact of Tofacitinib on the Individual Components of the ACR Composite Score in Patients With Rheumatoid Arthritis: A Post Hoc Analysis of Phase 3 Trials Bessette, L., Dougados, M., Mysler, E., Genovese, M., Kinch, C., Kwok, K., Lukic, T., Girard, T., Landry, P., van Vollenhoven, R. J RHEUMATOL PUBL CO. 2020: 1106–7

  View details for Web of Science ID 000578896800208

• Patient Disease Trajectories in Baricitinib-2mg-treated Patients with Rheumatoid Arthritis and Inadequate Response to csDMARDs Pope, J., Li, Z., Genovese, M., Otawa, S., Sun, L., Chandran, S., Keystone, E., Dougados, M. J RHEUMATOL PUBL CO. 2020: 1127–28

  View details for Web of Science ID 000578896800268

• Patient Disease Trajectories in Baricitinib 2-mg-Treated Patients with Rheumatoid Arthritis and Inadequate Response to Biologic DMARDs Genovese, M., Weinblatt, M., Wu, J., Jia, B., Quebe, A., Sun, L., Chen, Y., Helt, C., Griffing, K., Reis, P., Pope, J. J RHEUMATOL PUBL CO. 2020: 1129

  View details for Web of Science ID 000578896800272

• Efficacy and safety of sarilumab in combination with csDMARDs or as monotherapy in subpopulations of patients with moderately to severely active rheumatoid arthritis in three phase III randomized, controlled studies. Arthritis research & therapy Genovese, M. C., Fleischmann, R., Kivitz, A., Lee, E., van Hoogstraten, H., Kimura, T., St John, G., Mangan, E. K., Burmester, G. R. 2020; 22 (1): 139

  Abstract

  BACKGROUND: The interleukin-6 receptor inhibitor sarilumab demonstrated efficacy in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or as monotherapy in patients with moderately to severely active rheumatoid arthritis (RA) with an inadequate response (IR) or intolerant (INT) to methotrexate (MTX) or tumour necrosis factor (TNF)-alpha inhibitors. This analysis investigated the efficacy and safety of sarilumab in patient subgroups.METHODS: Data were included from phase III studies: two placebo-controlled studies of subcutaneous sarilumab 150/200mg every 2weeks (q2w) either + MTX in MTX-IR patients (52weeks) or + csDMARDs in TNF-IR/INT patients (24weeks), and a monotherapy study of sarilumab 200mg q2w vs. adalimumab 40mg q2w in MTX-IR/INT patients (24weeks). Prespecified and post hoc subgroups included patient demographics, disease characteristics, and prior treatments. Prespecified and post hoc endpoints included clinical, radiographic, and physical function measures, and p values are considered nominal. Safety was assessed during double-blind treatment.RESULTS: The superiority of sarilumab (either as monotherapy vs. adalimumab or in combination with csDMARDs vs. placebo+csDMARDs) across clinical endpoints was generally consistent across subgroups defined by patient demographics, disease characteristics, and prior treatments, demonstrating the benefit of sarilumab treatment for a wide range of patient types. Interaction p values of <0.05 were consistently observed across studies only for baseline anti-cyclic citrullinated peptide antibody (ACPA) status for American College of Rheumatology 20% response, but not American College of Rheumatology 50% or 70% response. Adverse events and worsening laboratory parameters occurred more frequently in sarilumab-treated vs. placebo-treated patients and were more frequent in the small number of patients ≥65years (n=289) vs. patients <65years (n=1819). Serious infections occurred in six patients aged ≥65years receiving sarilumab, although the incidence of serious infections was generally higher in patients aged ≥65years regardless of treatment.CONCLUSIONS: Apart from ACPA status, there were no consistent signals indicating differential effects of sarilumab in any of the subpopulations assessed. Sarilumab demonstrated consistent efficacy and safety across a wide range of patients with RA.TRIAL REGISTRATION: ClinicalTrials.gov NCT01061736, registered on February 03, 2010; ClinicalTrials.gov NCT01709578, registered on October 18, 2012; ClinicalTrials.gov NCT02332590, registered on January 07, 2015.

  View details for DOI 10.1186/s13075-020-02194-z

  View details for PubMedID 32522251

• Safety profile of baricitinib for the treatment of rheumatoid arthritis over a median of 3 years of treatment: an updated integrated safety analysis LANCET RHEUMATOLOGY Genovese, M. C., Smolen, J. S., Takeuchi, T., Burmester, G., Brinker, D., Rooney, T. P., Zhong, J., Mo Daojun, Saifan, C., Cardoso, A., Issa, M., Wu, W., Winthrop, K. L. 2020; 2 (6): E347–E357

  View details for Web of Science ID 000547846500022

• Safety of ixekizumab in adult patients with plaque psoriasis, psoriatic arthritis and axial spondyloarthritis: data from 21 clinical trials. Rheumatology (Oxford, England) Genovese, M. C., Mysler, E., Tomita, T., Papp, K. A., Salvarani, C., Schwartzman, S., Gallo, G., Patel, H., Lisse, J. R., Kronbergs, A., Leage, S. L., Adams, D. H., Xu, W., Marzo-Ortega, H., Lebwohl, M. G. 2020

  Abstract

  OBJECTIVES: The aim of this integrated analysis is to evaluate the long-term safety and tolerability of ixekizumab in adults with psoriasis, PsA and axial SpA.METHODS: Integrated safety data from 21 clinical trials are presented by indication in patients who received at least one dose of ixekizumab. Adverse events (AEs) and treatment-emergent adverse events (TEAEs) adjusted incidence rates (IRs) per 100 patient-years (PY) up to 5years' exposure are reported.RESULTS: A total of 8228 patients with an ixekizumab exposure of 20895.9 PY were included in this analysis. The most common TEAEs were nasopharyngitis, upper respiratory tract infection and injection-site reactions. Across populations, IRs were low for AEs leading to discontinuation (IRs ≤5.1 per 100 PY), serious AEs (IRs ≤6.0 per 100 PY) and death (IRs ≤0.3 per 100 PY). The most reported TEAEs of special interest were infections (IRs ≤35.8 per 100 PY). Patients rarely reported malignancies (IR ≤0.8), IBD including ulcerative colitis and Crohn's disease (IR ≤0.8) and major adverse cardiovascular events (IR ≤0.5). TEAEs were most commonly reported the first 2years of exposure with ixekizumab and IR decreased over the years (infections, injection-site reactions and depression) or remained constant over the entire treatment period (serious infections, major adverse cardiovascular events, malignancies and IBD).CONCLUSION: This long-term analysis on the safety of ixekizumab was consistent with previously published reports and did not show any new safety signals. The safety profile and tolerability reported in this integrated analysis remained consistent with the known safety profile for ixekizumab.

  View details for DOI 10.1093/rheumatology/keaa189

  View details for PubMedID 32449924

• Fenebrutinib versus Placebo or Adalimumab in Rheumatoid Arthritis: A Randomized, Double-Blind, Phase II Trial (ANDES Study). Arthritis & rheumatology (Hoboken, N.J.) Cohen, S., Tuckwell, K., Katsumoto, T. R., Zhao, R., Galanter, J., Lee, C., Rae, J., Toth, B., Ramamoorthi, N., Hackney, J. A., Berman, A., Damjanov, N., Fedkov, D., Jeka, S., Chinn, L. W., Townsend, M. J., Morimoto, A. M., Genovese, M. C. 2020

  Abstract

  OBJECTIVE: To evaluate fenebrutinib, an oral and highly selective non-covalent inhibitor of Bruton's tyrosine kinase (BTK), in patients with active rheumatoid arthritis (RA).METHODS: Patients with RA and inadequate response to methotrexate (cohort 1, n=480) were randomized to fenebrutinib (50 mg once daily, 150 mg once daily, 200 mg twice daily), 40 mg adalimumab every other week, or placebo. Patients with RA and inadequate response to tumor necrosis factor inhibitors (cohort 2, n=98) received fenebrutinib (200 mg twice daily) or placebo. Both cohorts continued methotrexate therapy.RESULTS: In cohort 1, American College of Rheumatology scores (ACR50) at week 12 were similar for fenebrutinib 50 mg once daily and placebo, and higher for fenebrutinib 150 mg once daily (28%) and 200 mg twice daily (35%) than placebo (15%) (p=0.017; p=0.0003). Fenebrutinib 200 mg twice daily and adalimumab (36%) were comparable (p=0.81). In cohort 2, more patients achieved ACR50 with fenebrutinib 200 mg twice daily (25%) than placebo (12%) (p=0.072). The most common adverse events for fenebrutinib included nausea, headache, anemia, and upper respiratory tract infections. Fenebrutinib had significant effects on myeloid and B cell biomarkers (CCL4 and rheumatoid factor). Fenebrutinib and adalimumab caused overlapping as well as distinct changes in B cell and myeloid biomarkers.CONCLUSION: Fenebrutinib demonstrated efficacy comparable to adalimumab in patients with an inadequate response to methotrexate, and safety consistent with existing immunomodulatory therapies for RA. These data support targeting both B and myeloid cells via this novel mechanism for potential efficacy in the treatment of RA.

  View details for DOI 10.1002/art.41275

  View details for PubMedID 32270926

• EFFECTS OF FILGOTINIB ON ANAEMIA, THROMBOCYTOPOENIA AND LEUKOPOENIA: RESULTS FROM A PHASE 3 STUDY IN PATIENTS WITH ACTIVE RA AND PRIOR INADEQUATE RESPONSE OR INTOLERANCE TO BDMARDS Walker, D., Genovese, M. C., Kalunian, K., Gottenberg, J., Bartok, B., Tan, Y., Guo, Y., Tasset, C., Sundy, J. S., de Vlam, K., Takeuchi, T. OXFORD UNIV PRESS. 2020: 99–100

  View details for Web of Science ID 000534330300177

• A PHASE 3 CLINICAL PROGRAM OF THREE, RANDOMIZED, DOUBLE-BLIND, PLACEBO- AND COIMPARATOR-CONTROLLED STUDIES TO ASSESS THE EFFICACY AND SAFETY OF OTILIMAB IN RA: STUDY DESIGN AND METHODOLOGY Genovese, M., Taylor, P. C., Boers, M., Strand, V., Saurigny, D., Davy, K., Gupta, A., Harrison, S., Hepburn, R., Patel, J., Layton, M., Wang, M., Fleischmann, R. LIPPINCOTT WILLIAMS & WILKINS. 2020: 20

  View details for Web of Science ID 000530661500057

• GLUCOCORTICOID DOSE IS PROGRESSIVELY REDUCED IN PATIENTS WITH RHEUMATOID ARTHRITIS RECEIVING SARILUMAB: RESULTS FROM THE OPEN-LABEL EXTEND STUDY Fleischmann, R., Selmi, C., Gonzalez-Gay, M., van Hoogstraten, H., Hagino, O., Rajput, T., St John, G., Buttgereit, F., Genovese, M. C. LIPPINCOTT WILLIAMS & WILKINS. 2020: 80

  View details for Web of Science ID 000530661500220

• INHIBITION OF STRUCTURAL JOINT DAMAGE WITH UPADACITINIB AS MONOTHERAPY OR IN COMBINATION WITH METHOTREXATE IN PATIENTS WITH RHEUMATOID ARTHRITIS Peterfy, C. G., Genovese, M. C., Song, I., Friedman, A., Hall, S., Mysler, E., Durez, P., Baraliakos, X., Enejosa, J. V., Shaw, T., Li, Y., Chen, S., Strand, V. LIPPINCOTT WILLIAMS & WILKINS. 2020: 9–10

  View details for Web of Science ID 000530661500026

• GLUCOCORTICOID DOSE IS PROGRESSIVELY REDUCED IN PATIENTS WITH RHEUMATOID ARTHRITIS (RA) RECEIVING SARILUMAB: RESULTS FROM THE OPEN LABEL EXTEND STUDY Fleischmann, R., Selmi, C., Angel Gonzalez-Gay, M., van Hoogstraten, H., Hagino, O., Rajput, T., St John, G., Buttgereit, F., Genovese, M. C. OXFORD UNIV PRESS. 2020: 108

  View details for Web of Science ID 000534330300196

• INHIBITION OF STRUCTURAL JOINT DAMAGE WITH UPADACITINIB AS MONOTHERAPY OR IN COMBINATION WITH MTX IN PATRIENTS WITH RA: ONE-YEAR OUTCOMES FROM THE SELECT PHASE 3 PROGRAMME Peterfy, C., Genovese, M. C., Song, I., Friedman, A., Hall, S., Mysler, E., Durez, P., Baraliakos, X., Enejosa, J., Shaw, T., Li, Y., Chen, S., Strand, V. OXFORD UNIV PRESS. 2020

  View details for Web of Science ID 000534330300187

• POOLED SAFETY ANALYSES FROM PHASE 3 STUDIES OF FILGOTINIB IN PATIENTS WITH RA Walker, D., Winthrop, K., Genovese, M. C., Combe, B. G., Tanaka, Y., Kivitiz, A., Matzkies, F., Bartok, B., Ye, L., Guo, Y., Tasset, C., Sundy, J. S., Keystone, E., Westhovens, R., Rigby, W., Burmester, G. R. OXFORD UNIV PRESS. 2020

  View details for Web of Science ID 000534330300010

• Long-term safety, immunogenicity and efficacy comparing FKB327 with the adalimumab reference product in patients with active rheumatoid arthritis: data from randomised double-blind and open-label extension studies. RMD open Genovese, M. C., Kellner, H., Arai, Y., Muniz, R., Alten, R. 2020; 6 (1)

  Abstract

  BACKGROUND/OBJECTIVE: FKB327 is a biosimilar of the antitumour necrosis factor adalimumab reference product (RP). A randomised, double-blind (DB) phase 3 study compared the efficacy of FKB327 with the RP in patients with active rheumatoid arthritis (RA) inadequately controlled with methotrexate (MTX). A subsequent randomised open-label extension (OLE) study with treatment switching assessed long-term safety, efficacy, pharmacokinetics and immunogenicity of FKB327 compared with the RP.METHODS: Patients with moderate-to-severe, active RA on a stable dose of MTX were randomised 1:1 to receive FKB327 or the RP (40 mg subcutaneously every other week) for 24 weeks. Patients who completed the DB study were enrolled in the OLE and rerandomised 2:1 to receive FKB327 or the RP; two-thirds continued on the same treatment and one-third switched for 30 weeks. All patients received FKB327 through Week 76. Long-term efficacy, safety and immunogenicity were assessed.RESULTS: Of 728 patients in the DB study, 645 were enrolled in the FKB327-OLE study. The American College of Rheumatology (ACR)20 response rates for all treatment groups at Week 30 in the OLE ranged from 83.2% to 85.9%. ACR20 response rates remained stable for all patients regardless of single- or double-switching treatment and were similar for all treatment sequences through Week 76. The safety profile and incidence of antidrug antibodies were comparable across sequences.CONCLUSION: Efficacy, safety and immunogenicity were similar among patients with RA treated with FKB327 or the RP for up to 2 years, and were not affected by single- or double-switching treatment.

  View details for DOI 10.1136/rmdopen-2019-000987

  View details for PubMedID 32371430

• CLINICAL AND FUNCTIONAL OUTCOMES AMONG RHEUMATOID ARTHRITIS PATIENTS SWITCHING BETWEEN JAK1-SELECTIVE INHIBITOR UPADACITINIB AND ADALIMUMAB FOLLOWING INSUFFICIENT RESPONSE Fleischmann, R., Genovese, M. C., Blanco, R., Hall, S., Thomson, G. D., Van den Bosch, F., Zerbini, C., Enejosa, J., Li, Y., DeMasi, R., Song, I. LIPPINCOTT WILLIAMS & WILKINS. 2020: 68

  View details for Web of Science ID 000530661500185

• The road to rheumatoid arthritis prevention: challenges and opportunities. Clinical rheumatology Chaichian, Y., Genovese, M. C., Weisman, M. H. 2020

  Abstract

  Rheumatoid arthritis (RA) is the most prevalent cause of chronic arthritis worldwide and contributes substantial health burden and socioeconomic costs, issues that are magnified by the aging population. Despite significantly improved outcomes in the management of RA with earlier diagnosis and advances in treatment, there is still no cure and disease prevention remains an area of intense interest. Studies examining different treatment regimens in varied subsets of patients with pre-clinical RA have been able to delay but not prevent onset of frank RA. In this timely issue of Clinical Rheumatology, Alpziar-Rodriguez D. and Finckh A. highlight the available literature on pre-clinical RA including modifiable risk factors, results of key intervention trials, and discuss whether prevention of RA is on the horizon. We offer additional thoughts on current areas of uncertainty in RA prevention studies, lessons to be learned from prevention trials in other disease states, and future directions to consider.

  View details for DOI 10.1007/s10067-020-05016-4

  View details for PubMedID 32170486

• Evaluation of hepatitis B virus in clinical trials of baricitinib in rheumatoid arthritis. RMD open Harigai, M., Winthrop, K., Takeuchi, T., Hsieh, T., Chen, Y., Smolen, J. S., Burmester, G., Walls, C., Wu, W., Dickson, C., Liao, R., Genovese, M. C. 2020; 6 (1)

  Abstract

  BACKGROUND: Reactivation of hepatitis B virus (HBV) replication is a well-recognised complication in patients receiving disease-modifying anti-rheumatic drugs (DMARDs) for rheumatoid arthritis (RA). Limited data exist on HBV reactivation among patients with RA treated with janus kinase (JAK) inhibitors. The objective of the current study was to assess HBV reactivation in clinical trials of baricitinib, an oral selective JAK1 and JAK2 inhibitor in RA.METHODS: Data were integrated from four completed Phase 3 trials and one ongoing long-term extension (data up to 1 April 2017) in patients naive to DMARDs or who had inadequate response (IR) to DMARDs including methotrexate (MTX)-IR and/or other conventional synthetic DMARD (csDMARD)-IR, or tumour necrosis factor inhibitors-IR. Within the clinical programme, baricitinib-treated patients may have received concomitant csDMARDs including MTX, or previous treatment with active comparators including MTX or adalimumab + MTX. At screening, all patients were tested for HBV surface antigen (HBsAg), core antibody (HBcAb) and surface antibody (HBsAb). Patients were excluded if they had (1) HBsAg+, (2) HBcAb+/HBsAb- (in Japan, could enrol if HBV DNA-) or (3) HBsAb+ andHBV DNA+. HBV DNA monitoring, following randomisation in the originating Phase 3 studies, was performed in Japan for patients with HBcAb+ and/or HBsAb+ at screening, and was later instituted globally for HBcAb+ patients in accordance with evolving guidance for HBV monitoring and management with immunomodulatory therapy.RESULTS: In total, 2890 patients received at least one dose of baricitinib in Phase 3 (6993 patient-years exposure). Of 215 patients with baseline serology suggestive of prior HBV infection (HbcAb+) who received a post-baseline DNA test, 32 (14.9%) were HBV DNA+ atsome point following treatment initiation; 8 of 215 patients (3.7%) had a single quantifiable result (≥29IU/mL). Of these eight patients, four met the definition of reactivation of HBV (HBV DNA level ≥100IU/mL); baricitinib was permanently discontinued in four patients, and temporarily interrupted in two patients. No patient developed clinical evidence of hepatitis and in five of eight patients, antiviral therapy was not used.CONCLUSION: HBV reactivation can occur among RA patients treated with DMARDs, including baricitinib, with prior HBV exposure. Our data suggest that such patients should be monitored for HBV DNA during treatment and might be treated safely with the use of antiviral therapy as needed. The risk of HBV reactivation in patients with HBsAg treated with baricitinib is unknown.

  View details for DOI 10.1136/rmdopen-2019-001095

  View details for PubMedID 32098857

• Safety results of ixekizumab with 1822.2 patient-years of exposure: an integrated analysis of 3 clinical trials in adult patients with psoriatic arthritis. Arthritis research & therapy Combe, B., Rahman, P., Kameda, H., Canete, J. D., Gallo, G., Agada, N., Xu, W., Genovese, M. C. 2020; 22 (1): 14

  Abstract

  BACKGROUND: The long-term safety was assessed in patients with psoriatic arthritis who were treated with ixekizumab in three clinical trials (SPIRIT-P1/-P2/-P3).METHODS: Integrated safety data from three trials (controlled and uncontrolled), including two pivotal phase 3, randomized, double-blind clinical trials: SPIRIT-P1 and SPIRIT-P2, were assessed. Safety data were integrated from the all ixekizumab exposure safety population (defined as all patients receiving ≥1 dose of ixekizumab). We report exposure-adjusted incidence rates (IRs) per 100 patient-years (PY) at 1-year intervals up to 3years for adverse events.RESULTS: Total exposure to IXE reached 1822.2 PY (1118 patients). The IRs/100 PY for the following treatment discontinuations were as follows: adverse events (5.3); serious infections (1.3); injection-site reactions (12.7); infections (34.2); and deaths (0.3). The IRs for treatment-emergent adverse events decreased or remained stable over time, the most common being upper respiratory tract infection, nasopharyngitis, and injection-site reactions. The IRs for serious adverse events and serious infections remained stable over time, whereas for injection-site reactions and general infections, IRs decreased with longer ixekizumab exposure. Opportunistic infections were limited to oral and esophageal candida and localized herpes zoster. No suicide or self-injury-related behaviors were reported. The IRs/100 PY for safety topics of special interest included inflammatory bowel disease (adjudicated; 0.1), depression (1.6), malignancies (0.7), and major adverse cardiovascular events (0.6).CONCLUSIONS: The findings of this integrated safety analysis in patients with psoriatic arthritis are consistent with the known safety profile of ixekizumab. No unexpected safety signals were observed with ixekizumab treatment in patients with psoriatic arthritis.TRIAL REGISTRATION: SPIRIT-P1 (NCT01695239; Registered August 08, 2012), SPIRIT-P2 (NCT02349295; September 23, 2014), and SPIRIT-P3 (NCT02584855; August 04, 2015).

  View details for DOI 10.1186/s13075-020-2099-0

  View details for PubMedID 31964419

• Comparative clinical efficacy and safety of the proposed biosimilar ABP 710 with infliximab reference product in patients with rheumatoid arthritis. Arthritis research & therapy Genovese, M. C., Sanchez-Burson, J. n., Oh, M. n., Balazs, E. n., Neal, J. n., Everding, A. n., Hala, T. n., Wojciechowski, R. n., Fanjiang, G. n., Cohen, S. n. 2020; 22 (1): 60

  Abstract

  ABP 710 is being developed as a biosimilar to infliximab reference product (RP). Analytical similarity and pharmacokinetic equivalence between the two have been previously demonstrated. Here we report results from a comparative clinical study that evaluated the efficacy and safety of ABP 710 relative to the RP in patients with rheumatoid arthritis (RA).In this multicenter, randomized, double-blind, 50-week equivalence study, patients with moderate to severe active RA despite methotrexate received 3-mg/kg infusions of ABP 710 or RP at predetermined intervals based on initial randomization and then with re-randomization at week 22. The primary endpoint was response difference (RD) of ACR20 at week 22, with clinical equivalence evaluated based on 90% CI of - 15%, 15%. Secondary endpoints included Disease Activity Score 28-joint count C-reactive protein (DAS28-CRP), ACR20, ACR50, and ACR70 across time, as well as safety and immunogenicity assessments.A total of 558 patients were randomized for the initial treatment (ABP 710 n = 279; RP n = 279). The estimated RD of ACR20 at week 22 was 9.37% with 90% CI (2.67%, 15.96%). The lower bound was within the pre-specified criteria, thus confirming non-inferiority; the upper bound exceeded the pre-specified criteria by 0.96% such that superiority could not be ruled out statistically. In a post hoc analysis with adjustment for random imbalance in baseline factors, the CI of RD was narrowed (0.75%, 13.62%). Changes from baseline in DAS28-CRP as well as ACR20, ACR50, and ACR70 response rates across time and hybrid ACR evaluations were similar for the initial and initial/re-randomized treatment groups. Adverse events and incidence of anti-drug antibodies were similar between treatment groups.These efficacy and safety results support similarity with no clinically meaningful differences between ABP 710 and infliximab RP. Although we were unable to statistically confirm non-superiority, post hoc analysis was supportive of non-superiority. DAS28-CRP, ACR20, ACR50, ACR70, and hybrid ACR evaluations over the entire study were consistently comparable as were safety and immunogenicity.ClinicalTrials.gov. Identifier: NCT02937701. Registered August 30, 2016.

  View details for DOI 10.1186/s13075-020-2142-1

  View details for PubMedID 32216829

• High Serum Interleukin-6 is Associated With Severe Progression of Rheumatoid Arthritis and Increased Treatment Response Differentiating Sarilumab from Adalimumab or Methotrexate in a Post Hoc Analysis. Arthritis & rheumatology (Hoboken, N.J.) Boyapati, A. n., Schwartzman, S. n., Msihid, J. n., Choy, E. n., Genovese, M. C., Burmester, G. R., Lam, G. n., Kimura, T. n., Sadeh, J. n., Weinreich, D. M., Yancopoulos, G. D., Graham, N. M. 2020

  Abstract

  The development of biomarkers to guide treatment decisions is a major research focus in rheumatoid arthritis (RA). Patients with RA have elevated interleukin-6 (IL-6) levels; however, the utility of IL-6 as a predictor of treatment response is unclear. The objective of this study was to investigate, by post hoc analysis, whether baseline IL-6 levels could predict sarilumab treatment responses in two phase III studies.Serum IL-6 concentrations were measured in patients with RA prior to receiving sarilumab 200 mg (n = 148) or adalimumab 40 mg (n = 152) every two weeks (Q2W) (MONARCH, NCT02332590) or sarilumab 150 or 200 mg+methotrexate (n = 401 and n = 396, respectively) or placebo+methotrexate (n = 397) Q2W (MOBILITY, NCT01061736). Efficacy and patient-reported outcomes were compared between and within groups according to IL-6 tertile using linear and logistic regression.In MONARCH, patients with high baseline IL-6 (n = 100; all ≥3×upper limit of normal) had higher disease activity at baseline than those with low IL-6 (n = 100). The magnitude of clinical improvement over 24 weeks with sarilumab versus adalimumab was greater in patients with high baseline IL-6 than patients with low baseline IL-6. In MOBILITY, patients with high IL-6 (n = 398) had higher disease activity and joint damage at baseline than those with low IL-6 (n = 397), were more likely to have joint progression, and had less clinical improvement over 52 weeks' treatment with placebo+methotrexate compared with sarilumab 150/200 mg+methotrexate. Baseline IL-6 and C-reactive protein were both predictive of outcomes. Safety profiles were similar between defined IL-6 tertiles.IL-6 may be a prognostic marker of disease progression and severity, and patients with high IL-6 may be likely to benefit from sarilumab compared with adalimumab or methotrexate. Prospective validation is warranted to confirm the results of these post hoc analyses.

  View details for DOI 10.1002/art.41299

  View details for PubMedID 32343882

• Radiographic progression based on baseline characteristics from TNF inhibitor biosimilar studies in patients with rheumatoid arthritis. Arthritis research & therapy Smolen, J. S., Kang, Y. M., Yoo, W. H., Emery, P. n., Weinblatt, M. E., Keystone, E. C., Genovese, M. C., Myung, G. n., Baek, I. n., Ghil, J. n. 2020; 22 (1): 188

  Abstract

  Phase III clinical trials of the tumour necrosis factor inhibitors SB4, SB2, and SB5 (biosimilars to etanercept, infliximab, and adalimumab, respectively) have demonstrated efficacy in moderate-to-severe rheumatoid arthritis (RA). Data from these trials were used to identify baseline characteristics associated with radiographic progression and to build a matrix risk model for its prediction.Patients with radiographic progression and baseline demographic and disease characteristic data were pooled across the 3 phase III studies of each biosimilar and its reference product. Baseline demographics and disease characteristics were evaluated for their relationship with radiographic progression (1-year mean change in mTSS > 0); 3 factors were selected based on strongest Pearson's correlation coefficient with the change in modified Total Sharp Score. Univariate logistic regression was performed to assess the association between each baseline factor and the rate of radiographic progression, with subsequent matrix model development performed using multivariate logistic regression.A total of 1371 patients were included in the analysis, with a radiographic progression rate of 27.4%. The 3 baseline predictors of radiographic progression, based on Pearson's correlation coefficient, were 28 swollen joint count (SJC28), C-reactive protein (CRP), and physician global assessment (PhGA). A matrix model showed that the predicted risk of radiographic progression was higher with the increased level of SJC28, CRP, and PhGA (P < 0.001).In this pooled analysis of phase III clinical trial data of biosimilars for RA, identifiable baseline factors (SJC28, CRP, and PhGA) associated with radiographic progression were similar to those described in prior studies. Even though radiographic progression was minimal, a small number of patients who have increased SJC28, CRP, and PhGA at baseline should be closely monitored and follow treat-to-target approach.EudraCT 2012-005026-30. Registered 30 April 2013, https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005026-30/results EudraCT 2012-005733-37. Registered 10 July 2013, https://www.clinicaltrialsregister.eu/ctr-search/trial/2012-005733-37/results EudraCT 2013-005013-13. Registered 01 April 2014, https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-005013-13/results.

  View details for DOI 10.1186/s13075-020-02267-z

  View details for PubMedID 32795341

• Pooled analysis of TNF inhibitor biosimilar studies comparing radiographic progression by disease activity states in rheumatoid arthritis. RMD open Smolen, J. S., Choe, J. Y., Weinblatt, M. E., Emery, P. n., Keystone, E. n., Genovese, M. C., Myung, G. n., Hong, E. n., Baek, I. n., Ghil, J. n. 2020; 6 (1)

  Abstract

  To evaluate the relationship between disease activity and radiographic progression in rheumatoid arthritis, three phase III studies of SB4, SB2 and SB5 (biosimilars of etanercept, infliximab and adalimumab) were pooled to assess radiographic progression by disease activity status.Patients from each study with radiographic data were pooled and grouped based on disease activity state (remission, low disease activity (LDA), moderate disease activity (MDA) and high disease activity (HDA)), determined by disease activity score based on 28-joint count (DAS28) per erythrocyte sedimentation rate, Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI) at different time points. Mean change in modified Total Sharp Score (mTSS) and the proportion of radiographic non-progressors of higher disease activity groups (LDA, MDA and HDA) in reference to remission were summarised descriptively, with comparison of ORs using logistic models.1265 patients were included. In all treatments combined, the 1 year mean change in mTSS was 0.03, 0.4, 0.3 and 1.3 and proportion of radiographic non-progressors was 79.8%, 78.1%, 74.1% and 58.4% in the week 24/30 DAS28-determined remission, LDA, MDA and HDA groups, respectively. ORs (95% CIs) of the proportion of non-progressors were lowest in the HDA group in reference to remission (0.35 (0.23 to 0.54)), followed by MDA (0.72 (0.50 to 1.05)) and LDA (0.90 (0.55 to 1.48)) groups. Similar trends were observed when disease activity was assessed using SDAI or CDAI.A pooled analysis of radiographic assessment data from three biosimilar studies showed that radiographic progression is small overall but increases with worse disease activity.NCT01895309, NCT01936181 and NCT02167139.

  View details for DOI 10.1136/rmdopen-2019-001096

  View details for PubMedID 31958281

• Safety and Efficacy of Poseltinib, Bruton's Tyrosine Kinase-Inhibitor, in Patients With Rheumatoid Arthritis: A Randomized, Double-Blind, Placebo-Controlled, 2-Part Phase-2 Study. The Journal of rheumatology Genovese, M. n., Spindler, A. n., Sagawa, A. n., Park, W. n., Dudek, A. n., Kivitz, A. n., Chao, J. n., Chan, L. S., Witcher, J. n., Barchuk, W. n., Nirula, A. n. 2020

  Abstract

  To evaluate efficacy and safety of poseltinib (formerly LY3337641/HM71224), an irreversible covalent inhibitor of Bruton's tyrosine kinase from a 2-part, Phase-2 trial (RAjuvenate) in adults with active rheumatoid arthritis (RA).In Part A, 36 patients with mildly active RA were randomized 1:1:1:1 to oral poseltinib 5-, 10-, or 30-mg or placebo once-daily for 4 weeks to assess safety/tolerability. No safety signals precluded moving to Part B where 250 patients with moderate-to-severe RA were randomized 1:1:1:1 to oral poseltinib 5- (N=63), 10- (N=62), or 30-mg (N=63) or placebo (N=62) once-daily for 12 weeks. Parts A and B permitted stable doses of background disease-modifying antirheumatic drugs. The primary endpoint in Part B was proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at Week 12. Logistic regression compared each poseltinib dose to placebo for primary/secondary endpoints. Nonresponder imputation was used for missing data.After interim analysis showed low likelihood of demonstrating significant efficacy, the sponsor discontinued Part B of the study. 189 (76%) patients completed 12 weeks in Part B; 61 discontinued study treatment (27 [44%] due to study termination by sponsor). There was no statistically significant difference in ACR20 response between any dose of poseltinib and placebo at Week 12 (p<0.05 for all comparisons). Five serious adverse events occurred (n=2, placebo; n=3, 30-mg); there was 1 death due to a fall.While no safety findings precluded continuation, the study was terminated after interim data demonstrated low likelihood of benefit in RA.

  View details for DOI 10.3899/jrheum.200893

  View details for PubMedID 33323529

• Interleukin-6 receptor blockade or TNFα inhibition for reducing glycaemia in patients with RA and diabetes: post hoc analyses of three randomised, controlled trials. Arthritis research & therapy Genovese, M. C., Burmester, G. R., Hagino, O. n., Thangavelu, K. n., Iglesias-Rodriguez, M. n., John, G. S., González-Gay, M. A., Mandrup-Poulsen, T. n., Fleischmann, R. n. 2020; 22 (1): 206

  Abstract

  Diabetes is common in patients with rheumatoid arthritis (RA). Interleukin (IL)-6 is implicated in both the pathogenesis of RA and in glucose homeostasis; this post hoc analysis investigated the effects of IL-6 receptor vs. tumour necrosis factor inhibition on glycosylated haemoglobin (HbA1c) in patients with RA with or without diabetes.Data were from two placebo-controlled phase III studies of subcutaneous sarilumab 150/200 mg q2w + methotrexate or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and a phase III monotherapy study of sarilumab 200 mg q2w vs. adalimumab 40 mg q2w. Patients with diabetes were identified by medical history or use of antidiabetic medication (patients with HbA1c ≥ 9% were excluded from all three studies). HbA1c was measured at baseline and weeks 12/24. Safety and efficacy were assessed in RA patients with or without diabetes.Patients with diabetes (n = 184) were older, weighed more and exhibited higher RA disease activity than patients without diabetes (n = 1928). Regardless of diabetes status, in patients on background csDMARDs, least squares (LS) mean difference (95% CI) in change from baseline in HbA1c for sarilumab 150 mg/200 mg vs. placebo at week 24 was - 0.28 (- 0.40, - 0.16; nominal p <  0.0001) and - 0.42 (- 0.54, - 0.31; nominal p <  0.0001), respectively. Without csDMARDs, LS mean difference for sarilumab 200 mg vs. adalimumab 40 mg at week 24 was - 0.13 (- 0.22, - 0.04; nominal p = 0.0043). Greater reduction in HbA1c than placebo or adalimumab was observed at week 24 with sarilumab in patients with diabetes and/or baseline HbA1c ≥ 7%. There was no correlation between baseline/change from baseline in HbA1c and baseline/change from baseline in C-reactive protein, 28-joint Disease Activity Score, or haemoglobin, nor between HbA1c change from baseline and baseline glucocorticoid use. Medical history of diabetes or use of diabetes treatments had limited impact on safety and efficacy of sarilumab and was consistent with overall phase III findings in patients with RA.In post hoc analyses, sarilumab was associated with a greater reduction in HbA1c than csDMARDs or adalimumab, independent of sarilumab anti-inflammatory effects. Prospective studies are required to further assess these preliminary findings.ClinTrials.gov NCT01061736: date of registration February 03, 2010; ClinTrials.gov NCT01709578: date of registration October 18, 2012; ClinTrials.gov NCT02332590: date of registration January 07, 2015.

  View details for DOI 10.1186/s13075-020-02229-5

  View details for PubMedID 32907617

• FKB327, an adalimumab biosimilar, versus the reference product: results of a randomized, Phase III, double-blind study, and its open-label extension. Arthritis research & therapy Genovese, M. C., Glover, J., Greenwald, M., Porawska, W., El Khouri, E. C., Dokoupilova, E., Vargas, J. I., Stanislavchuk, M., Kellner, H., Baranova, E., Matsunaga, N., Alten, R. 2019; 21 (1): 281

  Abstract

  OBJECTIVE: To compare the efficacy, serum drug concentrations, immunogenicity, and safety of FKB327 with the adalimumab reference product (RP) in combination with methotrexate in patients with moderate-to-severe, active rheumatoid arthritis (RA).METHODS: Patients were randomized 1:1 in a double-blind study (NCT02260791), received 40mg of FKB327 or RP by subcutaneous injection every other week for 24weeks (Period I), then re-randomized 2:1, remaining on the same study drug or switching to the other up to week 54 in an open-label extension (Period II, NCT02405780). Efficacy was evaluated using American College of Rheumatology (ACR20) response rate difference at week 24 with equivalence margins of ±13% and -12% to +15% using 95% and 90% confidence intervals (CIs), respectively. Efficacy, serum drug concentrations, immunogenicity, and safety were compared at week 54.RESULTS: A total of 730 patients were randomized in Period I (n=367 FKB327, n=363 RP), and 645 transitioned to Period II (n=216 FKB327-FKB327, n=108 FKB327-RP, n=108 RP-FKB327, n=213 RP-RP). At week 24, ACR20 response rates were 74.1% with FKB327 versus 75.7% with RP. 95% and 90% CI of the response rate difference were -7.9 to 4.7% and -7.3 to 3.6%, respectively, meeting predefined equivalence margins. The ACR20 response rate remained over 70% of patients to week 54 with all treatment sequences. In Period I, mean trough serum drug concentrations were slightly higher for patients receiving FKB327 than those receiving RP. Mean concentrations were stable over time and reflected steady state in Period II. The proportions of patients with samples positive for neutralizing antidrug antibodies (ADAs) were comparable (57.7% with FKB327 vs. 55.5% with RP) at week 24, and no consistent difference in ADA were seen between continuous and switched treatments in Period II. Efficacy was slightly reduced in the small proportion of patients with high ADA titers in all treatment groups. No clinically significant differences were observed in the incidence of commonly reported treatment-emergent adverse events between the treatments across Periods I and II.CONCLUSION: FKB327 was equivalent to RP in clinical efficacy and demonstrated comparable safety and immunogenicity in patients with moderate-to-severe RA. No effect of switching between FKB327 and RP was observed.TRIAL REGISTRATION: ClinicalTrials.gov, NCT02260791, Registered 29 July 2014. ClinicalTrials.gov, NCT02405780, Registered 17 July 2015.

  View details for DOI 10.1186/s13075-019-2046-0

  View details for PubMedID 31831079

• Pooled Safety Analyses from Phase 3 Studies of Filgotinib in Patients with Rheumatoid Arthritis Winthrop, K., Genovese, M., Combe, B., Tanaka, Y., Kivitz, A., Matzkies, F., Bartok, B., Ye, L., Guo, Y., Tasset, C., Sundy, J., Keystone, E., Westhovens, R., Rigby, W. C., Burmester, G. WILEY. 2019

  View details for Web of Science ID 000507466902187

• Clinical and Functional Outcomes Among Rheumatoid Arthritis Patients Switching Between JAK1-Selective Inhibitor Upadacitinib and Adalimumab Following Insufficient Response Fleischmann, R., Genovese, M., Blanco, R., Hall, S., Thomson, G., Van den Bosch, F., Zerbini, C. A., Enejosa, J., Li, Y., DeMasi, R., Song, I. WILEY. 2019

  View details for Web of Science ID 000507466905137

• Safety and Effectiveness of Upadacitinib or Adalimumab in Patients with Rheumatoid Arthritis: Results at 48 Weeks Fleischmann, R., Enejosa, J., Song, I., Mysler, E., Bessette, L., Peterfy, C., Durez, P., Ostor, A., Zhou, Y., Genovese, M. WILEY. 2019

  View details for Web of Science ID 000507466900528

• Novel Approach to the Treatment of Cardiac Sarcoidosis with TNF-alpha Inhibition Baker, M., Sheth, K., Simard, J., Shoor, S., Genovese, M. WILEY. 2019

  View details for Web of Science ID 000507466900378

• Neurostimulation for Treatment of Drug Refractory Rheumatoid Arthritis: A First-in-Human Study Using a Novel Vagus Nerve Stimulator Gaylis, N., Sikes, D., Kivitz, A., Horowitz, D., Peterfy, C., Levine, Y., Chernoff, D., Genovese, M. WILEY. 2019

  View details for Web of Science ID 000507466901353

• Safety and Efficacy of Olokizumab in a Phase III Trial of Patients with Moderately to Severely Active Rheumatoid Arthritis Inadequately Controlled by Methotrexate-CREDO1 Study Nasonov, E., Fatenejad, S., Korneva, E., Krechikova, D., Maslyansky, A., Plaksina, T., Stanislav, M., Stoilov, R., Tyabut, T., Yakushin, S., Zonova, E., Genovese, M. WILEY. 2019

  View details for Web of Science ID 000507466905171

• Real-World Evidence: Clinical and Economic Burden of Anemia, Venous Thromboembolism, and Malignancy Among Rheumatoid Arthritis Patients Switching from First Biologic DMARD to Another Treatment in the US Dore, R., Antonova, J., Gorritz, M., Chang, L., He, J., Genovese, M. WILEY. 2019

  View details for Web of Science ID 000507466900205

• Safety Profile of Ixekizumab Treatment in Patients with Moderate-to-Severe Plaque Psoriasis and Psoriatic Arthritis: Integrated Analysis of 18 Clinical Trials Genovese, M., Kameda, H., Rahman, P., Canete, J., Garces, S., Xu, W., Hufford, M. M., Combe, B. WILEY. 2019

  View details for Web of Science ID 000507466902360

• A Subgroup Analysis of Clinical Efficacy Response and Quality of Life Outcomes from Phase 3 Study of Filgotinib in Patients with Inadequate Response to Biologic DMARDs Genovese, M., de Vlam, K., Gottenberg, J., Bartok, B., Tiamiyu, I., Guo, Y., Tasset, C., Sundy, J., Walker, D., Takeuchi, T., Kalunian, K. WILEY. 2019

  View details for Web of Science ID 000507466900518

• Inhibition of Structural Joint Damage with Upadacitinib as Monotherapy or in Combination with Methotrexate in Patients with Rheumatoid Arthritis Peterfy, C., Genovese, M., Song, I., Friedman, A., Hall, S., Mysler, E., Durez, P., Baraliakos, X., Enejosa, J., Shaw, T., Li, Y., Chen, S., Strand, V. WILEY. 2019

  View details for Web of Science ID 000507466900548

• Treatment Patterns, Dose Change, and Treatment Discontinuation in RA Patients Switching from First Biologic DMARD to Another Treatment in the US Dore, R., Antonova, J., Burudpakdee, C., Chang, L., He, J., Genovese, M. WILEY. 2019

  View details for Web of Science ID 000507466900251

• Upadacitinib in Patients with Rheumatoid Arthritis and Inadequate Response or Intolerance to Biological DMARDs: Results at 60 Weeks Genovese, M., Combe, B., Hall, S., Rubbert-Roth, A., Zhong, S., Meerwein, S., Pangan, A., Fleischmann, R. WILEY. 2019

  View details for Web of Science ID 000507466900519

• Impact of Tofacitinib on the Individual Components of the ACR Composite Score in Patients with Rheumatoid Arthritis: A Post Hoc Analysis of Phase 3 Trials Bessette, L., Dougados, M., Mysler, E., Genovese, M., Kinch, C., Kwok, K., Lukic, T., Girard, T., Landry, P., van Vollenhoven, R. WILEY. 2019

  View details for Web of Science ID 000507466902206

• Contribution of Pain Relief to Function, Fatigue, and Quality of Life When Inflammation Is Controlled in Patients with Rheumatoid Arthritis van de Laar, M. J., Pope, J., Lee, Y., Fautrel, B., Ikeda, K., Quebe, A., Zhang, X., Gaich, C., De Leonardis, F., Lisse, J., Workman, J., Fleischmann, R., Genovese, M., Taylor, P. WILEY. 2019

  View details for Web of Science ID 000507466900418

• A Subgroup Analysis of the Efficacy of Filgotinib in Demographic and Clinical Subgroups of Patients with Refractory Rheumatoid Arthritis Kalunian, K., Genovese, M., Gottenberg, J., Bartok, B., Pechonkina, A., Guo, Y., Tasset, C., Sundy, J., de Vlam, K., Walker, D., Takeuchi, T. WILEY. 2019

  View details for Web of Science ID 000507466900505

• Safety Profile of Baricitinib for the Treatment of Rheumatoid Arthritis up to 7 Years: An Updated Integrated Safety Analysis Genovese, M., Smolen, J., Takeuchi, T., Burmester, G., Brinker, D., Rooney, T., Zhong, J., Mo, D., Saifan, C., Cardoso, A., Issa, M., Wu, W., Winthrop, K. WILEY. 2019

  View details for Web of Science ID 000507466901270

• Real-World Evidence: Infections Among RA Patients Switching from First Biologic DMARD to Another Treatment in the US Dore, R., Antonova, J., Huang, H., Chang, L., Wang, X., Genovese, M. WILEY. 2019

  View details for Web of Science ID 000507466902232

• Glucocorticoid Dose Is Progressively Reduced in Patients with RA Receiving Sarilumab: Results from the Open-Label EXTEND Study Fleischmann, R., Selmi, C., Gonzalez-Gay, M., van Hoogstraten, H., Hagino, O., Rajput, T., St John, G., Buttgereit, F., Genovese, M. WILEY. 2019

  View details for Web of Science ID 000507466902237

• Patient Disease Trajectories in Baricitinib-2 Mg-Treated Patients with Rheumatoid Arthritis and Inadequate Response to Biologic DMARDs Genovese, M., Weinblatt, M., Wu, J., Jia, B., Quebe, A., Sun, L., Chen, Y., Helt, C., Bacani, A., Reis, P., Pope, J. WILEY. 2019

  View details for Web of Science ID 000507466902208

• Efficacy and Safety Results from a Phase 3 Study of Biosimilar Candidate ABP 710 in Subjects with Moderate to Severe RA Genovese, M., Sanchez-Burson, J., Balazs, E., Everding, A., Oh, M., Fanjiang, G., Cohen, S. WILEY. 2019

  View details for Web of Science ID 000507466900521

• Efficacy and Safety of Fenebrutinib, a BTK Inhibitor, Compared to Placebo in Rheumatoid Arthritis Patients with Active Disease Despite TNF Inhibitor Treatment: Randomized, Double Blind, Phase 2 Study Cohen, S., Tuckwell, K., Kunder, R., Katsumoto, T., Zhao, R., Berman, A., Damjanov, N., Fedkov, D., Jeka, S., Genovese, M. WILEY. 2019

  View details for Web of Science ID 000507466901352

• Efficacy of Biosimilar Candidate ABP 710 in a Phase 3 Study in Subjects with Moderate to Severe RA: Additional Analysis Focusing on the ACR Individual Components Genovese, M., Sanchez-Burson, J., Balazs, E., Everding, A., Oh, M., Fanjiang, G., Cohen, S. WILEY. 2019

  View details for Web of Science ID 000507466900520

• Treatment Patterns and Persistency Following the First Biologic DMARD in Patients with Rheumatoid Arthritis: Real-World Analysis of 2012-2016 US Medicare Data Dore, R., Chang, L., Ji, Y., Li, S., Antonova, J., Genovese, M. WILEY. 2019

  View details for Web of Science ID 000507466901376

• Safety, Tolerability, Pharmacokinetics, and Clinical Outcomes Following Single-Dose IA Administration of UBX0101, a Senolytic MDM2/p53 Interaction Inhibitor, in Patients with Knee OA Hsu, B., Visich, J., Genovese, M., Walter, K., An, M., Laberge, R., Dananberg, J. WILEY. 2019

  View details for Web of Science ID 000507466905164

• Effects of Filgotinib on Anemia, Thrombocytopenia and Leukopenia: Results from a Phase 3 Study in Patients with Active Rheumatoid Arthritis and Prior Inadequate Response or Intolerance to Biological DMARDs Genovese, M., Kalunian, K., Gottenberg, J., Bartok, B., Tan, Y., Guo, Y., Tasset, C., Sundy, J., de Vlam, K., Walker, D., Takeuchi, T. WILEY. 2019

  View details for Web of Science ID 000507466905105

• Rheumatoid Arthritis Treatment with Filgotinib: Week 156 Safety and Efficacy Data from a Phase 2b Open-Label Extension Study Kavanaugh, A., Westhovens, R., Winthrop, K., Lee, S., Greer, J., DeZure, A., An, D., Ye, L., Sundy, J., Besuyen, R., Meuleners, L., Alten, R., Genovese, M. WILEY. 2019

  View details for Web of Science ID 000507466900551

• Unique Sjogren's syndrome patient subsets defined by molecular features. Rheumatology (Oxford, England) James, J. A., Guthridge, J. M., Chen, H., Lu, R., Bourn, R. L., Bean, K., Munroe, M. E., Smith, M., Chakravarty, E., Baer, A. N., Noaiseh, G., Parke, A., Boyle, K., Keyes-Elstein, L., Coca, A., Utset, T., Genovese, M. C., Pascual, V., Utz, P. J., Holers, V. M., Deane, K. D., Sivils, K. L., Aberle, T., Wallace, D. J., McNamara, J., Franchimont, N., St Clair, E. W. 2019

  Abstract

  OBJECTIVE: To address heterogeneity complicating primary SS (pSS) clinical trials, research and care by characterizing and clustering patients by their molecular phenotypes.METHODS: pSS patients met American-European Consensus Group classification criteria and had at least one systemic manifestation and stimulated salivary flow of ⩾0.1 ml/min. Correlated transcriptional modules were derived from gene expression microarray data from blood (n = 47 with appropriate samples). Patients were clustered based on this molecular information using an unbiased random forest modelling approach. In addition, multiplex, bead-based assays and ELISAs were used to assess 30 serum cytokines, chemokines and soluble receptors. Eleven autoantibodies, including anti-Ro/SSA and anti-La/SSB, were measured by Bio-Rad Bioplex 2200.RESULTS: Transcriptional modules distinguished three clusters of pSS patients. Cluster 1 showed no significant elevation of IFN or inflammation modules. Cluster 2 showed strong IFN and inflammation modular network signatures, as well as high plasma protein levels of IP-10/CXCL10, MIG/CXCL9, BLyS (BAFF) and LIGHT. Cluster 3 samples exhibited moderately elevated IFN modules, but with suppressed inflammatory modules, increased IP-10/CXCL10 and B cell-attracting chemokine 1/CXCL13 and trends toward increased MIG/CXCL9, IL-1alpha, and IL-21. Anti-Ro/SSA and anti-La/SSB were present in all three clusters.CONCLUSION: Molecular profiles encompassing IFN, inflammation and other signatures can be used to separate patients with pSS into distinct clusters. In the future, such profiles may inform patient selection for clinical trials and guide treatment decisions.

  View details for DOI 10.1093/rheumatology/kez335

  View details for PubMedID 31497844

• Two-Year Safety and Effectiveness of Peficitinib in Moderate-To-Severe Rheumatoid Arthritis: A Phase IIb, Open-Label Extension Study. Rheumatology and therapy Genovese, M. C., Greenwald, M. W., Gutierrez-Urena, S. R., Cardiel, M. H., Poiley, J. E., Zubrzycka-Sienkiewicz, A., Codding, C. E., Wang, A., He, W., Amos, R., Vinueza, R., Wang, X., Garg, J. P., Kivitz, A. J. 2019

  Abstract

  INTRODUCTION: Peficitinib is a novel orally bioavailable, once-daily Janus kinase (JAK) inhibitor approved in Japan for the treatment of rheumatoid arthritis (RA). This 2-year extension study of two global phaseIIbtrials investigated the long-term safety and effectiveness of peficitinib.METHODS: All eligible patients with moderate-to-severe RA including patients in the placebo group who participated in one of two global phase IIb trials ('with methotrexate' or 'without methotrexate') were included in this 2-year open-label extension study and were converted to peficitinib100mg once daily. The primary objective was to evaluate an additional 2years of safety by assessing treatment-emergent adverse events (AEs) and clinical laboratory evaluations for 105weeks. Evaluation of an additional 2years of effectiveness using American College of Rheumatology (ACR) 20/50/70 responses was the exploratory objective.RESULTS: Overall, 611 patients were enrolled in the extension study: 319 (52.2%) patients completed the study and 292 (48%) discontinued treatment, including for withdrawal of patient consent (n=96), failure to achieve low disease activity (n=62), and AE not including death (n=41). AEs were reported in 463(76%) patients. The most common AEs (per 100 patient-years) were upper respiratory tract infections (9.9) and urinary tract infections (7.2). Serious AEs were reported in 80 (13%) patients, with incidences per 100 patient-years of serious infections 2.7, herpes zoster 1.5 (including one herpes zoster ophthalmic), and malignancies 0.6 (most frequently basal cell carcinoma). At week 105, 269 (44%) patients demonstrated an ACR20 response relative to their respective phaseIIb trial baselines.CONCLUSION: Among 319 patients who completed this 2-year extension of two global phase IIb studies, peficitinib 100mg once daily demonstrated a stable safety profile and sustained effectiveness in patients with moderate-to-severe RA.TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01711814. Registered 19 October 2012.FUNDING: Astellas Pharma Global Development, Inc.

  View details for DOI 10.1007/s40744-019-00167-6

  View details for PubMedID 31410787

• Patient Perceptions of Unmet Medical Need in Rheumatoid Arthritis: A Cross-Sectional Survey in the USA. Rheumatology and therapy Radawski, C., Genovese, M. C., Hauber, B., Nowell, W. B., Hollis, K., Gaich, C. L., DeLozier, A. M., Gavigan, K., Reynolds, M., Cardoso, A., Curtis, J. R. 2019

  Abstract

  INTRODUCTION: Many rheumatoid arthritis (RA) patients do not achieve their treatment goals and experience symptoms that affect psychosocial outcomes and daily activities. This study aimed to identify and quantify the unmet needs perceived by US patients with RA currently taking a disease-modifying antirheumatic drug (DMARD).METHODS: A cross-sectional, web-based survey was conducted with RA patients recruited through CreakyJoints, an online patient support community, and ArthritisPower, an online patient research registry, from December 2017 to January 2018. Participant patients were aged≥21years, failed≥1 DMARDs, and were receiving their current DMARD(s) for≥6months; they answered 50 questions about treatment history, RA symptoms, and flares and completed the Rheumatoid Arthritis Impact of Disease (RAID) questionnaire and the Treatment Satisfaction Questionnaire for Medication (TSQM). Treatment satisfaction was defined by a TSQM global satisfaction score≥80.RESULTS: Of 415 patients screened, 258 (62%) were eligible and completed the survey; 87% were women, and 87% white, with mean (SD) age of 54.5 (11.4) years. A total of 232 patients (90%) had current or past biologic DMARD (bDMARD) use, with 67% currently on a bDMARD, 65% on≥1 conventional synthetic DMARD, and 40% on methotrexate. Forty-three percent of patients reported daily/almost daily use of prescription pain medications, and 44% reported a current flare. Mean (SD) TSQM scores were 59 [20] for effectiveness, 59 [26] for side effects, 72 [18] for convenience, and 65 [21] for global satisfaction. The mean (SD) RAID overall score was 5.1 (2.0) on a 0-10 scale. Only 26% (67 patients) were satisfied with their RA treatment. Patients not satisfied with treatment reported higher RAID scores overall and by domain, and approximately half reported a current flare.CONCLUSIONS: Results from this real-world survey suggest that three-fourths of RA patients are not satisfied with treatments, which include bDMARDs. Patients continued to experience bothersome symptoms that impacted their daily activities and life. There remains a need for improved disease management among currently treated RA patients.FUNDING: Eli Lilly and Company (Indianapolis, IN, USA).

  View details for DOI 10.1007/s40744-019-00168-5

  View details for PubMedID 31385264

• MRI and Dose Selection in a Phase II Trial of Baricitinib with Conventional Synthetic Disease-modifying Antirheumatic Drugs in Rheumatoid Arthritis JOURNAL OF RHEUMATOLOGY Peterfy, C., DiCarlo, J., Emery, P., Genovese, M. C., Keystone, E. C., Taylor, P. C., Schlichting, D. E., Beattie, S. D., Luchi, M., Macias, W. 2019; 46 (8): 887–95

  View details for DOI 10.3899/jrheum.171469

  View details for Web of Science ID 000478078100004

• Effect of Filgotinib vs Placebo on Clinical Response in Patients With Moderate to Severe Rheumatoid Arthritis Refractory to Disease-Modifying Antirheumatic Drug Therapy: The FINCH 2 Randomized Clinical Trial. JAMA Genovese, M. C., Kalunian, K., Gottenberg, J., Mozaffarian, N., Bartok, B., Matzkies, F., Gao, J., Guo, Y., Tasset, C., Sundy, J. S., de Vlam, K., Walker, D., Takeuchi, T. 2019; 322 (4): 315–25

  Abstract

  Importance: Patients with active rheumatoid arthritis (RA) despite treatment with biologic disease-modifying antirheumatic drug (bDMARD) therapy need treatment options.Objective: To evaluate the effects of filgotinib vs placebo on the signs and symptoms of RA in a treatment-refractory population.Design, Setting, and Participants: A 24-week, randomized, placebo-controlled, multinational phase 3 trial conducted from July 2016 to June 2018 at 114 sites internationally, randomizing 449 adult patients (and treating 448) with moderately to severely active RA and inadequate response/intolerance to 1 or more prior bDMARDs.Interventions: Filgotinib, 200 mg (n=148); filgotinib, 100 mg (n=153); or placebo (n=148) once daily; patients continued concomitant stable conventional synthetic DMARDs (csDMARDs).Main Outcomes and Measures: The primary end point was the proportion of patients who achieved 20% improvement in the American College of Rheumatology criteria (ACR20) at week 12. Secondary outcomes included week 12 assessments of low disease activity (disease activity score in 28 joints-C-reactive protein [DAS28-CRP] ≤3.2) and change in Health Assessment Questionnaire-Disability Index, 36-Item Short-Form Health Survey Physical Component, and Functional Assessment of Chronic Illness Therapy-Fatigue scores, as well as week 24 assessment of remission (DAS28-CRP <2.6) and adverse events.Results: Among 448 patients who were treated (mean [SD] age, 56 [12] years; 360 women [80.4%]; mean [SD] DAS28-CRP score, 5.9 [0.96]; 105 [23.4%] with ≥3 prior bDMARDs), 381 (85%) completed the study. At week 12, more patients receiving filgotinib, 200 mg (66.0%) or 100 mg (57.5%), achieved ACR20 response (placebo, 31.1%; difference vs placebo: 34.9% [95% CI, 23.5%-46.3%] and 26.4% [95% CI, 15.0%-37.9%], respectively; both P<.001), including among patients with prior exposure to 3 or more bDMARDs (70.3%, 58.8%, and 17.6%, respectively; difference vs placebo: 52.6% [95% CI, 30.3%-75.0%] for filgotinib, 200 mg, and 41.2% [95% CI, 17.3%-65.0%] for filgotinib, 100 mg; both P<.001). The most common adverse events were nasopharyngitis (10.2%) for filgotinib, 200 mg; headache, nasopharyngitis, and upper respiratory infection (5.9% each) for filgotinib, 100 mg; and RA (6.1%) for placebo. Four uncomplicated herpes zoster cases and 1 retinal vein occlusion were reported with filgotinib; there were no opportunistic infections, active tuberculosis, malignancies, gastrointestinal perforations, or deaths.Conclusions and Relevance: Among patients with active RA who had an inadequate response or intolerance to 1 or more bDMARDs, filgotinib, 100 mg daily or 200 mg daily, compared with placebo resulted in a significantly greater proportion achieving a clinical response at week 12. However, further research is needed to assess longer-term efficacy and safety.Trial Registration: ClinicalTrials.gov Identifier: NCT02873936.

  View details for DOI 10.1001/jama.2019.9055

  View details for PubMedID 31334793

• Long-term safety of sarilumab in rheumatoid arthritis: an integrated analysis with up to 7 years' follow-up. Rheumatology (Oxford, England) Fleischmann, R., Genovese, M. C., Lin, Y., St John, G., van der Heijde, D., Wang, S., Gomez-Reino, J. J., Maldonado-Cocco, J. A., Stanislav, M., Kivitz, A. J., Burmester, G. R. 2019

  Abstract

  OBJECTIVE: Sarilumab is a human monoclonal antibody that blocks IL-6 from binding to membrane-bound and soluble IL-6 receptor-alpha. We assessed the long-term safety of sarilumab in patients from eight clinical trials and their open-label extensions.METHODS: Data were pooled from patients with rheumatoid arthritis who received at least one dose of sarilumab in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs; combination group) or as monotherapy (monotherapy group). Treatment-emergent adverse events (AEs) and AEs and laboratory values of special interest were assessed.RESULTS: 2887 patients received sarilumab in combination with csDMARDs and 471 patients received sarilumab monotherapy, with mean exposure of 2.8 years and 1.7 years, maximum exposure 7.3 and 3.5 years, and cumulative AE observation period of 8188 and 812 patient-years, respectively. Incidence rates per 100 patient-years in the combination and monotherapy groups, respectively, were 9.4 and 6.7 for serious AEs, 3.7 and 1.0 for serious infections, 0.6 and 0.5 for herpes zoster (no cases were disseminated), 0.1 and 0 for gastrointestinal perforations, 0.5 and 0.2 for major adverse cardiovascular events, and 0.7 and 0.6 for malignancy. Absolute neutrophil counts <1000 cells/mm3 were recorded in 13% and 15% of patients, respectively. Neutropenia was not associated with increased risk of infection or serious infection. Analysis by 6-month interval showed no signal for increased rate of any AE over time.CONCLUSION: The long-term safety profile of sarilumab, either in combination with csDMARDs or as monotherapy, remained stable and consistent with the anticipated profile of a molecule that inhibits IL6 signalling.

  View details for DOI 10.1093/rheumatology/kez265

  View details for PubMedID 31312844

• Upadacitinib versus Placebo or Adalimumab in Patients with Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results of a Phase 3, Double-Blind, Randomized Controlled Trial. Arthritis & rheumatology (Hoboken, N.J.) Fleischmann, R., Pangan, A. L., Song, I., Mysler, E., Bessette, L., Peterfy, C., Durez, P., Ostor, A. J., Li, Y., Zhou, Y., Othman, A. A., Genovese, M. C. 2019

  Abstract

  OBJECTIVE: To evaluate efficacy, including inhibition of radiographic progression, and safety of upadacitinib, a JAK1-selective inhibitor, vs placebo and adalimumab in patients with rheumatoid arthritis and an inadequate response to methotrexate.METHODS: 1629 patients with inadequate response to methotrexate were randomized (2:2:1) to once-daily upadacitinib 15mg, placebo, or adalimumab 40mg, on stable background methotrexate. Primary endpoints were ACR20 and DAS28CRP<2.6 versus placebo at Week12; inhibition of radiographic progression was evaluated at Week26. The study was designed and powered to test for non-inferiority and superiority of upadacitinib versus adalimumab clinically and functionally.RESULTS: At Week12, both primary endpoints were met for upadacitinib versus placebo (p≤0.001). ACR20 was achieved by 71% versus 36%, and DAS28CRP<2.6 by 29% versus 6%. Upadacitinib was superior to adalimumab for ACR50, DAS28CRP≤3.2, DeltaPain and DeltaHAQ-DI. At Week26, more patients on upadacitinib vs placebo or adalimumab achieved low disease activity or remission (p≤0.001). Radiographic progression was less and observed in fewer patients receiving upadacitinib versus placebo (p≤0.001). Up to Week26, adverse events (AEs) including serious infections were comparable for upadacitinib and adalimumab. The proportions of patients with serious AEs and AEs leading to discontinuation were highest for adalimumab; the proportion with herpes zoster and CPK elevations was highest for upadacitinib. Three malignancies, five MACE, and four deaths were reported, none on upadacitinib. Six venous thromboembolic events were reported [placebo, one; upadacitinib, two; adalimumab, three].CONCLUSION: Upadacitinib was superior to placebo and adalimumab for improving signs, symptoms and physical function in RA patients on background methotrexate, and significantly inhibited radiographic progression versus placebo, while the overall safety profile was generally similar to adalimumab, except for higher rates of herpes zoster and CPK elevations on upadacitinib. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/art.41032

  View details for PubMedID 31287230

• Long-Term Safety of Ixekizumab in 17034.7 Patient-Years from 15 Global Clinical Trials in Psoriasis and Psoriatic Arthritis: 3-Year Results Combe, B., Rahman, P., Kameda, H., Canete, J., Gallo, G., Agada, N., Xu, W., Genovese, M., Janos, B. J RHEUMATOL PUBL CO. 2019: 845

  View details for Web of Science ID 000475840400244

• Safety Profile of Baricitinib for the Treatment of Rheumatoid Arthritis up to 6 Years: An Updated Integrated Safety Analysis Keystone, E., Genovese, M., Smolen, J., Takeuchi, T., Rooney, T., Dickson, C., Saifan, C., Cardoso, A., Issa, M., Ishii, T., Winthrop, K. J RHEUMATOL PUBL CO. 2019: 804–5

  View details for Web of Science ID 000475840400130

• Assessment of Pain Relief with Baricitinib in Patients with Refractory Rheumatoid Arthritis Pope, J., Quebe, A., Zhu, B., Sun, L., Gaich, C., De Leonardis, F., Cardoso, A., Genovese, M. J RHEUMATOL PUBL CO. 2019: 807

  View details for Web of Science ID 000475840400136

• Dose Reduction of Baricitinib in Patients with Rheumatoid Arthritis Achieving Sustained Disease Control: Results of a Prospective Study Takeuchi, T., Genovese, M., Haraoui, B., Li, Z., Xie, L., Klar, R., Correia, A., Otawa, S., Lopez-Romero, P., de la Torre, I., Rooney, T., Smolen, J. J RHEUMATOL PUBL CO. 2019: 807–8

  View details for Web of Science ID 000475840400138

• CLINICAL SIMILARITY OF ABP 710 WITH INFLIXIMAB (REFERENCE PRODUCT) IN SUBJECTS WITH MODERATE TO SEVERE RHEUMATOID ARTHRITIS Genovese, M. C., Sanchez-Burson, J., Oh, M., Balazs, E., Neal, J., Fanjiang, G., Cohen, S. BMJ PUBLISHING GROUP. 2019: 1648–49

  View details for DOI 10.1136/annrheumdis-2019-eular.4928

  View details for Web of Science ID 000472207105071

• SAFETY AND EFFECTIVENESS OF UPADACITINIB OR ADALIMUMAB IN PATIENTS WITH RHEUMATOID ARTHRITIS: RESULTS AT 48 WEEKS FROM THE SELECT-COMPARE STUDY Fleischmann, R., Enejosa, J., Song, I., Mysler, E., Bessette, L., Peterfy, C., Durez, P., Ostor, A., Li Yihan, Zhou, Y., Genovese, M. C. BMJ PUBLISHING GROUP. 2019: 744–45

  View details for DOI 10.1136/annrheumdis-2019-eular.4258

  View details for Web of Science ID 000472207102190

• SWITCHING BETWEEN THE JAK1-SELECTIVE INHIBITOR-UPADACITINIB AND ADALIMUMAB FOLLOWING INITIAL NON-RESPONSE: CLINICAL AND FUNCTIONAL OUTCOMES AMONG RHEUMATOID ARTHRITIS PATIENTS Genovese, M. C., Fleischmann, R., Blanco, R., Hall, S., Thomson, G., van den Bosch, F., Zerbini, C., Enejosa, J., Li Yihan, Demasi, R., Song, I. BMJ PUBLISHING GROUP. 2019: 83–84

  View details for DOI 10.1136/annrheumdis-2019-eular.2886

  View details for Web of Science ID 000472207100243

• SYSTEMATIC ANALYSIS OF INJECTION-SITE PAIN CAUSED BY SUBCUTANEOUS ADMINISTRATION OF THE ADALIMUMAB BIOSIMILAR FKB327 VERSUS ADMINISTRATION OF THE ADALIMUMAB REFERENCE PRODUCT VIA DIFFERENT DELIVERY METHODS Alten, R., Genovese, M. C., Boyce, M., Yonemura, T., Ito, T., Kellner, H. BMJ PUBLISHING GROUP. 2019: 699

  View details for DOI 10.1136/annrheumdis-2019-eular.1292

  View details for Web of Science ID 000472207102118

• INHIBITION OF STRUCTURAL JOINT DAMAGE WITH UPADACITINIB AS MONOTHERAPY OR IN COMBINATION WITH METHOTREXATE IN PATIENTS WITH RHEUMATOID ARTHRITIS: 1 YEAR OUTCOMES FROM THE SELECT PHASE 3 PROGRAM Peterfy, C., Genovese, M. C., Song, I., Friedman, A., Hall, S., Mysler, E., Durez, P., Baraliakos, X., Enejosa, J., Shaw, T., Li Yihan, Su Chen, Strand, V. BMJ PUBLISHING GROUP. 2019: 369–70

  View details for DOI 10.1136/annrheumdis-2019-eular.2871

  View details for Web of Science ID 000472207101097

• SHORT DURATION OF CONVENTIONAL SYNTHETIC DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS (CSDMARDS) BEFORE AND AFTER BECOMING A CSDMARD INADEQUATE RESPONDER IN RHEUMATOID ARTHRITIS PATIENTS Dore, R. K., Antonova, J., Huan, H., Gorritz, M., Genovese, M. C. BMJ PUBLISHING GROUP. 2019: 700

  View details for DOI 10.1136/annrheumdis-2019-eular.1848

  View details for Web of Science ID 000472207102120

• PATIENTS (PTS) SWITCHED TO SARILUMAB FROM ADALIMUMAB ACHIEVE CLINICALLY IMPORTANT IMPROVEMENTS IN RA DISEASE ACTIVITY: RESULTS FROM MONARCH TRIAL OPEN-LABEL EXTENSION (OLE) Burmester, G., Amital, H., Rubbert-Roth, A., van Hoogstraten, H., Gervitz, L., Thangavelu, K., St John, G., Genovese, M. C. BMJ PUBLISHING GROUP. 2019: 1138–39

  View details for DOI 10.1136/annrheumdis-2019-eular.4646

  View details for Web of Science ID 000472207103323

• TREATMENT PATTERNS, PERSISTENCE, AND DURABILITY IN RHEUMATOID ARTHRITIS PATIENTS WITH INADEQUATE RESPONSE TO BIOLOGIC DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS (BDMARDS) Dore, R. K., Antonova, J., Burudpakdee, C., Wang, X., Ozbay, B., Genovese, M. C. BMJ PUBLISHING GROUP. 2019: 1135–36

  View details for DOI 10.1136/annrheumdis-2019-eular.2920

  View details for Web of Science ID 000472207103319

• SAFETY PROFILE OF BARICITINIB FOR THE TREATMENT OF RHEUMATOID ARTHRITIS UP TO 7 YEARS: AN UPDATED INTEGRATED SAFETY ANALYSIS Genovese, M. C., Smolen, J. S., Takeuchi, T., Burmester, G., Brinker, D., Rooney, T., Zhong, J., Mo, D., Saifan, C., Cardoso, A., Issa, M., Wu, W., Winthrop, K. BMJ PUBLISHING GROUP. 2019: 308–9

  View details for DOI 10.1136/annrheumdis-2019-eular.691

  View details for Web of Science ID 000472207100652

• HIGH UNMET NEED AMONG RHEUMATOID ARTHRITIS PATIENTS WITH INADEQUATE RESPONSE TO BIOLOGIC DMARD: REAL-WORLD ANALYSIS OF 2012-2016 US MEDICARE DATA Dore, R. K., Antonova, J., Guo, H., Li Suying, Ozbay, B., Genovese, M. C. BMJ PUBLISHING GROUP. 2019: 1640

  View details for DOI 10.1136/annrheumdis-2019-eular.801

  View details for Web of Science ID 000472207105056

• SAFETY AND EFFICACY OF FILGOTINIB IN ACTIVE RHEUMATOID ARTHRITIS BY PRIOR BIOLOGICAL DMARD EXPOSURE IN PATIENTS WITH PRIOR INADEQUATE RESPONSE OR INTOLERANCE TO BIOLOGICAL DMARDS (BDMARD-IR) Genovese, M. C., Kalunian, K., Gottenberg, J., Mozaffarian, N., Bartok, B., Matzkies, F., Gao, J., Guo, Y., de Vlam, K., Walker, D., Takeuchi, T. BMJ PUBLISHING GROUP. 2019: 709–10

  View details for DOI 10.1136/annrheumdis-2019-eular.1729

  View details for Web of Science ID 000472207102135

• GS-9876, A NOVEL, HIGHLY SELECTIVE, SYK INHIBITOR IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS: SAFETY, TOLERABILITY AND EFFICACY RESULTS OF A PHASE 2 STUDY Kivitz, A., Mehta, D., Matzkies, F., Mozaffarian, A., Kunder, R., Di Paolo, J. A., Mozaffarian, N., Hsueh, S., Kim, J., Jiang, W., Liu, L., Sundy, J., Genovese, M. C. BMJ PUBLISHING GROUP. 2019: 746–47

  View details for DOI 10.1136/annrheumdis-2019-eular.2144

  View details for Web of Science ID 000472207102193

• SAFETY AND EFFICACY OF FILGOTINIB IN PATIENTS AGED 65 YEARS AND OLDER: RESULTS FROM A PHASE 3 STUDY IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS AND PRIOR INADEQUATE RESPONSE OR INTOLERANCE TO BIOLOGICAL DMARDS (BDMARD-IR) Kalunian, K., Gottenberg, J., Genovese, M. C., Mozaffarian, N., Bartok, B., Matzkies, F., Gao, J., Guo, Y., Takeuchi, T., de Vlam, K., Walker, D. BMJ PUBLISHING GROUP. 2019: 748–49

  View details for DOI 10.1136/annrheumdis-2019-eular.2121

  View details for Web of Science ID 000472207102197

• SAFETY AND EFFICACY OF FILGOTINIB IN JAPANESE PATIENTS ENROLLED IN A GLOBAL PHASE 3 TRIAL OF PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS AND INADEQUATE RESPONSE OR INTOLERANCE TO BIOLOGIC DMARDS Takeuchi, T., Matsubara, T., Atsumi, T., Amano, K., Ishiguro, N., Sugiyama, E., Yamaoka, K., Genovese, M. C., Kalunian, K., Walker, D., Gottenberg, J., de Vlam, K., Mozaffarian, N., Bartok, B., Matzkies, F., Gao, J., Guo, Y., Tasset, C., Sundy, J., Tanaka, Y. BMJ PUBLISHING GROUP. 2019: 1686–87

  View details for DOI 10.1136/annrheumdis-2019-eular.2123

  View details for Web of Science ID 000472207105142

• UPADACITINIB IN PATIENTS WITH RHEUMATOID ARTHRITIS AND INADEQUATE RESPONSE OR INTOLERANCE TO BIOLOGICAL DMARDS: RESULTS AT 60 WEEKS FROM THE SELECT-BEYOND STUDY Genovese, M. C., Combe, B., Hall, S., Rubbert-Roth, A., Zhong, S., Meerwein, S., Pangan, A., Fleischmann, R. BMJ PUBLISHING GROUP. 2019: 360–61

  View details for DOI 10.1136/annrheumdis-2019-eular.2285

  View details for Web of Science ID 000472207101081

• LONG-TERM SAFETY, IMMUNOGENICITY AND EFFICACY IN RANDOMIZED, DOUBLE-BLIND, AND OPEN-LABEL EXTENSION STUDIES COMPARING FKB327, AN ADALIMUMAB BIOSIMILAR, WITH THE ADALIMUMAB REFERENCE PRODUCT IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS Alten, R., Genovese, M. C., Arai, Muniz, R., Kellner, H. BMJ PUBLISHING GROUP. 2019: 1135

  View details for DOI 10.1136/annrheumdis-2019-eular.972

  View details for Web of Science ID 000472207103318

• SAFETY AND EFFICACY OF LY3337641, A BRUTON'S TYROSINE KINASE INHIBITOR IN PATIENTS WITH RHEUMATOID ARTHRITIS: A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, 2-PART PHASE 2 STUDY Genovese, M. C., Spindler, A., Sagawa, A., Park, W., Dudek, A., Kivitz, A., Chao, J., Chan, L., Barchuk, W., Nirula, A. BMJ PUBLISHING GROUP. 2019: 1109–10

  View details for DOI 10.1136/annrheumdis-2019-eular.2672

  View details for Web of Science ID 000472207103275

• EFFECT OF SARILUMAB ON GLYCOSYLATED HEMOGLOBIN IN PATIENTS WITH RHEUMATOID ARTHRITIS AND DIABETES Genovese, M. C., Burmester, G., Hagino, O., van Hoogstraten, H., Mangan, E., Thangavelu, K., Fleischmann, R., Mandrup-Poulsen, T. BMJ PUBLISHING GROUP. 2019: 1128–29

  View details for DOI 10.1136/annrheumdis-2019-eular.3259

  View details for Web of Science ID 000472207103307

• FILGOTINIB IN PATIENTS WITH RHEUMATOID ARTHRITIS AND PRIOR INADEQUATE RESPONSE OR INTOLERANCE TO BIOLOGICAL DMARDS (BDMARD-IR) BY RACE & GEOGRAPHIC REGION Gottenberg, J., Genovese, M. C., Kalunian, K., Mozaffarian, N., Bartok, B., Matzkies, F., Gao, J., Guo, Y., Walker, D., Takeuchi, T., de Vlam, K. BMJ PUBLISHING GROUP. 2019: 361

  View details for DOI 10.1136/annrheumdis-2019-eular.2323

  View details for Web of Science ID 000472207101082

• FIRST-IN-HUMAN STUDY OF NOVEL IMPLANTED VAGUS NERVE STIMULATION DEVICE TO TREAT RHEUMATOID ARTHRITIS Genovese, M. C., Gaylis, N., Sikes, D., Kivitz, A., Horowitz, D. M., Peterfy, C., Levine, Y., Chernoff, D. BMJ PUBLISHING GROUP. 2019: 264

  View details for DOI 10.1136/annrheumdis-2019-eular.8716

  View details for Web of Science ID 000472207100570

• FENEBRUTINIB COMPARED TO PLACEBO AND ADALIMUMAB IN PATIENTS WITH INADEQUATE RESPONSE TO EITHER METHOTREXATE THERAPY OR PRIOR TNF THERAPY: PHASE 2 STUDY Cohen, S., Tuckwell, K., Katsumoto, T. R., Zhao, R., Lee, C., Berman, A., Damjanov, N., Fedkov, D., Jeka, S., Genovese, M. C. BMJ PUBLISHING GROUP. 2019: 80–81

  View details for DOI 10.1136/annrheumdis-2019-eular.4469

  View details for Web of Science ID 000472207100239

• SAFETY PROFILE OF BARICITINIB FOR THE TREATMENT OF RHEUMATOID ARTHRITIS UP TO 6 YEARS: AN UPDATED INTEGRATED SAFETY ANALYSIS Genovese, M., Smolen, J., Takeuchi, T., Rooney, T., Dickson, C., Yang, X., Saifan, C., Cardoso, A., Issa, M., Ishii, T., Winthrop, K., Gomez, D. LIPPINCOTT WILLIAMS & WILKINS. 2019: S49–S50

  View details for Web of Science ID 000507308400158

• SAFETY AND EFFICACY OF FILGOTINIB IN A PHASE 3 TRIAL OF PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS AND INADEQUATE RESPONSE OR INTOLERANCE TO BIOLOGIC DISEASE MODIFYING ANTI-RHEUMATIC DRUGS Walker, D., Genovese, M. C., Kalunian, K., Gottenberg, J., de Vlam, K., Mozaffarian, N., Bartok, B., Matzkies, F., Gao, J., Guo, Y., Tasset, C., Sundy, J. S., Takeuchi, T. OXFORD UNIV PRESS. 2019

  View details for Web of Science ID 000478086100124

• ASSESSMENT OF PAIN IMPROVEMENT IN RHEUMATOID ARTHRITIS PATIENTS TREATED WITH BARICITINIB, WHO WERE INADEQUATE RESPONDERS TO METHOTREXATE AND TUMOR NECROSIS FACTOR INHIBITORS Taylor, P. C., Fleischmann, R., Takeuchi, T., Pope, J., Genovese, M. C., Zhu, B., Gaich, C., Zhang, X., Dickson, C., Quebe, A., De Leonardis, F., Cardoso, A., Kouris, I., Durez, P. OXFORD UNIV PRESS. 2019: 72

  View details for Web of Science ID 000478086100114

• Dose reduction of baricitinib in patients with rheumatoid arthritis achieving sustained disease control: results of a prospective study Takeuchi, T., Genovese, M. C., Haraoui, B., Li, Z., Xie, L., Klar, R., Pinto-Correia, A., Otawa, S., Lopez-Romero, P., de la Torre, I., Macias, W., Rooney, T. P., Smolen, J. S. BMJ PUBLISHING GROUP. 2019: 171–78

  Abstract

  This study investigated the effects of dose step-down in patients with rheumatoid arthritis (RA) who achieved sustained disease control with baricitinib 4 mg once a day.Patients who completed a baricitinib phase 3 study could enter a long-term extension (LTE). In the LTE, patients who received baricitinib 4 mg for ≥15 months and maintained CDAI low disease activity (LDA) or remission (REM) were blindly randomised to continue 4 mg or taper to 2 mg. Patients could rescue (to 4 mg) if needed. Efficacy and safety were assessed through 48 weeks.Patients in both groups maintained LDA (80% 4 mg; 67% 2 mg) or REM (40% 4 mg; 33% 2 mg) over 48 weeks. However, dose reduction resulted in small, statistically significant increases in disease activity at 12, 24 and 48 weeks. Dose reduction also produced earlier and more frequent relapse (loss of step-down criteria) over 48 weeks compared with 4 mg maintenance (23% 4 mg vs 37% 2 mg, p=0.001). Rescue rates were 10% for baricitinib 4 mg and 18% for baricitinib 2 mg. Dose reduction was associated with a numerically lower rate of non-serious infections (30.6 for baricitinib 4 mg vs 24.9 for 2 mg). Rates of serious adverse events and adverse events leading to discontinuation were similar across groups.In a large randomised, blinded phase 3 study, maintenance of RA control following induction of sustained LDA/REM with baricitinib 4 mg was greater with continued 4 mg than after taper to 2 mg. Nonetheless, most patients tapered to 2 mg could maintain LDA/REM or recapture with return to 4 mg if needed.

  View details for PubMedID 30194275

  View details for PubMedCentralID PMC6352419

• Use of Magnetic Resonance Imaging to Support Dose Selection in a Phase II Trial of Baricitinib Combined with Conventional Synthetic Disease-modifying Antirheumatic Drugs in Rheumatoid Arthritis. The Journal of rheumatology Peterfy, C., DiCarlo, J., Emery, P., Genovese, M. C., Keystone, E. C., Taylor, P. C., Schlichting, D. E., Beattie, S. D., Luchi, M., Macias, W. 2019

  Abstract

  OBJECTIVE: Magnetic resonance imaging (MRI) was used in a Phase IIb study (NCT01185353) of baricitinib in patients with RA to support dose selection for the Phase III program.METHODS: 301 patients with active RA on stable methotrexate were randomized 2:1:1:1:1 to placebo or once-daily baricitinib (1-, 2-, 4-, or 8-mg) for up to 24 weeks. 154 patients with definitive radiographic erosion had MRI of the hand/wrist at baseline and weeks 12 and 24. Two expert radiologists, blinded to treatment and visit order, scored images for synovitis, osteitis, bone erosion, and cartilage loss. Combined inflammation (osteitis + 3x synovitis score) and total joint damage (erosion + 2.5x cartilage loss score) scores were calculated. Treatment groups were compared using analysis of covariance adjusting for baseline scores.RESULTS: Mean changes from baseline to week 12 for synovitis were -0.10, -1.50, and -1.60 for patients treated with placebo, baricitinib 4-mg, and baricitinib 8-mg, respectively (P=0.003 vs placebo for baricitinib 4- and 8-mg); mean changes for osteitis were 0.00, -3.20, and -2.10 (P=0.001 vs placebo for baricitinib 4-mg and P=0.037 for 8-mg) and mean changes for bone erosion were 0.90, 0.10, and 0.40 (P=0.089 for 4-mg and P=0.275 for 8 mg), respectively in these treatment groups.CONCLUSION: Using MRI findings in this subgroup of patients suggest suppression of synovitis, osteitis, and combined inflammation by baricitinib 4- and 8-mg, which corroborate previously demonstrated clinical efficacy of baricitinib and increase confidence that baricitinib 4-mg could positively effect reduction of the radiographic progression in Phase III studies.

  View details for PubMedID 30647190

• Safety Profile of Baricitinib in Patients with Active Rheumatoid Arthritis with over 2 Years Median Time in Treatment JOURNAL OF RHEUMATOLOGY Smolen, J. S., Genovese, M. C., Takeuchi, T., Hyslop, D. L., Macias, W. L., Rooney, T., Chen, L., Dickson, C. L., Camp, J., Cardillo, T. E., Ishii, T., Winthrop, K. L. 2019; 46 (1): 7–18

  View details for DOI 10.3899/jrheum.171361

  View details for Web of Science ID 000454612100004

• TNF-alpha inhibition for the treatment of cardiac sarcoidosis. Seminars in arthritis and rheumatism Baker, M. C., Sheth, K. n., Witteles, R. n., Genovese, M. C., Shoor, S. n., Simard, J. F. 2019

  Abstract

  Tumor necrosis factor alpha (TNF-α) inhibitors are increasingly being used for treating refractory cardiac sarcoidosis. There is a theoretical risk, however, that these therapies can worsen heart failure, and reports on efficacy and safety are lacking.We conducted a retrospective review of all cardiac sarcoidosis patients seen at Stanford University from 2009 to 2018. Data were collected on patient demographics, diagnostic testing, and treatment outcomes.We identified 77 cardiac sarcoidosis patients, of which 20 (26%) received TNF-α inhibitor treatment. The majority were treated for progressive heart failure or tachyarrhythmia, along with worsening imaging findings. All TNF-α inhibitor treated patients demonstrated meaningful benefit, as assessed by changes in advanced imaging, echocardiographic measures of cardiac function, and prednisone use.A large cohort (n = 77) of cardiac sarcoidosis patients has been treated at Stanford University. Roughly one-fourth of these patients (n = 20) received TNF-α inhibitors. Of these patients, none had worsening heart failure and all saw clinical benefit. These results help support the use of TNF-α inhibitors for the treatment of cardiac sarcoidosis based on real-world evidence and highlight the need for future prospective studies.

  View details for DOI 10.1016/j.semarthrit.2019.11.004

  View details for PubMedID 31806154

• Safety and efficacy of switching from adalimumab to sarilumab in patients with rheumatoid arthritis in the ongoing MONARCH open-label extension. RMD open Burmester, G. R., Strand, V., Rubbert-Roth, A., Amital, H., Raskina, T., Gomez-Centeno, A., Pena-Rossi, C., Gervitz, L., Thangavelu, K., St John, G., Boklage, S., Genovese, M. C. 2019; 5 (2): e001017

  Abstract

  Objective: Evaluate open-label sarilumab monotherapy in patients with rheumatoid arthritis switching from adalimumab monotherapy in MONARCH (NCT02332590); assess long-term safety and efficacy in patients continuing sarilumab during open-label extension (OLE).Methods: During the 48-week OLE, patients received sarilumab 200mg subcutaneously once every 2weeks. Safety (March 2017 cut-off) and efficacy, including patient-reported outcomes, were evaluated.Results: In the double-blind phase, patients receiving sarilumab or adalimumab monotherapy showed meaningful improvements in disease activity; sarilumab was superior to adalimumab for improving signs, symptoms and physical function. Overall, 320/369 patients completing the 24-week double-blind phase entered OLE (155 switched from adalimumab; 165 continued sarilumab). Sarilumab safety profile was consistent with previous reports. Treatment-emergent adverse events were similar between groups; no unexpected safety signals emerged in the first 10 weeks postswitch. Among switch patients, improvement in disease activity was evident at OLE week 12: 47.1%/34.8% had changes ≥1.2 in Disease Activity Score (28 joints) (DAS28)-erythrocyte sedimentation rate/DAS28-C-reactive protein. In switch patients achieving low disease activity (LDA: Clinical Disease Activity Index (CDAI) ≤10; Simplified Disease Activity Index (SDAI) ≤11) by OLE week 24, 70.7%/69.5% sustained CDAI/SDAI LDA at both OLE weeks 36 and 48. Proportions of switch patients achieving CDAI ≤2.8and SDAI ≤3.3 by OLE week 24 increased through OLE week 48. Improvements postswitch approached continuation-group values, including scores ≥normative values.Conclusions: During this OLE, there were no unexpected safety issues in patients switching from adalimumab to sarilumab monotherapy, and disease activity improved in many patients. Patients continuing sarilumab reported safety consistent with prolonged use and had sustained benefit.

  View details for DOI 10.1136/rmdopen-2019-001017

  View details for PubMedID 31673415

• Long-term safety and efficacy of sarilumab plus methotrexate on disease activity, physical function and radiographic progression: 5 years of sarilumab plus methotrexate treatment. RMD open Genovese, M. C., van der Heijde, D., Lin, Y., St John, G., Wang, S., van Hoogstraten, H., Gomez-Reino, J. J., Kivitz, A., Maldonado-Cocco, J. A., Seriolo, B., Stanislav, M., Burmester, G. R. 2019; 5 (2): e000887

  Abstract

  Objective: In MOBILITY (NCT01061736), sarilumab significantly reduced disease activity, improved physical function and inhibited radiographic progression at week 52 versus placebo in patients with rheumatoid arthritis (RA) and an inadequate response to methotrexate. We report 5-year safety, efficacy and radiographic outcomes of sarilumab from NCT01061736 and the open-label extension (EXTEND; NCT01146652), in which patients received sarilumab 200mg every 2 weeks (q2w) + methotrexate.Methods: Patients (n=1197) with moderately to severely active RA were initially randomised to placebo, sarilumab 150mg or sarilumab 200mg subcutaneously q2w plus weekly methotrexate for 52 weeks. Completers were eligible to enrol in the open-label extension and receive sarilumab 200mg q2w + methotrexate.Results: Overall, 901 patients entered the open-label extension. The safety profile remained stable over 5-year follow-up and consistent with interleukin-6 receptor blockade. Absolute neutrophil count <1000cells/mm3 was observed but not associated with increased infection rate. Initial treatment with sarilumab 200 mg + methotrexate was associated with reduced radiographic progression over 5 years versus sarilumab 150 mg + methotrexateor placebo + methotrexate (mean±SE change from baseline in van der Heijde-modified Total Sharp Score: 1.46±0.27, 2.35±0.28and 3.68±0.27, respectively (p<0.001 for each sarilumab dose versus placebo)). Clinical efficacy was sustained through 5 years according to Disease Activity Score (28-joint count) using C reactive protein, Clinical Disease Activity Index (CDAI) and Health Assessment Questionnaire-Disability Index. The number of patients achieving CDAI ≤2.8 at 5 years was similar among initial randomisation groups (placebo, 76/398 (19%); sarilumab 150mg, 68/400 (17%); sarilumab 200mg, 84/399 (21%)).Conclusion: Clinical efficacy, including inhibition of radiographic progression, reduction in disease activity and improvement in physical function, was sustained with sarilumab + methotrexate over 5 years. Safety appeared stable over the 5-year period.

  View details for DOI 10.1136/rmdopen-2018-000887

  View details for PubMedID 31452928

• Safety and effectiveness of upadacitinib or adalimumab plus methotrexate in patients with rheumatoid arthritis over 48 weeks with switch to alternate therapy in patients with insufficient response. Annals of the rheumatic diseases Fleischmann, R. M., Genovese, M. C., Enejosa, J. V., Mysler, E. n., Bessette, L. n., Peterfy, C. n., Durez, P. n., Ostor, A. n., Li, Y. n., Song, I. H. 2019

  Abstract

  In SELECT-COMPARE, a randomised double-blind study, upadacitinib 15 mg once daily was superior to placebo or adalimumab on background methotrexate (MTX) for treating rheumatoid arthritis signs and symptoms and inhibited radiographical progression versus placebo at 26 weeks. Here we report 48-week safety and efficacy in patients who continued their original medication or were rescued to the alternative medication for insufficient response.Patients on MTX received upadacitinib 15 mg, placebo or adalimumab for 48 weeks. Rescue without washout, from placebo or adalimumab to upadacitinib or upadacitinib to adalimumab occurred if patients had <20% improvement in tender joint count (TJC) or swollen joint count (SJC) (weeks 14/18/22) or Clinical Disease Activity Index (CDAI) >10 (week 26); remaining placebo patients were switched to upadacitinib at week 26. Efficacy was analysed by randomised group (non-responder imputation), as well as separately for rescued patients (as observed). Treatment-emergent adverse events per 100 patient-years were summarised.Consistent with responses through week 26, from weeks 26 to 48, responses by randomised group including low disease activity, clinical remission and improvements in pain and function remained superior for upadacitinib versus adalimumab; radiographical progression remained lower for upadacitinib versus placebo (linear extrapolation). Although both switch groups responded, a higher proportion of patients rescued to upadacitinib from adalimumab achieved CDAI ≤10 at 6 months postswitch versus patients rescued from upadacitinib to adalimumab. Safety at week 48 was comparable to week 26.Upadacitinib+MTX demonstrated superior clinical and functional responses versus adalimumab+MTX and maintained inhibition of structural damage versus placebo+MTX through week 48. Patients with an insufficient response to adalimumab or upadacitinib safely achieved clinically meaningful responses after switching to the alternative medication without washout.

  View details for DOI 10.1136/annrheumdis-2019-215764

  View details for PubMedID 31362993

• Tissue metabolite of type I collagen, C1M, and CRP predicts structural progression of rheumatoid arthritis. BMC rheumatology Bay-Jensen, A. C., Platt, A., Jenkins, M. A., Weinblatt, M. E., Byrjalsen, I., Musa, K., Genovese, M. C., Karsdal, M. A. 2019; 3: 3

  Abstract

  Background: Biomarkers of rheumatoid arthritis (RA) disease activity typically measure inflammation or autoimmunity (e.g. CRP, RF). C1M and C3M, metabolites of type I and III collagen, are markers reflecting tissue metabolism. These markers have been documented to provide additional prognostic and predictive value compared to commonly used biomarkers. We investigated the relationship of high serum levels of C1M or C3M to radiographic progression, and benchmarked them to CRP and RF.Methods: Placebo treated patients of the OSK1, 2 and 3 studies (Phase III clinical trials testing efficacy of fostamatinib) with baseline serum biomarkers C1M, C3M, CRP and RF were included (nBL=474). Van der Heijde mTSS was calculated at baseline and 24-week (n24=261). Progression was defined as moderate or rapid by DeltamTSS ≥0.5 or≥5units/year. Patients were divided into subgroups; low (L), high (H) or very high (V) C1M, C3M and CRP, or RF negative, positive and high positive. Difference in clinical parameters were analyzed by Mann-Whitney or chi2tests, and modelling for prediction of progression by logistic regression including covariates (age, gender, BMI, and clinical assessment scores).Results: Levels of C1M, C3M, CRP and RF were significantly (p<0.05) associated with measures of disease activity and mTSS at baseline. For prognostic measures, there were 2.5 and 4-fold as many rapid progressors in the C1MH and CRPH (p<0.05), and in the C1MV and CRPV groups (p<0.001) compared C1ML and CRPL, respectively. C1M and CRP performed similarly in the predictive analysis, where high levels predicted moderate and rapid progression with odds ratio of 2.1 to 3.8 and 3.7 to 13.1 after adjustment for covariates. C3M and RF did not provide prognostic value alone.Discussion: Serum C1M and CRP showed prognostic value and may be tools for enrichment of clinical trials with structural progressor. The two markers reflect two different aspect of disease pathogenesis (tissue turnover vs. inflammation), thus may provide individual and supplementary information.

  View details for PubMedID 30886991

• Methotrexate in the Treatment of Idiopathic Granulomatous Mastitis. The Journal of rheumatology Postolova, A. n., Troxell, M. L., Wapnir, I. L., Genovese, M. C. 2019

  Abstract

  Idiopathic granulomatous mastitis (IGM) is a disfiguring inflammatory breast disease without effective treatment. We report the largest IGM cohort treated with methotrexate monotherapy.Chart review was performed on patients evaluated by the Rheumatology Clinic, with histopathologically-established IGM, treated with methotrexate, and at least one follow up appointment.Nineteen female patients with an mean age of 33.5 years were identified. Most failed treatment with antibiotics, prednisone, and surgical intervention. By 15 months of treatment with methotrexate, 94% had disease improvement and 75% achieved disease remission.Methotrexate monotherapy is an effective treatment for IGM.

  View details for DOI 10.3899/jrheum.181205

  View details for PubMedID 31203215

• Phase II Study of ABT-122, a Tumor Necrosis Factor- and Interleukin-17A-Targeted Dual Variable Domain Immunoglobulin, in Patients With Psoriatic Arthritis With an Inadequate Response to Methotrexate ARTHRITIS & RHEUMATOLOGY Mease, P. J., Genovese, M. C., Weinblatt, M. E., Peloso, P. M., Chen, K., Othman, A. A., Li, Y., Mansikka, H. T., Khatri, A., Wishart, N., Liu, J. 2018; 70 (11): 1778–89

  Abstract

  To investigate the safety and efficacy of ABT-122, a tumor necrosis factor (TNF)- and interleukin-17A (IL-17A)-targeted dual variable domain immunoglobulin, in patients with active psoriatic arthritis (PsA) who have experienced an inadequate response to methotrexate.Patients (n = 240) were randomized to receive ABT-122 (120 or 240 mg every week), adalimumab (40 mg every other week), or placebo in a 12-week double-blind, parallel-group study. The primary efficacy end point was the proportion of patients achieving ≥20% improvement in disease activity according to the American College of Rheumatology response criteria (ACR20) at week 12. Secondary and exploratory 12-week end points included 50% improvement (ACR50) and 70% improvement (ACR70) response rates, and proportion of patients meeting the Psoriasis Area and Severity Index (PASI) response criteria for ≥75% (PASI75) and ≥90% (PASI90) improvement in skin scores among those with ≥3% of their body surface area affected by psoriasis.In both ABT-122 dose groups, ACR20 response rates at week 12 (64.8-75.3%) were superior to that in patients receiving placebo (25.0%) (P < 0.001) but similar to that in patients receiving adalimumab (68.1%). ACR50 and ACR70 response rates were also superior in both ABT-122 dose groups (36.6-53.4% and 22.5-31.5%, respectively) compared to the placebo group (12.5% and 4.2%, respectively) (P < 0.05). Among eligible patients in the placebo, adalimumab, ABT-122 120 mg every week, and ABT-122 240 mg every week treatment groups, PASI75 responses were achieved in 27.3%, 57.6%, 74.4%, and 77.6% of patients, respectively, whereas PASI90 responses were achieved in 18.2%, 45.5%, 48.8%, and 46.9% of patients, respectively. Frequencies of treatment-emergent adverse events, including infections, were similar across all treatment groups, causing no discontinuations. No serious infections or systemic hypersensitivity reactions were reported with ABT-122.Dual neutralization of TNF and IL-17A with ABT-122 had efficacy and safety that was similar to, and not broadly differentiated from, that of adalimumab over a 12-week treatment course in patients with PsA.

  View details for PubMedID 29855175

  View details for PubMedCentralID PMC6221045

• Safety Profile of Baricitinib in Patients with Active Rheumatoid Arthritis with over 2 Years Median Time in Treatment. The Journal of rheumatology Smolen, J. S., Genovese, M. C., Takeuchi, T., Hyslop, D. L., Macias, W. L., Rooney, T., Chen, L., Dickson, C. L., Riddle Camp, J., Cardillo, T. E., Ishii, T., Winthrop, K. L. 2018

  Abstract

  OBJECTIVE: Baricitinib is an oral, once-daily selective Janus kinase (JAK1/JAK2) inhibitor for adults with moderately to severely active rheumatoid arthritis (RA). We evaluated baricitinib's safety profile through 288 weeks (up to September 1, 2016) with an integrated database [8 phase III/II/Ib trials, 1 longterm extension (LTE)].METHODS: The "all-bari-RA" group included patients who received any baricitinib dose. Placebo comparison was based on the 6 studies with 4 mg and placebo up to Week 24 ("placebo-4 mg" dataset). Dose response assessment was based on 4 studies with 2 mg and 4 mg including LTE data ("2 mg-4 mg-extended"). The uncommon events description used the non-controlled all-bari-RA.RESULTS: There were 3492 patients who received baricitinib for 6637 total patient-years (PY) of exposure (median 2.1 yrs, maximum 5.5 yrs). No differences in rates of death, adverse events leading to drug discontinuation, malignancies, major adverse cardiovascular event (MACE), or serious infections were seen for 4 mg versus placebo or for 4 mg versus 2 mg. Infections including herpes zoster were significantly more frequent for 4 mg versus placebo. Deep vein thrombosis/pulmonary embolism were reported with 4 mg but not placebo [all-bari-RA incidence rate (IR) 0.5/100 PY]; the IR did not differ between doses (0.5 vs 0.6/100 PY, 2 mg vs 4 mg, respectively) or compared to published RA rates. All-bari-RA had 6 cases of lymphoma (IR 0.09/100 PY), 3 gastrointestinal perforations (0.05/100 PY), 10 cases of tuberculosis (all in endemic areas; 0.15/100 PY), and 22 all-cause deaths (0.33/100 PY). IR for malignancies (0.8/100 PY) and MACE (0.5/100 PY) were low and did not increase with prolonged exposure.CONCLUSION: In this integrated analysis of patients with moderate to severe active RA with exposure up to 5.5 years, baricitinib has an acceptable safety profile in the context of demonstrated efficacy. Trial registration numbers: NCT01185353, NCT00902486, NCT01469013, NCT01710358, NCT01721044, NCT01721057, NCT01711359, and NCT01885078 at clinicaltrials.gov.

  View details for PubMedID 30219772

• Radiographic Progression Based on Baseline Demographics and Disease Characteristics from Three TNF-Alpha Inhibitor Biosimilar Studies in Patients with Rheumatoid Arthritis Smolen, J. S., Kang, Y., Yoo, W., Emery, P., Weinblatt, M. E., Keystone, E. C., Genovese, M. C., Myung, G., Hong, E., Baek, I., Ghil, J. WILEY. 2018

  View details for Web of Science ID 000447268901092

• Long-Term Treatment with Sarilumab Plus Conventional Synthetic Disease-Modifying Anti-Rheumatic Drugs (csDMARDs): Pooled Safety and Efficacy with over 4 Years' Treatment Genovese, M. C., van Hoogstraten, H., St John, G., Dong, Q., Jose Gomez-Reino, J., Maldonado-Cocco, J. A., Carlos Salazar, J., Huizinga, T. J., Burmester, G. R. WILEY. 2018

  View details for Web of Science ID 000447268904242

• GS-9876, a Novel, Highly Selective, SYK Inhibitor in Patients with Active Rheumatoid Arthritis: Safety, Tolerability and Efficacy Results of a Phase 2 Study Kivitz, A. J., Mehta, D. P., Matzkies, F., Mozaffarian, A., Kunder, R., Di Paolo, J., Mozaffarian, N., Hsueh, S., Kim, J., Jiang, W., Liu, L., Sundy, J. S., Genovese, M. C. WILEY. 2018

  View details for Web of Science ID 000447268904251

• Impact of Immunogenicity on Clinical Efficacy and Administration Related Reaction in TNF Inhibitors: A Pooled-Analysis from Three Biosimilar Studies in Patients with Rheumatoid Arthritis Emery, P., Weinblatt, M. E., Smolen, J. S., Keystone, E. C., Genovese, M. C., Vencovsky, J., Kay, J., Hong, E., Ghil, J. WILEY. 2018

  View details for Web of Science ID 000447268902631

• Assessment of Pain Relief with Baricitinib By Treatment History in Patients with Refractory Rheumatoid Arthritis Pope, J. E., Quebe, A., Zhu, B., Sun, L., Gaich, C. L., de Leonardis, F., Cardoso, A., Genovese, M. C. WILEY. 2018

  View details for Web of Science ID 000447268904264

• A Phase 3, Randomized, Double-Blind Study Comparing Upadacitinib to Placebo and to Adalimumab, in Patients with Active Rheumatoid Arthritis with Inadequate Response to Methotrexate Fleischmann, R., Pangan, A. L., Mysler, E., Bessette, L., Peterfy, C., Durez, P., Ostor, A., Li, Y., Zhou, Y., Othman, A. A., Song, I., Genovese, M. C. WILEY. 2018

  View details for Web of Science ID 000447268901423

• Longitudinal Efficacy Analysis of Patients with Active Rheumatoid Arthritis and Inadequate Response to Conventional Synthetic Dmards: Response Following Rescue from Baricitinib 2mg to 4mg Once-Daily Fleischmann, R., Genovese, M. C., Cardoso, A., Sun, L., Chen, Y., Walls, C. D., Schlichting, D. E., Takeuchi, T., Dougados, M., Smolen, J. S., Curtis, J. R. WILEY. 2018

  View details for Web of Science ID 000447268901107

• A Phase IIa Mechanistic Study of Anti-GM-CSF (GSK3196165) with Methotrexate Treatment in Patients with Rheumatoid Arthritis (RA) and an Inadequate Response to Methotrexate Genovese, M. C., Berkowitz, M., Conaghan, P. G., Davy, K., Inman, D., Fisheleva, E., Gupta, A., Janiczek, R., Layton, M., Mitchell, N., Patel, J., Smith, J. E., Williamson, R., Tak, P. WILEY. 2018

  View details for Web of Science ID 000447268904243

• Incidence of Inflammatory Bowel Disease Among Patients Treated with Ixekizumab: An Update on Adjudicated Data from an Integrated Database of Patients with Psoriasis and Psoriatic Arthritis Genovese, M. C., Colombel, J., Gellett, A. M., Xu, W., Hardin, D. WILEY. 2018

  View details for Web of Science ID 000447268903069

• Safety Profile of Baricitinib for the Treatment of Rheumatoid Arthritis up to 6 Years: An Updated Integrated Safety Analysis Genovese, M. C., Smolen, J. S., Takeuchi, T., Rooney, T. P., Dickson, C. L., Yang, X., Saifan, C., Cardoso, A., Issa, M., Ishii, T., Winthrop, K. WILEY. 2018

  View details for Web of Science ID 000447268902063

• Unique Changes in Hemoglobin with Sarilumab Versus Adalimumab Are Independent of Better Disease Control in Patients with Rheumatoid Arthritis (RA) Burmestert, G. R., Hagino, O., Dong, Q., Stanislav, M., Gomez-Centeno, A., Selmi, C., Huizinga, T. J., Mangan, E., Gabay, C., Genovese, M. C. WILEY. 2018

  View details for Web of Science ID 000447268902627

• Methotrexate in the Treatment of Granulomatous Mastitis: A Retrospective Review of 19 Cases Postolova, A., Genovese, M. C. WILEY. 2018

  View details for Web of Science ID 000447268903467

• Rheumatoid Arthritis Treatment with Filgotinib: Week 132 Safety Data from a Phase 2b Open-Label Extension Study Kavanaugh, A., Genovese, M. C., Winthrop, K., Creenwald, M., Ponce, L., Sosa, F., Stanislavchuk, M., Mazur, M., Spindler, A., Cseuz, R., Nikulenkova, N., Glowacka-Kulesz, M., Szombati, I., Dudek, A., Mozaffarian, N., Greer, J., Kunder, R., An, D., Meulener, L., Besuyen, R., Alten, R., Westhovens, R. WILEY. 2018

  View details for Web of Science ID 000447268904284

• A First-in-Man Bioelectronic Therapy for Biologic-Refractory Rheumatoid Arthritis Chernoff, D., Levine, Y., Peterfy, C., Genovese, M. C. WILEY. 2018

  View details for Web of Science ID 000447268904241

• Clinical Efficacy and Safety of Baminercept, a Lymphotoxin beta Receptor Fusion Protein, in Primary Sjogren's Syndrome Results From a Phase II Randomized, Double-Blind, Placebo-Controlled Trial ARTHRITIS & RHEUMATOLOGY St Clair, E., Baer, A. N., Wei, C., Noaiseh, G., Parke, A., Coca, A., Utset, T. O., Genovese, M. C., Wallace, D. J., McNamara, J., Boyle, K., Keyes-Elstein, L., Browning, J. L., Franchimont, N., Smith, K., Guthridge, J. M., Sanz, I., James, J. A., Autoimmunity Centers Excellence 2018; 70 (9): 1470–80

  Abstract

  To evaluate the clinical efficacy and safety of baminercept, a lymphotoxin β receptor IgG fusion protein (LTβR-Ig), for the treatment of primary Sjögren's syndrome (SS), and to explore the possible mechanisms of action of this treatment.In this multicenter trial, 52 patients with primary SS were randomized in a 2:1 ratio to receive subcutaneous injections of 100 mg of baminercept every week for 24 weeks or matching placebo. The primary end point was the change between screening and week 24 in the stimulated whole salivary flow (SWSF) rate. Secondary end points included the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI), as well as measurements of select chemokines and cytokines and enumeration of peripheral blood B and T cell subsets.The change from baseline to week 24 in the SWSF rate was not significantly different between the baminercept and placebo treatment groups (baseline-adjusted mean change -0.01 versus 0.07 ml/minute; P = 0.332). The change in the ESSDAI during treatment was also not significantly different between the treatment groups (baseline-adjusted mean change -1.23 versus -0.15; P = 0.104). Although the incidence of adverse events was similar between the treatment groups, baminercept therapy was associated with a higher incidence of liver toxicity, including 2 serious adverse events. Baminercept also produced a significant decrease in plasma levels of CXCL13 and significant changes in the number of circulating B and T cells, consistent with its known inhibitory effects on LTβR signaling.In this trial, treatment with baminercept failed to significantly improve glandular and extraglandular disease in patients with primary SS, despite evidence from mechanistic studies showing that it blocks LTβR signaling.

  View details for PubMedID 29604186

  View details for PubMedCentralID PMC6115299

• Patients' perceptions of unmet medical need in rheumatoid arthritis Curtis, J., Genovese, M., Radawski, C., Hauber, B., Nowell, W., Hollis, K., Gaich, C., DeLozier, A., Gavigan, K., Cardoso, A. WILEY. 2018: 56

  View details for Web of Science ID 000441893800113

• Safety and efficacy of ixekizumab in patients with PsA and previous inadequate response to TNF inhibitors: week 52 results from SPIRIT-P2. Rheumatology (Oxford, England) Genovese, M. C., Combe, B., Kremer, J. M., Tsai, T., Behrens, F., Adams, D. H., Lee, C., Kerr, L., Nash, P. 2018

  Abstract

  Objectives: To assess the long-term safety and efficacy of ixekizumab, an IL-17A antagonist, in patients with active PsA.Methods: In SPIRIT-P2 (NCT02349295), patients (n = 363) with previous inadequate response to TNF inhibitors entered the double-blind period (weeks 0-24) and received placebo or ixekizumab 80 mg every 4 weeks (IXEQ4W) or every 2 weeks (IXEQ2W) following a 160-mg starting dose at week 0. During the extension period (weeks 24-156), patients maintained their original ixekizumab dose, and placebo patients received IXEQ4W or IXEQ2W (1:1). We present the accumulated safety findings (week 24 up to 156) at the time of this analysis for patients who entered the extension period (n = 310). Exposure-adjusted incidence rates (IRs) per 100 patient years are presented. ACR responses are presented on an intent-to-treat basis using non-responder imputation up to week 52.Results: From week 24 up to 156 (with 228 patient years of ixekizumab exposure), 140 [61.3 IR] and 15 (6.6 IR) patients reported infections and serious adverse events, respectively. Serious adverse events included one death and four serious infections. In all patients initially treated with IXEQ4W and IXEQ2W at week 0 (non-responder imputation), ACR20 (61 and 51%), ACR50 (42 and 33%) and ACR70 (26 and 18%) responses persisted out to week 52. Placebo patients re-randomized to ixekizumab demonstrated efficacy as measured by ACR responses at week 52.Conclusion: During the extension period, the overall safety profile of ixekizumab remained consistent with that observed with the double-blind period, and clinical improvements persisted up to 1 year.

  View details for PubMedID 30053162

• Dual inhibition of tumour necrosis factor and interleukin-17A with ABT-122: open-label long-term extension studies in rheumatoid arthritis or psoriatic arthritis. Rheumatology (Oxford, England) Genovese, M. C., Weinblatt, M. E., Mease, P. J., Aelion, J. A., Peloso, P. M., Chen, K., Li, Y., Liu, J., Othman, A. A., Khatri, A., Mansikka, H. T., Leszczynski, P. 2018

  Abstract

  Objectives: To evaluate the safety and maintenance of efficacy with ABT-122, a bi-specific monoclonal antibody targeting TNF and IL-17A, in patients with RA or PsA in open-label, 24-week extensions [open-label extensions (OLEs)] of 12-week, randomized, double-blind studies.Methods: All patients received ABT-122 (RA, 120 mg; PsA, 240 mg) subcutaneously every other week on background MTX. Safety assessments included adverse events (AEs) and laboratory parameters. Efficacy was evaluated with ACR responses, 28-joint DAS using high-sensitivity CRP [DAS28 (hsCRP)], and Psoriasis Area and Severity Index (PsA study).Results: The RA OLE study enrolled 158 patients; the PsA OLE study enrolled 168 patients. In the RA OLE study, the incidence of treatment emergent AEs (TEAEs; 41%) appeared similar to the double-blind study (36-43%). In the PsA OLE study, 57% of patients reported ⩾1 TEAE (double-blind study, 42-53%). Most TEAEs were mild or moderate in severity. There were no neutrophil abnormalities greater than grade 2. Grade 3 and/or 4 laboratory abnormalities were reported for lymphocytes, alanine aminotransferase, aspartate aminotransferase, bilirubin and haemoglobin; the number of these severe laboratory values was low (0.6-3.0%), except grade 3 lymphocyte count decreased (11.5%) in the RA study. In both OLE studies, efficacy assessed by ACR responses and other disease activity scores was maintained over the 24 weeks.Conclusion: ABT-122 demonstrated acceptable tolerability and maintenance of efficacy for up to 36 weeks in patients with RA or PsA receiving background MTX.Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT02433340 and NCT02429895.

  View details for PubMedID 30032191

• Dose Reduction of Baricitinib in Patients with Rheumatoid Arthritis Achieving Sustained Disease Control: Results of a Prospective Study Takeuchi, T., Genovese, M., Haraoui, B., Li, Z., Xie, L., Klar, R., Correia, A., Otawa, S., Lopez-Romero, P., de la Torre, I., Rooney, T., Smolen, J. J RHEUMATOL PUBL CO. 2018: 1054

  View details for Web of Science ID 000438512300257

• Safety Profile of Baricitinib for the Treatment of Rheumatoid Arthritis up to 5.5 Years: An Updated Integrated Safety Analysis Keystone, E., Genovese, M., Smolen, J., Takeuchi, T., Hyslop, D., Macias, W., Rooney, T., Chen, L., Dickson, C., Camp, J., Cardillo, T., Ishii, T., Winthrop, K., Otawa, S. J RHEUMATOL PUBL CO. 2018: 1003

  View details for Web of Science ID 000438512300117

• Efficacy and Safety of Switching from Adalimumab to Sarilumab in an Open-label Extension of a Phase 3 Monotherapy Trial in Patients with Active Rheumatoid Arthritis Burmester, G., Fiore, S., Hu, C., Fay, J., Lee, E., Genovese, M. J RHEUMATOL PUBL CO. 2018: 1035

  View details for Web of Science ID 000438512300204

• Efficacy and Safety of Ixekizumab in Patients with Active Psoriatic Arthritis and Previous Inadequate Response to TNF inhibitors: 52-week Results from a Phase 3 Study Genovese, M., Helliwell, P., Combe, B., Kremer, J., Adams, D., Lee, C., Kerr, L., Nash, P., Rahman, P. J RHEUMATOL PUBL CO. 2018: 996

  View details for Web of Science ID 000438512300097

• Safety and efficacy of upadacitinib in patients with active rheumatoid arthritis refractory to biologic disease-modifying anti-rheumatic drugs (SELECT-BEYOND): a double-blind, randomised controlled phase 3 trial. Lancet (London, England) Genovese, M. C., Fleischmann, R., Combe, B., Hall, S., Rubbert-Roth, A., Zhang, Y., Zhou, Y., Mohamed, M. F., Meerwein, S., Pangan, A. L. 2018

  Abstract

  BACKGROUND: Phase 2 studies with upadacitinib, a selective Janus kinase 1 (JAK1) inhibitor, have shown safety and efficacy in the treatment of patients with active rheumatoid arthritis. We did this study to further assess the safety and efficacy of upadacitinib in patients with an inadequate response to biologic disease-modifying anti-rheumatic drugs (bDMARDs).METHODS: We did this double-blind, randomised controlled phase 3 trial at 153 sites in 26 countries. Patients were aged 18 years or older, had active rheumatoid arthritis and previous inadequate response or intolerance to bDMARDs, and were receiving concomitant background conventional synthetic DMARDS (csDMARDs). We randomly assigned patients (2:2:1:1) by interactive response technology to receive once-daily oral extended-release upadacitinib 15 mg or 30 mg or placebo for 12 weeks, followed by upadacitinib 15 mg or 30 mg from week 12 onwards. The two separate primary endpoints were the proportions of patients achieving a 20% improvement in American College of Rheumatology criteria (ACR20) at week 12 and the proportion of patients achieving a 28-joint disease activity score using C-reactive protein (DAS28[CRP]) of 3·2 or less at week 12. Efficacy and safety analyses were done in the modified intention-to-treat population of all patients who received at least one dose of study drug. Data are presented up to week 24 of this ongoing study. The trial is registered with ClinicalTrials.gov (NCT02706847).FINDINGS: Between March 15, 2016, and Jan 10, 2017, 499 patients were randomly assigned (n=165 upadacitinib 15 mg; n=165 upadacitinib 30 mg; n=85 placebo then upadacitinib 15 mg; and n=84 placebo then upadacitinib 30 mg) and one patient was withdrawn from the 15 mg upadacitinib group before the start of study treatment. Mean disease duration was 13·2 years (SD 9·5); 235 (47%) of 498 patients had received one previous bDMARD, 137 (28%) had received two, and 125 (25%) had received at least three; 451 (91%) patients completed treatment up to week 12 and 419 (84%) patients completed treatment up to week 24. At week 12, ACR20 was achieved by 106 (65%; 95% CI 57-72) of 164 patients receiving upadacitinib 15 mg and 93 (56%; 49-64) of 165 patients receiving upadacitinib 30 mg compared with 48 (28%; 22-35) of 169 patients receiving placebo (p<0·0001 for each dose vs placebo). DAS28(CRP) of 3·2 or less was achieved by 71 (43%; 95% CI 36-51) of 164 patients receiving upadacitinib 15 mg and 70 (42%; 35-50) of 165 patients receiving upadacitinib 30 mg versus 24 (14%; 9-20) of 169 patients receiving placebo (p<0·0001 for each dose vs placebo). Up to week 12, overall numbers of patients with adverse events were similar for the placebo group (95 [56%] of 169) and the upadacitinib 15 mg group (91 [55%] of 164), but higher in the upadacitinib 30 mg group (111 [67%] of 165). At week 12, the most common adverse events occurring in at least 5% of patients in any treatment group were upper respiratory tract infection (13 [8%] of 169 in the placebo group; 13 [8%] of 164 in the upadacitinib 15 mg group; ten [6%] of 165 in the upadacitinib 30 mg group), nasopharyngitis (11 [7%]; seven [4%]; nine [5%]), urinary tract infection (ten [6%]; 15 [9%]; nine [5%]), and worsening of rheumatoid arthritis (ten [6%]; four [2%]; six [4%]). The number of patients with serious adverse events was higher in the upadacitinib 30 mg group (12 [7%]) than in the upadacitinib 15 mg group (eight [5%]); no serious adverse events were reported in patients receiving placebo. More patients in the upadacitinib 30 mg group had serious infections, herpes zoster, and adverse events leading to discontinuation than in the upadacitinib 15 mg and placebo groups. During the placebo-controlled phase of the study, one case of pulmonary embolism, three malignancies, one major adverse cardiovascular event, and one death were reported in patients receiving upadacitinib; none were reported in patients receiving placebo.INTERPRETATION: Both doses of upadacitinib led to rapid and significant improvements compared with placebo over 12 weeks in patients with refractory rheumatoid arthritis.FUNDING: AbbVie Inc.

  View details for PubMedID 29908670

• ABT-122, a Bispecific DVD-Immunoglobulin Targeting TNF- and IL-17A, in RA With Inadequate Response to Methotrexate: A Randomized, Double-Blind Study. Arthritis & rheumatology (Hoboken, N.J.) Genovese, M. C., Weinblatt, M. E., Aelion, J. A., Mansikka, H. T., Peloso, P. M., Chen, K., Li, Y., Othman, A. A., Khatri, A., Khan, N. S., Padley, R. J. 2018

  Abstract

  OBJECTIVE: Tumor necrosis factor (TNF) and interleukin-17A (IL-17A) may independently contribute to the pathophysiology of rheumatoid arthritis (RA). The objective of this study was to evaluate the safety and efficacy of ABT-122, a novel dual variable domain immunoglobulin (DVD-Ig ) targeting human TNF and IL-17A in patients with RA with inadequate response to methotrexate.METHODS: Patients with active RA receiving methotrexate and no prior exposure to biologic agents (N=222) were enrolled in a 12-week phase 2, randomized, double-blind, active-controlled, parallel-group study (NCT02141997). Patients were randomized to receive ABT-122 60 mg every other week (EOW), 120 mg EOW, or 120 mg every week (EW), or adalimumab 40 mg EOW subcutaneously. The primary efficacy endpoint was American College of Rheumatology (ACR) 20 response at week 12.RESULTS: Treatment-emergent adverse events were similar across all treatment groups, with no serious infections or systemic hypersensitivity reactions reported with ABT-122. ACR20 response rates at week 12 were 62%, 75%, and 80% with ABT-122 60 mg EOW, 120 mg EOW, and 120 mg EW, respectively, compared with 68% with adalimumab. Corresponding ACR50 and ACR70 response rates were, respectively, 35%, 46%, 47%, and 48% and 22%, 18%, 36%, and 21%.CONCLUSIONS: Dual inhibition of TNF and IL-17A with ABT-122 produced a safety profile consistent with inhibition of TNF alone with adalimumab over the 12-week study period. The efficacy of ABT-122 120 mg EOW and 120 mg EW was not meaningfully differentiated from that of adalimumab 40 mg EOW over 12 weeks in patients with RA receiving concomitant methotrexate. This article is protected by copyright. All rights reserved.

  View details for PubMedID 29855172

• Two years of sarilumab in patients with rheumatoid arthritis and an inadequate response to MTX: safety, efficacy and radiographic outcomes. Rheumatology (Oxford, England) Genovese, M. C., van Adelsberg, J., Fan, C., Graham, N. M., van Hoogstraten, H., Parrino, J., Mangan, E. K., Spindler, A., Huizinga, T. W., van der Heijde, D., EXTEND study investigators 2018

  Abstract

  Objectives: To examine 2-year safety, efficacy and radiographic outcomes of sarilumab in adults with RA and inadequate response to MTX (MTX-IR).Methods: In the randomized, placebo-controlled MOBILITY trial, MTX-IR patients received subcutaneous sarilumab (150 or 200 mg) or placebo every 2 weeks (q2w) plus MTX for up to 1 year. Upon study completion, patients could enrol in the open-label, long-term extension study (EXTEND, NCT011046652), in which all patients received sarilumab 200 mg q2w plus MTX. Dose reduction to 150 mg q2w was allowed for abnormal laboratory findings and per investigator's discretion.Results: Of 1197 patients participating in MOBILITY, 901 entered EXTEND. Over the 2-year period, treatment-emergent adverse events (TEAEs) and serious AEs occurred at rates of 279.6 events per 100 patient-years and 16.6 events per 100 patient-years, respectively. The most common TEAEs were neutropenia, injection site erythema, increased alanine aminotransferase and upper respiratory tract infections. After 1 year in the open-label, long-term extension, disease activity reached similar levels regardless of initial treatment. Modified total Sharp scores at year 1 were maintained through year 2. Best radiographic outcomes were observed in patients initially randomized to sarilumab 200 mg q2w. After dose reduction, 89.4% of patients continued the study through 2 years.Conclusion: Sarilumab safety through year 2 was consistent with IL-6 receptor blockade. Clinical response was similar irrespective of initial treatment, and radiographic progression stabilized. Patients initiated on sarilumab 200 mg q2w had the best radiographic outcomes. Dose reduction allowed most patients to continue with the study.

  View details for PubMedID 29746672

• Longterm Safety and Efficacy of Subcutaneous Abatacept in Patients with Rheumatoid Arthritis: 5-year Results from a Phase IIIb Trial. The Journal of rheumatology Genovese, M. C., Pacheco-Tena, C., Covarrubias, A., Leon, G., Mysler, E., Keiserman, M., Valente, R. M., Nash, P., Simon-Campos, J. A., Box, J., Legerton, C. W., Nasonov, E., Durez, P., Elegbe, A., Wong, R., Li, X., Banerjee, S., Alten, R. 2018

  Abstract

  OBJECTIVE: To assess 5-year safety, tolerability, and efficacy of subcutaneous (SC) abatacept (ABA) in methotrexate (MTX)-refractory patients with rheumatoid arthritis (RA).METHODS: The Abatacept Comparison of sub[QU]cutaneous versus intravenous in Inadequate Responders to methotrexatE (ACQUIRE) phase IIIb, randomized, double-dummy, multinational trial compared efficacy and safety of SC and intravenous (IV) ABA in patients with RA. In the initial 6-month double-blind (DB) period, patients received IV or SC ABA, plus MTX, and in the subsequent open-label longterm extension (LTE) period, all patients received SC ABA (125 mg/wk). The final 5-year safety, tolerability, and efficacy analyses are reported.RESULTS: Of 1385 patients who completed the DB period, 1372 entered LTE and 945 (68.8%) completed ≥ 5 years of treatment. During LTE, 97 (7.1%) patients discontinued treatment because of an adverse event (AE). Incidence rate (IR; event/100 patient-yrs of exposure; based on LTE data, 95% CI) for AE of interest were the following: serious AE 7.73 (6.96-8.58), infection 38.60 (36.24-41.12), serious infection 1.68 (1.35-2.07), malignancies 1.09 (0.84-1.42), and autoimmune disorders 1.33 (1.05-1.69), and were stable over time. No association between immunogenicity and either worsening of ABA safety or loss of efficacy was noted. Efficacy in the LTE was consistent with the DB period and was maintained to the end of the study.CONCLUSION: These 5-year data establish that SC ABA (125 mg/wk) has a consistent safety profile and durable efficacy for longterm treatment of patients with RA who had an inadequate response to MTX.

  View details for PubMedID 29657147

• DURABILITY, MAINTENANCE AND EFFECTS OF DOSE REDUCTION FOLLOWING PROLONGED TREATMENT WITH BARICITINIB Smolen, J. S., Dougados, M., Takeuchi, T., Genovese, M. C., Haraoui, B., Klar, R., Kavanaugh, A., Alonso, R. B., Dudler, J., Taylor, P. C., Nash, P., Zerbini, C. A., Durez, P., Pum, G., Arthanari, S., De Leonardis, F., van Vollenhoven, R. OXFORD UNIV PRESS. 2018

  View details for Web of Science ID 000431142100367

• SAFETY SUMMARY RESULTS OF BARICITINIB FOCUSING ON SERIOUS INFECTIONS EVENTS AND PRESELECTED COMORBIDITIES Combe, B., Balsa, A., Winthrop, K., Tony, H., Genovese, M. C., Harigai, M., Smolen, J. S., Emery, P., Dudler, J., Hall, S., Zerbini, C. A., Van Den Bosch, F., Durand, F., Arthanari, S., Rogai, V., Zhong, J., Meszaros, G., Dougados, M. OXFORD UNIV PRESS. 2018

  View details for Web of Science ID 000431142100353

• IMPROVEMENTSIN REMISSION AND LOW DISEASE ACTIVITY ARE ACHIEVED WITH ONGOING SARILUMABTREATMENT, IN PATIENTS WITH RHEUMATOID ARTHRITIS IN TWO PHASE III STUDIES Genovese, M. C., Mangan, E. K., Fay, J., Kimura, T., van Hoogstraten, H., Fleischmann, R. OXFORD UNIV PRESS. 2018

  View details for Web of Science ID 000431142100351

• EFFICACY AND SAFETY OF SWITCHING FROM ADALIMUMAB TO SARILUMAB IN AN OPEN-LABEL EXTENSIONOF A PHASE III MONOTHERAPY TRIAL IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS Burrnester, G. R., Fiore, S., Hu, C., Fay, J., Lee, E., Genovese, M. C. OXFORD UNIV PRESS. 2018

  View details for Web of Science ID 000431142100348

• Effect of filgotinib, a selective JAK 1 inhibitor, with and without methotrexate in patients with rheumatoid arthritis: patient-reported outcomes ARTHRITIS RESEARCH & THERAPY Genovese, M., Westhovens, R., Meuleners, L., Van der Aa, A., Harrison, P., Tasset, C., Kavanaugh, A. 2018; 20: 57

  Abstract

  The aim was to assess patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA) treated with filgotinib during two phase 2b, 24-week, randomized, placebo-controlled studies.Patients with moderate-to-severe active RA and an inadequate response to methotrexate (MTX) were randomized to daily placebo or filgotinib 50 mg, 100 mg, or 200 mg as add-on therapy to MTX (NCT01888874) or as monotherapy (NCT01894516). At week 12, nonresponders receiving filgotinib 50 mg in both studies or placebo in the add-on study, and all patients receiving placebo as monotherapy, were re-assigned to filgotinib 100 mg. PROs were measured using the Health Assessment Questionnaire - Disability Index (HAQ-DI) including Patient Pain assessed by visual analog scale, and the Patient Global Assessment of Disease Activity (Patient Global), the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue Scale (Version 4), and the 36-Item Short Form Health Survey (SF-36).At week 12, improvements in all PROs, apart from the SF-36 mental component in the add-on study, were statistically better with filgotinib than placebo; some improvements were noted as early as the first assessment time point (week 1 or week 4). Filgotinib improved HAQ-DI by 0.58-0.84 points, FACIT-Fatigue by 6.9-11.4 points, Patient Global by 25.2-35.6 mm, and Pain by 24.2-37.9 mm; scores were maintained or improved to week 24. Across all PROs, more patients achieved minimal clinically important differences and normative values with filgotinib 200 mg than placebo. Patients re-assigned to filgotinib 100 mg at week 12 experienced improvements in PROs between weeks 12 to 24.Filgotinib as MTX add-on therapy or as monotherapy demonstrated rapid and sustained (to 24 weeks) improvements in health-related quality of life and functional status in patients with active RA.MTX add-on study: ClinicalTrials.gov , NCT01888874 . Registered on 28 June 2013. Monotherapy study: ClinicalTrials.gov , NCT01894516 . Registered on 10 July 2013.

  View details for DOI 10.1186/s13075-018-1541-z

  View details for Web of Science ID 000428258300001

  View details for PubMedID 29566740

  View details for PubMedCentralID PMC5865354

• Response to baricitinib therapy in patients with rheumatoid arthritis with inadequate response to csDMARDs as a function of baseline characteristics. RMD open Kremer, J. M., Schiff, M., Muram, D., Zhong, J., Alam, J., Genovese, M. C. 2018; 4 (1): e000581

  Abstract

  We analysed the effects of baseline characteristics on the safety and efficacy of baricitinib in patients with rheumatoid arthritis (RA) with inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) from two phase III trials.In RA-BEAM (NCT01710358), patients with inadequate response to methotrexate were randomised to placebo, baricitinib 4 mg or adalimumab 40 mg. RA-BUILD (NCT01721057) patients had inadequate response to ≥1 csDMARDs and were randomised to either placebo or once-daily baricitinib (2 or 4 mg). Both study populations were naïve to biologic DMARDs (bDMARDs). Primary end point for both studies was American College of Rheumatology 20% improvement (ACR20) response at week 12. Pooled data from the two trials were analysed post hoc based on select subgroups defined by age, previous csDMARD use, baseline RA disease activity, etc, with assessment of clinical and safety outcomes at week 12 and radiographic outcomes at week 24 for the baricitinib 4 mg and placebo-treated patients.Efficacy was observed with baricitinib 4 mg treatment irrespective of patient demographics and baseline disease characteristics. ORs primarily favoured baricitinib over placebo in the ACR20 response. In other outcomes such as Disease Activity Score for 28 joints based on high-sensitivity C reactive protein levels, Simplified Disease Activity Index score ≤11 and radiographic progression, baricitinib 4 mg showed better responses than placebo regardless of baseline characteristics. Safety events were more common in patients over 65 years, but similar between baricitinib 4 mg and placebo patients.Baseline characteristics did not substantially affect clinical response to baricitinib 4 mg in patients with RA with inadequate response to csDMARDs.

  View details for DOI 10.1136/rmdopen-2017-000581

  View details for PubMedID 29479473

  View details for PubMedCentralID PMC5822634

• Response to baricitinib based on prior biologic use in patients with refractory rheumatoid arthritis. Rheumatology (Oxford, England) Genovese, M. C., Kremer, J. M., Kartman, C. E., Schlichting, D. E., Xie, L., Carmack, T., Pantojas, C., Sanchez Burson, J., Tony, H., Macias, W. L., Rooney, T. P., Smolen, J. S. 2018; 57 (5): 900–908

  Abstract

  Objective: RA patients who have failed biologic DMARDs (bDMARDs) represent an unmet medical need. We evaluated the effects of baseline characteristics, including prior bDMARD exposure, on baricitinib efficacy and safety.Methods: RA-BEACON patients (previously reported) had moderate to severe RA with insufficient response to one or more TNF inhibitor and were randomized 1:1:1 to once-daily placebo or 2 or 4 mg baricitinib. Prior bDMARD use was allowed. The primary endpoint was a 20% improvement in ACR criteria (ACR20) at week 12 for 4 mg vs placebo. An exploratory, primarily post hoc, subgroup analysis evaluated efficacy at weeks 12 and 24 by ACR20 and Clinical Disease Activity Index (CDAI) ⩽10. An interaction P-value ⩽0.10 was considered significant, with significance at both weeks 12 and 24 given more weight.Results: The odds ratios predominantly favored baricitinib over placebo and were generally similar to those in the overall study (3.4, 2.4 for ACR20 weeks 12 and 24, respectively). Significant quantitative interactions were observed for baricitinib 4 mg vs placebo at weeks 12 and 24: ACR20 by region (larger effect Europe) and CDAI ⩽10 by disease duration (larger effect ⩾10 years). No significant interactions were consistently observed for ACR20 by age; weight; disease duration; seropositivity; corticosteroid use; number of prior bDMARDs, TNF inhibitors or non-TNF inhibitors; or a specific prior TNF inhibitor. Treatment-emergent adverse event rates, including infections, appeared somewhat higher across groups with greater prior bDMARD use.Conclusion: Baricitinib demonstrated a consistent, beneficial treatment effect in bDMARD-refractory patients across subgroups based on baseline characteristics and prior bDMARD use.Trial registration: ClinicalTrials.gov (https://clinicaltrials.gov/), NCT01721044.

  View details for PubMedID 29415145

• Safety and Efficacy of Baricitinib Through 128 Weeks in an Open-label, Longterm Extension Study in Patients with Rheumatoid Arthritis JOURNAL OF RHEUMATOLOGY Keystone, E. C., Genovese, M. C., Schlichting, D. E., de la Torre, I., Beattie, S. D., Rooney, T. P., Taylor, P. C. 2018; 45 (1): 14–21

  Abstract

  To assess the safety and efficacy of baricitinib in patients with rheumatoid arthritis (RA) up to 128 weeks in a phase IIb study (NCT01185353).After a 24-week blinded period, eligible patients entered an initial 52-week open-label extension (OLE); patients receiving 8 mg once daily (QD) continued with that dose and all others received 4 mg QD. Doses could be escalated to 8 mg QD at 28 or 32 weeks at investigator discretion when ≥ 6 tender and ≥ 6 swollen joints were present. Patients completing the first OLE were eligible to enter a second 52-week OLE and receive 4 mg QD regardless of previous dose.In the 4-mg (n = 108) and 8-mg (n = 93) groups, treatment-emergent adverse events (AE) occurred in 63% and 67%, serious AE in 16% and 13%, infections in 35% and 40%, and serious infections in 5% and 3% of patients, respectively. Exposure-adjusted incidence rates for AE for all baricitinib groups in the second OLE were similar to or lower than rates observed in the first OLE. No opportunistic infections, tuberculosis cases, or lymphomas were observed through 128 weeks; 1 death occurred during the first OLE. Among all patients in both OLE, the proportions who achieved disease improvement at Week 24 were similar or increased at weeks 76 and 128.In a phase IIb study in RA, the safety and tolerability profile of baricitinib, up to 128 weeks, remained consistent with earlier observations, without unexpected late signals. Clinical improvements seen in the 24-week blinded period were maintained during the OLE.

  View details for PubMedID 28811354

• Response to baricitinib therapy in patients with rheumatoid arthritis with inadequate response to csDMARDs as a function of baseline characteristics RMD OPEN Kremer, J. M., Schiff, M., Muram, D., Zhong, J., Alam, J., Genovese, M. C. 2018; 4 (1)

  View details for DOI 10.1136/rmdopen-2017-000581

  View details for Web of Science ID 000427250300009

• Secukinumab in Active Rheumatoid Arthritis after Anti-TNF alpha Therapy: A Randomized, Double-Blind Placebo-Controlled Phase 3 Study RHEUMATOLOGY AND THERAPY Tahir, H., Deodhar, A., Genovese, M., Takeuchi, T., Aelion, J., Van den Bosch, F., Haemmerle, S., Richards, H. B. 2017; 4 (2): 475–88

  Abstract

  'REASSURE' (NCT01377012), a phase 3 study, evaluated the efficacy and safety of secukinumab in patients with active rheumatoid arthritis (RA) who had an inadequate response to, or intolerance of, tumor necrosis factor inhibitors (TNF-inhibitors).A total of 637 patients were randomized (1:1:1) to receive intravenous secukinumab 10 mg/kg (baseline, weeks 2 and 4) followed by subcutaneous secukinumab 150 mg or 75 mg every 4 weeks (starting from week 8) or placebo at the same dosing schedule. The primary endpoint was the American College of Rheumatology 20% improvement criteria (ACR20) at week 24. Other predefined hierarchical endpoints included Health Assessment Questionnaire-Disability Index, van der Heijde modified total Sharp score (vdH-mTSS) at week 24, and major clinical response (MCR; continuous 6 month period of ACR70 response) at 1 year.The primary efficacy endpoint was met with both secukinumab dose groups: ACR20 response rate at week 24 was 35.2% for both secukinumab dose groups (P = 0.0009) vs 19.6% for placebo. The improvements in secondary endpoints were greater in the secukinumab dose groups vs placebo but did not meet statistical significance. The overall safety profile was similar across all treatment groups.Secukinumab demonstrated efficacy in reducing disease activity over placebo as measured by ACR20 in patients with active RA who had an inadequate response to TNF-inhibitors. Secukinumab demonstrated a safety profile similar to other biologics currently approved for RA.Novartis Pharma AG.ClinicalTrials.gov identifier: NCT01377012.

  View details for PubMedID 29138986

• Correlation of Multi-Biomarker Disease Activity Score with Clinical Disease Activity Measures for the JAK1-Selective Inhibitor Filgotinib As Monotherapy and in Combination with Methotrexate in Rheumatoid Arthritis Patients Genovese, M. C., Galien, R., Pan, Y., Van der Aa, A., Jamoul, C., Harrison, P., Tasset, C., Goyal, L., Li, W., Tarrant, J. WILEY. 2017

  View details for Web of Science ID 000411824102375

• Safety Profile of Baricitinib for the Treatment of Rheumatoid Arthritis up to 5.5 Years: An Updated Integrated Safety Analysis Genovese, M. C., Smolen, J. S., Takeuchi, T., Hyslop, D., Macias, W. L., Rooney, T. P., Chen, L., Dickson, C. L., Camp, J., Cardillo, T., Ishii, T., Winthrop, K. WILEY. 2017

  View details for Web of Science ID 000411824100510

• Efficacy and Safety of Switching from Adalimumab to Sarilumab in an Open-Label Extension of a Phase 3 Monotherapy Trial in Patients with Active Rheumatoid Arthritis Burmester, G. R., Fiore, S., Hu, C., Fay, J., Lee, E., Genovese, M. C. WILEY. 2017

  View details for Web of Science ID 000411824105324

• The Effect of Sarilumab in Combination with Dmards on Fasting Glucose and Glycosylated Hemoglobin in Patients with Rheumatoid Arthritis with and without Diabetes Genovese, M. C., Fleischmann, R., Hagino, O., Hu, C., Pena-Rossi, C., Sadeh, J., Graham, N. H., Mangan, E. K., van Hoogstraten, H., Mandrup-Poulsen, T. WILEY. 2017

  View details for Web of Science ID 000411824104052

• Dose Reduction of Baricitinib in Patients with Rheumatoid Arthritis Achieving Sustained Disease Control: Results of a Prospective Study Takeuchi, T., Genovese, M. C., Haraoui, B., Li, Z., Xie, L., Klar, R., Correia, A., Otawa, S., Lopez-Romero, P., de la Torre, I., Rooney, T. P., Smolen, J. S. WILEY. 2017

  View details for Web of Science ID 000411824104051

• Long Term Safety of Filgotinib in the Treatment of Rheumatoid Arthritis: Week 84 Data from a Phase 2b Open-Label Extension Study Genovese, M. C., Kavanaugh, A., Winthrop, K., Greenwald, M., Ponce, L., Enriquez Sosa, F., Stanislavchuk, M., Mazur, M., Spindler, A., Cseuz, R., Nikulenkova, N., Glowacka-Kulesz, M., Szombati, I., Dudek, A., Mozaffarian, N., Greer, J., Ding, X., Harrison, P., Van der Aa, A., Westhovens, R., Alten, R. WILEY. 2017

  View details for Web of Science ID 000411824104139

• Association between Clinical Response and Normalization of Patient-Reported Outcome Measures in Rheumatoid Arthritis: Post-Hoc Analysis from Two Phase 2b Filgotinib Studies Genovese, M. C., Van der Aa, A., Jamoul, C., Tasset, C., Harrison, P., Westhovens, R., Kavanaugh, A. WILEY. 2017

  View details for Web of Science ID 000411824100509

• Improvements in Remission and Low Disease Activity Are Achieved with Ongoing Sarilumab Treatment, in Patients with Rheumatoid Arthritis in 2 Phase 3 Studies Genovese, M. C., Mangan, E. K., Fay, J., Kimura, T., van Hoogstraten, H., Fleischmann, R. WILEY. 2017

  View details for Web of Science ID 000411824105322

• Long-Term Safety and Efficacy of Upadacitinib (ABT-494), an Oral JAK-1 Inhibitor in Patients with Rheumatoid Arthritis in an Open Label Extension Study Genovese, M. C., Kremer, J., Zhong, S., Friedman, A. WILEY. 2017

  View details for Web of Science ID 000411824100508

• Efficacy and Safety of Ixekizumab in Patients with Active Psoriatic Arthritis and Previous Inadequate Response to TNF Inhibitors: 52-Week Results from a Phase 3 Study Genovese, M. C., Combe, B., Kremer, J., Adams, D., Lee, C., Kerr, L., Nash, P. WILEY. 2017

  View details for Web of Science ID 000411824106473

• Efficacy and safety of the biosimilar ABP 501 compared with adalimumab in patients with moderate to severe rheumatoid arthritis: a randomised, double-blind, phase III equivalence study ANNALS OF THE RHEUMATIC DISEASES Cohen, S., Genovese, M. C., Choy, E., Perez-Ruiz, F., Matsumoto, A., Pavelka, K., Pablos, J. L., Rizzo, W., Hrycaj, P., Zhang, N., Shergy, W., Kaur, P. 2017; 76 (10): 1679–87

  Abstract

  ABP 501 is a Food and Drug Administration-approved biosimilar to adalimumab; structural, functional and pharmacokinetic evaluations have shown that the two are highly similar. We report results from a phase III study comparing efficacy, safety and immunogenicity between ABP 501 and adalimumab.In this randomised, double-blind, active comparator-controlled, 26-week equivalence study, patients with moderate to severe active rheumatoid arthritis (RA) despite methotrexate were randomised (1:1) to ABP 501 or adalimumab (40 mg) every 2 weeks. Primary endpoint was risk ratio (RR) of ACR20 between groups at week 24. Primary hypothesis that the treatments were equivalent would be confirmed if the 90% CI for RR of ACR20 at week 24 fell between 0.738 and 1.355, demonstrating that ABP 501 is similar to adalimumab. Secondary endpoints included Disease Activity Score 28-joint count-C reactive protein (DAS28-CRP). Safety was assessed via adverse events (AEs) and laboratory evaluations. Antidrug antibodies were assessed to determine immunogenicity.A total of 526 patients were randomised (n=264, ABP 501; n=262 adalimumab) and 494 completed the study. ACR20 response at week 24 was 74.6% (ABP 501) and 72.4% (adalimumab). At week 24, the RR of ACR20 (90% CI) between groups was 1.039 (0.954, 1.133), confirming the primary hypothesis. Changes from baseline in DAS28-CRP, ACR50 and ACR70 were similar. There were no clinically meaningful differences in AEs and laboratory abnormalities. A total of 38.3% (ABP 501) and 38.2% (adalimumab) of patients tested positive for binding antidrug antibodies.Results from this study demonstrate that ABP 501 is similar to adalimumab in clinical efficacy, safety and immunogenicity in patients with moderate to severe RA.NCT01970475; Results.

  View details for PubMedID 28584187

  View details for PubMedCentralID PMC5629940

• Molecular Features Define Unique Sjogren's Syndrome Patient Subsets James, J. A., Guthridge, J. M., Chen, H., Lu, R., Bourn, R. L., Baer, A. N., Noaiseh, G., Parke, A., Coca, A., Utset, T., Genovese, M. C., Aberle, T., Wallace, D. J., Boyle, K., Keyes-Elstein, L., Franchimont, N., Clair, E., Pascual, V., Utz, P. J., Sivils, K. L. WILEY. 2017

  View details for Web of Science ID 000411824106379

• Efficacy, Safety and Immunogenicity in Randomized, Double-Blind (DB) and OpenLabel Extension (OLE) Studies Comparing FKB327, an Adalimumab Biosimilar, with the Adalimumab Reference Product (Humira (R); RP) in Patients (pts) with Active Rheumatoid Arthritis (RA) Genovese, M. C., Glover, J., Matsunaga, N., Chisholm, D., Alten, R. WILEY. 2017

  View details for Web of Science ID 000411824106303

• Duration of Response in a Phase 3 Study of Sarilumab Plus Methotrexate in Patients with Active, Moderate-to-Severe Rheumatoid Arthritis Genovese, M. C., Mangan, E. K., Kimura, T., Iglesias-Rodriguez, M., Huizinga, T. J. WILEY. 2017

  View details for Web of Science ID 000411824105321

• Transaminase Levels and Hepatic Events During Tocilizumab Treatment Pooled Analysis of Long-Term Clinical Trial Safety Data in Rheumatoid Arthritis ARTHRITIS & RHEUMATOLOGY Genovese, M. C., Kremer, J. M., van Vollenhoven, R. F., Alten, R., Jose Scali, J., Kelman, A., Dimonaco, S., Brockwell, L. 2017; 69 (9): 1751–61

  Abstract

  To investigate liver enzyme abnormalities and hepatic adverse events (AEs) during long-term tocilizumab treatment for rheumatoid arthritis in clinical trials.Data were pooled from patients who received intravenous tocilizumab (4, 8, or 10 mg/kg with or without disease-modifying antirheumatic drugs [DMARDs]) in phase III or IV clinical trials, long-term extensions, and a pharmacology study. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured routinely in these trials. AE rates were measured per 100 patient-years of tocilizumab exposure for this pooled analysis.Overall, 16,204.8 patient-years of tocilizumab exposure (mean ± SD duration of exposure 3.9 ± 2.0 years) were evaluated for 4,171 patients. ALT and AST elevations greater than the upper limit of normal (ULN) occurred in 70.6% and 59.4% of patients, respectively. ALT/AST elevations were >1-3× ULN in 59%/55% of patients, >3-5× ULN in 8.9%/3.3% of patients, and >5× ULN in 2.9%/0.9% of patients. Most elevations occurred during the first year of treatment. Single ALT/AST elevations >3× ULN occurred in 7.7%/3.6% of patients, and ≥2 consecutive elevations >3× ULN occurred in 1.9%/0.4% of patients. Elevations >3× ULN returned to normal in 80% of patients (median of 5.6 weeks to normalization). A total of 2.5% of patients withdrew from tocilizumab treatment following ALT/AST elevations. A total of 7 hepatic serious AEs (SAEs) (0.04 per 100 patient-years [95% confidence interval 0.02-0.09]) occurred in the tocilizumab studies.Transaminase elevations with tocilizumab were frequent, but rates of hepatic SAEs were low in this clinical trial data set. Regular monitoring, with dose adjustment of tocilizumab/DMARDs for persistent elevations, is recommended.

  View details for PubMedID 28597609

• Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial LANCET Nash, P., Kirkham, B., Okada, M., Rahman, P., Combe, B., Burmester, G., Adams, D. H., Kerr, L., Lee, C., Shuler, C. L., Genovese, M., SPIRIT-P Study Grp 2017; 389 (10086): 2317–27

  Abstract

  Patients who have had inadequate response to tumour necrosis factor inhibitors have fewer treatment options and are generally more treatment refractory to subsequent therapeutic interventions than previously untreated patients. We report the efficacy and safety of ixekizumab, a monoclonal antibody that selectively targets interleukin-17A, in patients with active psoriatic arthritis and previous inadequate response to tumour necrosis factor inhibitors.In this double-blind, multicentre, randomised, placebo-controlled, phase 3 study (SPIRIT-P2), patients were recruited from 109 centres across ten countries in Asia, Australia, Europe, and North America. Patients were aged 18 years or older, had a confirmed diagnosis of psoriatic arthritis for at least 6 months, and had a previous inadequate response, distinguished by being refractory to therapy or had loss of efficacy, or were intolerant to tumour necrosis factor inhibitors. Patients were randomly assigned (1:1:1) by a computer-generated random sequence to receive a subcutaneous injection of 80 mg ixekizumab every 4 weeks or every 2 weeks after a 160 mg starting dose or placebo. The primary endpoint was the proportion of patients who attained at least 20% improvement in the American College of Rheumatology response criteria (ACR-20) at week 24. This study is registered with ClinicalTrials.gov, number NCT02349295.Between March 3, 2015, to March 22, 2016, 363 patients were randomly assigned to placebo (n=118), ixekizumab every 4 weeks (n=122), or ixekizumab every 2 weeks (n=123). At week 24, a higher proportion of patients attained ACR-20 with ixekizumab every 4 weeks (65 [53%] patients; effect size vs placebo 33·8% [95% CI 22·4-45·2]; p<0·0001) and ixekizumab every 2 weeks (59 [48%] patients; 28.5% [17·1-39.8]; p<0·0001) than did patients with placebo (23 [20%] patients). Up to week 24, serious adverse events were reported in three (3%) patients with ixekizumab every 4 weeks, eight (7%) with ixekizumab every 2 weeks, and four (3%) with placebo; no deaths were reported. Infections were reported in 47 (39%) patients with ixekizumab every 4 weeks, 47 (38%) with ixekizumab every 2 weeks, and 35 (30%) with placebo. Three (2%) serious infections, all in patients in the ixekizumab every 2 weeks group, were reported.Both the 2-week and 4-week ixekizumab dosing regimens improved the signs and symptoms of patients with active psoriatic arthritis and who had previously inadequate response to tumour necrosis factor inhibitors, with a safety profile consistent with previous studies investigating ixekizumab.Eli Lilly and Company.

  View details for PubMedID 28551073

• Sarilumab Dose Reduction in an Open-label Extension Study in RA Patients Genovese, M., Fay, J., Parrino, J., Beyer, D., Iglesias-Rodriguez, M., van Hoogstraten, H., Graham, N., Boddy, A., Simon, A., Martincova, R., Burmester, G., Fiore, S. J RHEUMATOL PUBL CO. 2017: 895–96

  View details for Web of Science ID 000404641800134

• Low immunogenicity of tocilizumab in patients with rheumatoid arthritis. Annals of the rheumatic diseases Burmester, G. R., Choy, E., Kivitz, A., Ogata, A., Bao, M., Nomura, A., Lacey, S., Pei, J., Reiss, W., Pethoe-Schramm, A., Mallalieu, N. L., Wallace, T., Michalska, M., Birnboeck, H., Stubenrauch, K., Genovese, M. C. 2017; 76 (6): 1078-1085

  Abstract

  Subcutaneous (SC) and intravenous formulations of tocilizumab (TCZ) are available for the treatment of patients with rheumatoid arthritis (RA), based on the efficacy and safety observed in clinical trials. Anti-TCZ antibody development and its impact on safety and efficacy were evaluated in adult patients with RA treated with intravenous TCZ (TCZ-IV) or TCZ-SC as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs).Data from 5 TCZ-SC and 8 TCZ-IV phase III clinical trials and 1 TCZ-IV clinical pharmacology safety study (>50 000 samples) were pooled to assess the immunogenicity profile of TCZ-SC and TCZ-IV (8974 total patients). The analysis included antidrug antibody (ADA) measurement following TCZ-SC or TCZ-IV treatment as monotherapy or in combination with csDMARDs, after dosing interruptions or in TCZ-washout samples, and the correlation of ADAs with clinical response, adverse events or pharmacokinetics (PK).The proportion of patients who developed ADAs following TCZ-SC or TCZ-IV treatment was 1.5% and 1.2%, respectively. ADA development was also comparable between patients who received TCZ monotherapy and those who received concomitant csDMARDs (0.7-2.0%). ADA development did not correlate with PK or safety events, including anaphylaxis, hypersensitivity or injection-site reactions, and no patients who developed ADAs had loss of efficacy.The immunogenicity risk of TCZ-SC and TCZ-IV treatment was low, either as monotherapy or in combination with csDMARDs. Anti-TCZ antibodies developed among the small proportion of patients had no evident impact on PK, efficacy or safety.

  View details for DOI 10.1136/annrheumdis-2016-210297

  View details for PubMedID 28007755

• Efficacy and Safety Analysis by Overall Anti-drug Antibody Result up to Week 30 in Patients with Rheumatoid Arthritis Treated with SB2 (an Infliximab Biosimilar) or Reference Infliximab in a Phase III Study Choe, J., Smolen, J., Keystone, E., Genovese, M., Lee, Y., Rho, Y., Therrien, F. J RHEUMATOL PUBL CO. 2017: 872

  View details for Web of Science ID 000404641800071

• Clinical and Radiographic Outcomes After 3 Years of Sarilumab in Patients with Rheumatoid Arthritis Genovese, M., van Adelsberg, J., van Hoogstraten, H., Iglesias-Rodriguez, M., Mangan, E., Graham, N., Jayawardena, S., Spindler, A., Fiore, S. J RHEUMATOL PUBL CO. 2017: 895

  View details for Web of Science ID 000404641800133

• Efficacy of Sarilumab Plus csDMARDs in Rheumatoid Arthritis Patients who had an Inadequate Response to One or More than One Prior TNF Inhibitor Genovese, M., Pinheiro, G., Mangan, E., Lin, Y., van Adelsberg, J., van Hoogstraten, H., Kimura, T., Fleischmann, R., Fiore, S. J RHEUMATOL PUBL CO. 2017: 896

  View details for Web of Science ID 000404641800135

• Impact of Anti-Drug Antibodies on Efficacy and Safety up to Week 24 from A Phase III Study Comparing SB5 (An Adalimumab Biosimilar) with Reference Adalimumab in Patients with Moderate to Severe Rheumatoid Arthritis Despite Methotrexate Therapy Genovese, M., Weinblatt, M., Keystone, E., Baranauskaite, A., Cheong, S., Ghil, J. J RHEUMATOL PUBL CO. 2017: 878

  View details for Web of Science ID 000404641800086

• Low immunogenicity of tocilizumab in patients with rheumatoid arthritis ANNALS OF THE RHEUMATIC DISEASES Burmester, G. R., Choy, E., Kivitz, A., Ogata, A., Bao, M., Nomura, A., Lacey, S., Pei, J., Reiss, W., Pethoe-Schramm, A., Mallalieu, N. L., Wallace, T., Michalska, M., Birnboeck, H., Stubenrauch, K., Genovese, M. C. 2017; 76 (6): 1078-1085

  Abstract

  Subcutaneous (SC) and intravenous formulations of tocilizumab (TCZ) are available for the treatment of patients with rheumatoid arthritis (RA), based on the efficacy and safety observed in clinical trials. Anti-TCZ antibody development and its impact on safety and efficacy were evaluated in adult patients with RA treated with intravenous TCZ (TCZ-IV) or TCZ-SC as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs).Data from 5 TCZ-SC and 8 TCZ-IV phase III clinical trials and 1 TCZ-IV clinical pharmacology safety study (>50 000 samples) were pooled to assess the immunogenicity profile of TCZ-SC and TCZ-IV (8974 total patients). The analysis included antidrug antibody (ADA) measurement following TCZ-SC or TCZ-IV treatment as monotherapy or in combination with csDMARDs, after dosing interruptions or in TCZ-washout samples, and the correlation of ADAs with clinical response, adverse events or pharmacokinetics (PK).The proportion of patients who developed ADAs following TCZ-SC or TCZ-IV treatment was 1.5% and 1.2%, respectively. ADA development was also comparable between patients who received TCZ monotherapy and those who received concomitant csDMARDs (0.7-2.0%). ADA development did not correlate with PK or safety events, including anaphylaxis, hypersensitivity or injection-site reactions, and no patients who developed ADAs had loss of efficacy.The immunogenicity risk of TCZ-SC and TCZ-IV treatment was low, either as monotherapy or in combination with csDMARDs. Anti-TCZ antibodies developed among the small proportion of patients had no evident impact on PK, efficacy or safety.

  View details for DOI 10.1136/annrheumdis-2016-210297

  View details for Web of Science ID 000401138800022

• Effects of Baricitinib on Lipid, Apolipoprotein, and Lipoprotein Particle Profiles in a Phase IIb Study of Patients With Active Rheumatoid Arthritis ARTHRITIS & RHEUMATOLOGY Kremer, J. M., Genovese, M. C., Keystone, E., Taylor, P. C., Zuckerman, S. H., Ruotolo, G., Schlichting, D. E., Crotzer, V. L., Nantz, E., Beattie, S. D., Macias, W. L. 2017; 69 (5): 943-952

  Abstract

  To assess the effects of baricitinib on lipid profiles in patients with moderate-to-severe rheumatoid arthritis.Treatment with once-daily doses of baricitinib (1, 2, 4, or 8 mg) or placebo was studied in 301 randomized patients. Changes in lipid profile and lipoprotein particle size and particle number were assessed at weeks 12 and 24, and associations with clinical efficacy were evaluated. Apolipoproteins were assessed at weeks 4 and 12 in the placebo group and the 4-mg and 8-mg baricitinib groups.Treatment with baricitinib resulted in dose-dependent increases in serum lipid levels from baseline to week 12 (low-density lipoprotein [LDL] cholesterol increases of 3.4 mg/dl and 11.8 mg/dl in the 1 mg and 8 mg treatment groups, respectively; high-density lipoprotein [HDL] cholesterol increases of 3.3 mg/dl and 8.1 mg/dl, respectively; triglycerides increases of 6.4 mg/dl and 15.4 mg/dl, respectively). Group-wise mean increases in LDL cholesterol were coincident with mean increases in large LDL particles and mean reductions in small dense LDL particles. Increases from baseline to week 12 in apolipoprotein A-I, apolipoprotein B, and apolipoprotein CIII were observed with 4-mg doses of baricitinib (9.5%, 6.8%, and 23.0%, respectively) and with 8-mg doses (12.2%, 7.1%, and 19.7%, respectively), with no increase in LDL-associated apolipoprotein CIII (-4.5% with 4-mg baricitinib; -9.0% with 8-mg baricitinib). Baricitinib reduced HDL-associated serum amyloid A when administered at 4 mg (-36.0%) and 8 mg (-32.0%); a significant reduction in lipoprotein (a) was observed only with 8-mg doses (-16.6%). Increased HDL cholesterol at week 12 correlated with improved Disease Activity Scores and Simplified Disease Activity Index; changes in total cholesterol, LDL cholesterol, and triglycerides did not reveal a similar relationship.Baricitinib-associated increases in serum lipid levels were observed in this study. Increases in levels of HDL cholesterol correlated with improved clinical outcomes.

  View details for DOI 10.1002/art.40036

  View details for Web of Science ID 000400068300009

• Effects of Baricitinib on Lipid, Apolipoprotein, and Lipoprotein Particle Profiles in a Phase IIb Study of Patients With Active Rheumatoid Arthritis. Arthritis & rheumatology (Hoboken, N.J.) Kremer, J. M., Genovese, M. C., Keystone, E., Taylor, P. C., Zuckerman, S. H., Ruotolo, G., Schlichting, D. E., Crotzer, V. L., Nantz, E., Beattie, S. D., Macias, W. L. 2017; 69 (5): 943-952

  Abstract

  To assess the effects of baricitinib on lipid profiles in patients with moderate-to-severe rheumatoid arthritis.Treatment with once-daily doses of baricitinib (1, 2, 4, or 8 mg) or placebo was studied in 301 randomized patients. Changes in lipid profile and lipoprotein particle size and particle number were assessed at weeks 12 and 24, and associations with clinical efficacy were evaluated. Apolipoproteins were assessed at weeks 4 and 12 in the placebo group and the 4-mg and 8-mg baricitinib groups.Treatment with baricitinib resulted in dose-dependent increases in serum lipid levels from baseline to week 12 (low-density lipoprotein [LDL] cholesterol increases of 3.4 mg/dl and 11.8 mg/dl in the 1 mg and 8 mg treatment groups, respectively; high-density lipoprotein [HDL] cholesterol increases of 3.3 mg/dl and 8.1 mg/dl, respectively; triglycerides increases of 6.4 mg/dl and 15.4 mg/dl, respectively). Group-wise mean increases in LDL cholesterol were coincident with mean increases in large LDL particles and mean reductions in small dense LDL particles. Increases from baseline to week 12 in apolipoprotein A-I, apolipoprotein B, and apolipoprotein CIII were observed with 4-mg doses of baricitinib (9.5%, 6.8%, and 23.0%, respectively) and with 8-mg doses (12.2%, 7.1%, and 19.7%, respectively), with no increase in LDL-associated apolipoprotein CIII (-4.5% with 4-mg baricitinib; -9.0% with 8-mg baricitinib). Baricitinib reduced HDL-associated serum amyloid A when administered at 4 mg (-36.0%) and 8 mg (-32.0%); a significant reduction in lipoprotein (a) was observed only with 8-mg doses (-16.6%). Increased HDL cholesterol at week 12 correlated with improved Disease Activity Scores and Simplified Disease Activity Index; changes in total cholesterol, LDL cholesterol, and triglycerides did not reveal a similar relationship.Baricitinib-associated increases in serum lipid levels were observed in this study. Increases in levels of HDL cholesterol correlated with improved clinical outcomes.

  View details for DOI 10.1002/art.40036

  View details for PubMedID 28029752

• Peficitinib, a JAK Inhibitor, in the Treatment of Moderate-to-Severe Rheumatoid Arthritis in Patients With an Inadequate Response to Methotrexate ARTHRITIS & RHEUMATOLOGY Kivitz, A. J., Gutierrez-Urena, S. R., Poiley, J., Genovese, M. C., Kristy, R., Shay, K., Wang, X., Garg, J. P., Zubrzycka-Sienkiewicz, A. 2017; 69 (4): 709-719

  View details for DOI 10.1002/art.39955

  View details for Web of Science ID 000397615900003

• Patient-reported outcomes from a randomised phase III study of baricitinib in patients with rheumatoid arthritis and an inadequate response to biological agents (RA-BEACON). Annals of the rheumatic diseases Smolen, J. S., Kremer, J. M., Gaich, C. L., DeLozier, A. M., Schlichting, D. E., Xie, L., Stoykov, I., Rooney, T., Bird, P., Sánchez Bursón, J. M., Genovese, M. C., Combe, B. 2017; 76 (4): 694-700

  Abstract

  To assess baricitinib on patient-reported outcomes (PROs) in patients with moderately to severely active rheumatoid arthritis, who had insufficient response or intolerance to ≥1 tumour necrosis factor inhibitors (TNFis) or other biological disease-modifying antirheumatic drugs (bDMARDs).In this double-blind phase III study, patients were randomised to once-daily placebo or baricitinib 2 or 4 mg for 24 weeks. PROs included the Short Form-36, EuroQol 5-D, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient's Global Assessment of Disease Activity (PtGA), patient's assessment of pain, duration of morning joint stiffness (MJS) and Work Productivity and Activity Impairment Questionnaire-Rheumatoid Arthritis. Treatment comparisons were performed with logistic regression for categorical measures or analysis of covariance for continuous variables.527 patients were randomised (placebo, 176; baricitinib 2 mg, 174; baricitinib 4 mg, 177). Both baricitinib-treated groups showed statistically significant improvements versus placebo in most PROs. Improvements were generally more rapid and of greater magnitude for patients receiving baricitinib 4 mg than 2 mg and were maintained to week 24. At week 24, more baricitinib-treated patients versus placebo-treated patients reported normal physical functioning (HAQ-DI <0.5; p≤0.001), reductions in fatigue (FACIT-F ≥3.56; p≤0.05), improvements in PtGA (p≤0.001) and pain (p≤0.001) and reductions in duration of MJS (p<0.01).Baricitinib improved most PROs through 24 weeks compared with placebo in this study of treatment-refractory patients with previously inadequate responses to bDMARDs, including at least one TNFi. PRO results aligned with clinical efficacy data for baricitinib.NCT01721044; Results.

  View details for DOI 10.1136/annrheumdis-2016-209821

  View details for PubMedID 27799159

  View details for PubMedCentralID PMC5530360

• RADIOGRAPHIC OUTCOMES IN PATIENTS ACHIEVING CLINICAL REMISSION OR LOW DISEASE ACTIVITY IN A PHASE 3 STUDY OF SARILUMAB PLUS METHOTREXATE IN PATIENTS WITH ACTIVE, MODERATE TO SEVERE RHEUMATOID ARTHRITIS van Hoogstraten, H., Mangan, E. K., Fay, J., van Adelsberg, J., Fan, C., Genovese, M. C. OXFORD UNIV PRESS. 2017: 204–5

  View details for Web of Science ID 000408202100527

• SARILUMAB DOSE REDUCTION IN AN OPEN-LABEL EXTENSION STUDY IN RHEUMATOID ARTHRITIS PATIENTS Genovese, M. C., Fay, J., Parrino, J., Beyer, D., Iglesias-Rodriguez, M., Graham, N., Boddy, A., Martincova, R., Burmester, G. R. OXFORD UNIV PRESS. 2017: 139

  View details for Web of Science ID 000408202100360

• CLINICAL AND RADIOGRAPHIC OUTCOMES AFTER 3 YEARS OF SARILUMAB IN PATIENTS WITH RHEUMATOID ARTHRITIS Genovese, M. C., van Adelsberg, J., van Hoogstraten, H., Iglesias-Rodriguez, M., Mangan, E. K., Graham, N., Spindler, A. OXFORD UNIV PRESS. 2017: 27–28

  View details for Web of Science ID 000408202100096

• EFFICACY AND SAFETY OF SARILUMAB IN SUBGROUPS OF PATIENTS WITH RHEUMATOID ARTHRITIS FROM 2 PHASE 3 STUDIES Genovese, M. C., Fleischmann, R., Mangan, E. K., van Adelsberg, J., Iglesias-Rodriguez, M., Fan, C., Huizinga, T. W. OXFORD UNIV PRESS. 2017: 137–38

  View details for Web of Science ID 000408202100356

• Effect of tocilizumab on neutrophils in adult patients with rheumatoid arthritis: pooled analysis of data from phase 3 and 4 clinical trials RHEUMATOLOGY Moots, R. J., Sebba, A., Rigby, W., Ostor, A., Porter-Brown, B., Donaldson, F., Dimonaco, S., Rubbert-Roth, A., van Vollenhoven, R., Genovese, M. C. 2017; 56 (4): 541-549

  Abstract

  To investigate changes in neutrophil count and occurrences of infection in RA patients treated with the IL-6 receptor-α inhibitor tocilizumab (TCZ).Data were pooled from patients who received i.v. TCZ (4 mg/kg + MTX, 8 mg/kg ± DMARDs, 10 mg/kg) or placebo + DMARDs in phase 3/4 clinical trials, long-term extensions or a pharmacology study. Neutrophil counts were measured routinely according to the Common Toxicity Criteria for Adverse Events grades; TCZ dosing was adjusted if necessary. Covariates associated with decreased neutrophil counts were assessed with multivariate regression analysis. Infection rates within 30 days of neutrophil count changes were calculated per 100 patient-years of TCZ exposure.In placebo-controlled parts of trials, more TCZ-treated than placebo-treated patients had grade 1/2 or 3/4 neutrophil counts (TCZ: 28.2%/3.1%; placebo: 8.9%/0.2%). In placebo-controlled trials + long-term extensions, 4171 patients provided 16204.8 patient-years of TCZ exposure. Neutrophil counts decreased through week 6 from baseline [mean ( s . d .) change, -2.17 (2.16) × 10 9 /l) and remained stable thereafter. Rates (95% CI) of serious infections within 30 days of normal [4.66 (4.31, 5.03)], grade 1/2 [2.48 (1.79, 3.34)] and 3/4 [2.77 (0.34, 10.01)] neutrophil counts were similar. Baseline neutrophil count <2 × 10 9 /l and female gender were associated with grade 3/4 neutrophil counts [odds ratio (OR) (95% CI): 19.02 (6.76, 53.52), 2.55 (1.40, 4.66)]. Patients who stopped TCZ in response to decreased neutrophil count returned more quickly to normal levels than patients who reduced or continued their dose.Decreases in neutrophil counts in patients taking TCZ do not appear to be associated with serious infections and are normalized by current risk mitigation guidelines.

  View details for DOI 10.1093/rheumatology/kew370

  View details for Web of Science ID 000398497700008

  View details for PubMedCentralID PMC5410975

• Patient-reported outcomes from a randomised phase III study of baricitinib in patients with rheumatoid arthritis and an inadequate response to biological agents (RA-BEACON) ANNALS OF THE RHEUMATIC DISEASES Smolen, J. S., Kremer, J. M., Gaich, C. L., DeLozier, A. M., Schlichting, D. E., Xie, L., Stoykov, I., Rooney, T., Bird, P., Sanchez Burson, J. M., Genovese, M. C., Combe, B. 2017; 76 (4)

  Abstract

  To assess baricitinib on patient-reported outcomes (PROs) in patients with moderately to severely active rheumatoid arthritis, who had insufficient response or intolerance to ≥1 tumour necrosis factor inhibitors (TNFis) or other biological disease-modifying antirheumatic drugs (bDMARDs).In this double-blind phase III study, patients were randomised to once-daily placebo or baricitinib 2 or 4 mg for 24 weeks. PROs included the Short Form-36, EuroQol 5-D, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient's Global Assessment of Disease Activity (PtGA), patient's assessment of pain, duration of morning joint stiffness (MJS) and Work Productivity and Activity Impairment Questionnaire-Rheumatoid Arthritis. Treatment comparisons were performed with logistic regression for categorical measures or analysis of covariance for continuous variables.527 patients were randomised (placebo, 176; baricitinib 2 mg, 174; baricitinib 4 mg, 177). Both baricitinib-treated groups showed statistically significant improvements versus placebo in most PROs. Improvements were generally more rapid and of greater magnitude for patients receiving baricitinib 4 mg than 2 mg and were maintained to week 24. At week 24, more baricitinib-treated patients versus placebo-treated patients reported normal physical functioning (HAQ-DI <0.5; p≤0.001), reductions in fatigue (FACIT-F ≥3.56; p≤0.05), improvements in PtGA (p≤0.001) and pain (p≤0.001) and reductions in duration of MJS (p<0.01).Baricitinib improved most PROs through 24 weeks compared with placebo in this study of treatment-refractory patients with previously inadequate responses to bDMARDs, including at least one TNFi. PRO results aligned with clinical efficacy data for baricitinib.NCT01721044; Results.

  View details for DOI 10.1136/annrheumdis-2016-209821

  View details for Web of Science ID 000396856100013

  View details for PubMedCentralID PMC5530360

• Adalimumab long-term safety: infections, vaccination response and pregnancy outcomes in patients with rheumatoid arthritis ANNALS OF THE RHEUMATIC DISEASES Burmester, G. R., Landew, R., Genovese, M. C., Friedman, A. W., Pfeifer, N. D., Varothai, N. A., Lacerda, A. P. 2017; 76 (2): 414-417

  Abstract

  Adalimumab has been used in patients with moderately to severely active rheumatoid arthritis (RA) for over 10 years and has a well-established safety profile across multiple indications.To update adverse events (AEs) of special interest from global adalimumab clinical trials in patients with RA.This analysis includes 15 132 patients exposed to adalimumab in global RA clinical trials. AEs of interest included overall infections, laboratory abnormalities and AEs associated with influenza vaccination. Pregnancy outcome data were collected from the Adalimumab Pregnancy Registry.Serious infections and tuberculosis occurred at a rate of 4.7 and 0.3 events/100 patient-years, respectively. Two patients experienced hepatitis B reactivation. No significant laboratory abnormalities were reported with adalimumab-plus-methotrexate compared with placebo-plus-methotrexate. Influenza-related AEs occurred in 5% of vaccinated patients compared with 14% of patients not vaccinated during the study. Relative risk of major birth defects and spontaneous abortions in adalimumab-exposed women were similar between that of unexposed women with RA and healthy women.This analysis confirms and expands the known safety profile of adalimumab and reports no additional safety risk of laboratory abnormalities, hepatitis B reactivation and pregnancy outcomes, including spontaneous abortions and birth defects. The benefits of influenza vaccination are reinforced.NCT00195663, NCT00195702, NCT00448383, NCT00049751, NCT00234845, NCT00650390, NCT00235859, NCT00647920, NCT00649545, NCT00647491, NCT00649922, NCT00538902, NCT00420927, NCT00870467, NCT00650156, NCT00647270, NCT01185288, NCT01185301.

  View details for DOI 10.1136/annrheumdis-2016-209322

  View details for Web of Science ID 000392426900014

  View details for PubMedCentralID PMC5284339

• Adalimumab long-term safety: infections, vaccination response and pregnancy outcomes in patients with rheumatoid arthritis. Annals of the rheumatic diseases Burmester, G. R., Landewé, R., Genovese, M. C., Friedman, A. W., Pfeifer, N. D., Varothai, N. A., Lacerda, A. P. 2017; 76 (2): 414-417

  Abstract

  Adalimumab has been used in patients with moderately to severely active rheumatoid arthritis (RA) for over 10 years and has a well-established safety profile across multiple indications.To update adverse events (AEs) of special interest from global adalimumab clinical trials in patients with RA.This analysis includes 15 132 patients exposed to adalimumab in global RA clinical trials. AEs of interest included overall infections, laboratory abnormalities and AEs associated with influenza vaccination. Pregnancy outcome data were collected from the Adalimumab Pregnancy Registry.Serious infections and tuberculosis occurred at a rate of 4.7 and 0.3 events/100 patient-years, respectively. Two patients experienced hepatitis B reactivation. No significant laboratory abnormalities were reported with adalimumab-plus-methotrexate compared with placebo-plus-methotrexate. Influenza-related AEs occurred in 5% of vaccinated patients compared with 14% of patients not vaccinated during the study. Relative risk of major birth defects and spontaneous abortions in adalimumab-exposed women were similar between that of unexposed women with RA and healthy women.This analysis confirms and expands the known safety profile of adalimumab and reports no additional safety risk of laboratory abnormalities, hepatitis B reactivation and pregnancy outcomes, including spontaneous abortions and birth defects. The benefits of influenza vaccination are reinforced.NCT00195663, NCT00195702, NCT00448383, NCT00049751, NCT00234845, NCT00650390, NCT00235859, NCT00647920, NCT00649545, NCT00647491, NCT00649922, NCT00538902, NCT00420927, NCT00870467, NCT00650156, NCT00647270, NCT01185288, NCT01185301.

  View details for DOI 10.1136/annrheumdis-2016-209322

  View details for PubMedID 27338778

  View details for PubMedCentralID PMC5284339

• Peficitinib, a JAK inhibitor, in combination with limited conventional synthetic DMARDs in the treatment of moderate-to-severe rheumatoid arthritis. Arthritis & rheumatology (Hoboken, N.J.) Genovese, M. C., Greenwald, M., Codding, C., Zubrzycka-Sienkiewicz, A., Kivitz, A. J., Wang, A., Shay, K., Wang, X., Garg, J. P., Cardiel, M. H. 2017

  Abstract

  To evaluate the efficacy and safety of orally administered once-daily peficitinib in combination with limited conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in patients with moderate-to-severe rheumatoid arthritis (RA).In this randomized, double-blind, phase IIb trial, patients with RA (n = 289) were treated with peficitinib 25 mg, 50 mg, 100 mg, or 150 mg or matching placebo once daily for 12 weeks. The primary end point was the percentage of patients who met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at week 12.ACR20 response rates at week 12 were 22.0%, 36.8%, 48.3% (P < 0.05), 56.3% (P < 0.01), and 29.4% in the peficitinib 25 mg, 50 mg, 100 mg, 150 mg, and placebo groups, respectively. Patients in the peficitinib 100 mg and 150 mg groups achieved a rapid and statistically significant ACR20 response compared with those in the placebo group (P < 0.05), reaching statistical significance by week 2. Overall, the incidence of adverse events (AEs) was similar between patients receiving peficitinib and those receiving placebo. The most common AEs were upper respiratory tract infection (5% [n = 15]), nausea (4% [n = 12]), and urinary tract infection (4% [n = 10]). There was 1 case of herpes zoster in the placebo group, and 1 serious infection (limb abscess) in the peficitinib 25 mg group. There were no incidences of grade 2 or higher neutropenia or lymphopenia.In patients with moderate-to-severe RA, orally administered once-daily peficitinib in combination with limited csDMARDs resulted in a dose-dependent ACR20 response rate over 12 weeks with satisfactory tolerability.

  View details for DOI 10.1002/art.40054

  View details for PubMedID 28118538

• Effect of tocilizumab on neutrophils in adult patients with rheumatoid arthritis: pooled analysis of data from phase 3 and 4 clinical trials. Rheumatology (Oxford, England) Moots, R. J., Sebba, A., Rigby, W., Ostor, A., Porter-Brown, B., Donaldson, F., Dimonaco, S., Rubbert-Roth, A., van Vollenhoven, R., Genovese, M. C. 2016

  Abstract

  To investigate changes in neutrophil count and occurrences of infection in RA patients treated with the IL-6 receptor-α inhibitor tocilizumab (TCZ).Data were pooled from patients who received i.v. TCZ (4 mg/kg + MTX, 8 mg/kg ± DMARDs, 10 mg/kg) or placebo + DMARDs in phase 3/4 clinical trials, long-term extensions or a pharmacology study. Neutrophil counts were measured routinely according to the Common Toxicity Criteria for Adverse Events grades; TCZ dosing was adjusted if necessary. Covariates associated with decreased neutrophil counts were assessed with multivariate regression analysis. Infection rates within 30 days of neutrophil count changes were calculated per 100 patient-years of TCZ exposure.In placebo-controlled parts of trials, more TCZ-treated than placebo-treated patients had grade 1/2 or 3/4 neutrophil counts (TCZ: 28.2%/3.1%; placebo: 8.9%/0.2%). In placebo-controlled trials + long-term extensions, 4171 patients provided 16204.8 patient-years of TCZ exposure. Neutrophil counts decreased through week 6 from baseline [mean ( s . d .) change, -2.17 (2.16) × 10 9 /l) and remained stable thereafter. Rates (95% CI) of serious infections within 30 days of normal [4.66 (4.31, 5.03)], grade 1/2 [2.48 (1.79, 3.34)] and 3/4 [2.77 (0.34, 10.01)] neutrophil counts were similar. Baseline neutrophil count <2 × 10 9 /l and female gender were associated with grade 3/4 neutrophil counts [odds ratio (OR) (95% CI): 19.02 (6.76, 53.52), 2.55 (1.40, 4.66)]. Patients who stopped TCZ in response to decreased neutrophil count returned more quickly to normal levels than patients who reduced or continued their dose.Decreases in neutrophil counts in patients taking TCZ do not appear to be associated with serious infections and are normalized by current risk mitigation guidelines.

  View details for DOI 10.1093/rheumatology/kew370

  View details for PubMedID 28013198

  View details for PubMedCentralID PMC5410975

• Efficacy and Safety of ABT-494, a Selective JAK-1 Inhibitor, in a Phase IIb Study in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate ARTHRITIS & RHEUMATOLOGY Genovese, M. C., Smolen, J. S., Weinblatt, M. E., Burmester, G. R., Meerwein, S., Camp, H. S., Wang, L., Othman, A. A., Khan, N., Pangan, A. L., Jungerwirth, S. 2016; 68 (12): 2857-2866

  Abstract

  To evaluate the efficacy and safety of ABT-494, a selective JAK-1 inhibitor, in patients with moderate-to-severe rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX).Three hundred RA patients receiving stable doses of MTX were randomly assigned equally to receive immediate-release ABT-494 at 3, 6, 12, or 18 mg twice daily, 24 mg once daily, or placebo for 12 weeks. The primary efficacy end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 12, as determined using the last observation carried forward method.At week 12, the proportion of ACR20 responses was higher with ABT-494 (62%, 68%, 80%, 64%, and 76% for the 3, 6, 12, 18, and 24 mg doses, respectively) than with placebo (46%) (using nonresponder imputation) (P < 0.05 for the 6, 12, and 24 mg doses). There was a significant dose-response relationship among all ABT-494 doses (P < 0.001). The proportions of patients achieving ACR50 and ACR70 responses were significantly higher for all ABT-494 doses (except the 12 mg dose for the ACR70 response) than for placebo, as were changes in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP). Rapid improvement was demonstrated by significant differences in ACR20 response rates and changes in the DAS28-CRP for all doses compared with placebo at week 2 (the first postbaseline visit). The incidence of adverse events was similar across groups; most were mild, and infections were the most frequent. One serious infection (community-acquired pneumonia) occurred with ABT-494 at 12 mg. There were dose-dependent increases in high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, but the LDL cholesterol:HDL cholesterol ratios were unchanged through week 12. Mean hemoglobin levels remained stable at lower doses, but decreases were observed at higher doses.This study evaluated a broad range of doses of ABT-494 in RA patients with an inadequate response to MTX. ABT-494 demonstrated efficacy, with a safety and tolerability profile similar to that of other JAK inhibitors.

  View details for DOI 10.1002/art.39808

  View details for Web of Science ID 000389153400006

  View details for PubMedID 27390150

  View details for PubMedCentralID PMC5132065

• Efficacy of VX-509 (decernotinib) in combination with a disease-modifying antirheumatic drug in patients with rheumatoid arthritis: clinical and MRI findings. Annals of the rheumatic diseases Genovese, M. C., Yang, F., Østergaard, M., Kinnman, N. 2016; 75 (11): 1979-1983

  Abstract

  To assess early effects on joint structures of VX-509 in combination with stable disease-modifying antirheumatic drug (DMARD) therapy using MRI in adults with rheumatoid arthritis (RA).This phase II, placebo-controlled, double-blind, dose-ranging study randomised patients with RA and inadequate DMARD response to VX-509 100 mg (n=11), 200 mg (n=10) or 300 mg (n=10) or placebo (n=12) once daily for 12 weeks. Outcome measures included American College of Rheumatology score (ACR20; improvement of ≥20%) and disease activity score (DAS28) using C reactive protein (CRP), and the RA MRI scoring (RAMRIS) system.ACR20 response at week 12 was 63.6%, 60.0% and 60.0% in the VX-509 100-mg, 200-mg and 300-mg groups, respectively, compared with 25.0% in the placebo group. DAS28-CRP scores decreased in a dose-dependent manner with increasing VX-509 doses. Decreases in RAMRIS synovitis scores were significantly different from placebo for all VX-509 doses (p<0.01) and for RAMRIS osteitis scores (p<0.01) for VX-509 300 mg. Treatment was generally well tolerated.VX-509 plus a DMARD reduced the signs and symptoms of RA in patients with an inadequate response to a DMARD alone. MRI responses were detected at week 12. Treatment was generally well tolerated.NCT01754935; results.

  View details for DOI 10.1136/annrheumdis-2015-208901

  View details for PubMedID 27084959

• Development of the American College of Rheumatology's Rheumatoid Arthritis Electronic Clinical Quality Measures ARTHRITIS CARE & RESEARCH Yazdany, J., Robbins, M., Schmajuk, G., DeSai, S., Lacaille, D., Neogi, T., Singh, J. A., Genovese, M., Myslinski, R., Fisk, N., Francisco, M., Newman, E. 2016; 68 (11): 1579-1590

  Abstract

  Electronic clinical quality measures (eCQMs) rely on computer algorithms to extract data from electronic health records (EHRs). On behalf of the American College of Rheumatology (ACR), we sought to develop and test eCQMs for rheumatoid arthritis (RA).Drawing from published ACR guidelines, a working group developed candidate RA process measures and subsequently assessed face validity through an interdisciplinary panel of health care stakeholders. A public comment period followed. Measures that passed these levels of review were electronically specified using the quality data model, which provides standard nomenclature for data elements (category, datatype, and value sets) obtained through an EHR. For each eCQM, 3 clinical sites using different EHR systems tested the scientific feasibility and validity of measures. Measures appropriate for accountability were presented for national endorsement.Expert panel validity ratings were high for all measures (median 8-9 of 9). Health system performance on the eCQMs was 53.6% for RA disease activity assessment, 69.1% for functional status assessment, 93.1% for disease-modifying antirheumatic drug (DMARD) use, and 72.8% for tuberculosis screening. Kappa statistics, which evaluated whether the eCQM validly captured data obtained from manual EHR chart review, demonstrated moderate to substantial agreement (0.54 for functional status assessment, 0.73 for tuberculosis screening, 0.84 for disease activity, and 0.85 for DMARD use).Four eCQMs for RA have achieved national endorsement and are recommended for use in federal quality reporting programs. Implementation and further refinement of these measures is ongoing in the ACR's registry, the Rheumatology Informatics System for Effectiveness (RISE).

  View details for DOI 10.1002/acr.22984

  View details for Web of Science ID 000387058800001

  View details for PubMedID 27564778

• Peficitinib, a JAK inhibitor, in the treatment of moderate-to-severe rheumatoid arthritis in methotrexate-inadequate responders. Arthritis & rheumatology Kivitz, A. J., Gutierrez-Ureña, S. R., Poiley, J., Genovese, M. C., Kristy, R., Shay, K., Wang, X., Garg, J. P., Zubrzycka-Sienkiewicz, A. 2016

  Abstract

  To evaluate efficacy and safety of orally administered once-daily peficitinib in combination with methotrexate (MTX) in patients with moderate-to-severe rheumatoid arthritis (RA) who had an inadequate response to MTX.In this multinational, phase IIb, randomized, double-blind, placebo-controlled, dose-ranging trial, patients with RA (N=378) were treated with peficitinib 25 mg, 50 mg, 100 mg, 150 mg + MTX, or matching placebo + MTX once daily for 12 weeks (NCT01554696). Primary endpoint was the percentage of patients achieving an American College of Rheumatology (ACR) 20% response at Week 12.ACR20 response rates at Week 12 were 43.9%, 61.5% (P<0.05), 46.4%, 57.7%, and 44.4% in the peficitinib 25 mg, 50 mg, 100 mg, 150 mg, and placebo groups, respectively. Significant decreases in DAS28-CRP levels were seen in peficitinib 50 mg (P<0.05) and 150 mg (P<0.01) groups compared with placebo. Overall, the incidence of adverse events (AEs) were similar between peficitinib and placebo. The most common AEs were urinary tract infection (22 [6%]), upper respiratory tract infection (16 [4%]), and diarrhea (16 [4%]). There were three cases of herpes zoster (peficitinib 100 mg [n=2] and 150 mg [n=1]) and two cases of serious infection (peficitinib 100 mg [viral infection] and 150 mg [erysipelas]).ACR20 response with peficitinib 50 mg + MTX was significantly different compared with placebo, but there were no apparent dose-dependent responses and the placebo response rate was high. Peficitinib + MTX in patients with moderate-to-severe RA was well tolerated with limited safety signals emerging. This article is protected by copyright. All rights reserved.

  View details for DOI 10.1002/art.39955

  View details for PubMedID 27748083

• Increased pretreatment serum IFN-/ ratio predicts non-response to tumour necrosis factor inhibition in rheumatoid arthritis ANNALS OF THE RHEUMATIC DISEASES Muskardin, T. W., Vashisht, P., Dorschner, J. M., Jensen, M. A., Chrabot, B. S., Kern, M., Curtis, J. R., Danila, M. I., Cofield, S. S., Shadick, N., Nigrovic, P. A., St Clair, E. W., Bingham, C. O., Furie, R., Robinson, W., Genovese, M., Striebich, C. C., O'Dell, J. R., Thiele, G. M., Moreland, L. W., Levesque, M., Bridges, S. L., Gregersen, P. K., Niewold, T. B. 2016; 75 (10): 1757-1762

  Abstract

  Studies suggest that circulating type I interferon (IFN) may predict response to biological agents in rheumatoid arthritis (RA). Prediction of response prior to initiating therapy would represent a major advancement.We studied sera from a test set of 32 patients with RA from the Auto-immune Biomarkers Collaborative Network Consortium and a validation set of 92 patients with RA from the Treatment Efficacy and Toxicity in Rheumatoid Arthritis Database and Repository registry. The test set included those with good response or no response to tumour necrosis factor (TNF) inhibitors at 14 weeks by European League Against Rheumatism criteria. The validation set included subjects with good, moderate or no response at 12 weeks. Total serum type I IFN activity, IFN-α and IFN-β activity were measured using a functional reporter cell assay.In the test set, an increased ratio of IFN-β to IFN-α (IFN-β/α activity ratio) in pretreatment serum associated with lack of response to TNF inhibition (p=0.013). Anti-cyclic citrullinated peptide antibody titre and class of TNF inhibitor did not influence this relationship. A receiver-operator curve supported a ratio of 1.3 as the optimal cut-off. In the validation set, subjects with an IFN-β/α activity ratio >1.3 were significantly more likely to have non-response than good response (OR=6.67, p=0.018). The test had 77% specificity and 45% sensitivity for prediction of non-response compared with moderate or good response. Meta-analysis of test and validation sets confirmed strong predictive capacity of IFN-β/α activity ratio (p=0.005).Increased pretreatment serum IFN-β/α ratio strongly associated with non-response to TNF inhibition. This study supports further investigation of serum type I IFN in predicting outcome of TNF inhibition in RA.

  View details for DOI 10.1136/annrheumdis-2015-208001

  View details for PubMedID 26546586

• Efficacy and Safety of Sarilumab in Subgroups of Patients with Rheumatoid Arthritis from 2 Phase 3 Studies Genovese, M. C., Fleischmann, R., Mangan, E., van Adelsberg, J., Iglesias-Rodriguez, M., Dukovic, D., Fan, C., Huizinga, T. J. WILEY. 2016

  View details for Web of Science ID 000417143402448

• The Effect of Filgotinib (GLPG0634), an Oral JAK1 Selective Inhibitor on Patient-Reported Outcomes: Results from Two 24-Week Phase 2B Dose Ranging Studies Genovese, M. C., Westhovens, R., Kavanaugh, A., Meuleners, L., Van der Aa, A., Harrison, P., Tasset, C. WILEY. 2016

  View details for Web of Science ID 000417143405149

• Olokizumab Treatment of Both Western and Asian Patients with Rheumatoid Arthritis Who Have Failed Anti-TNF Treatment Results in Sustained Improvements in Patient-Reported Outcomes Genovese, M. C., Durez, P., Fleischmann, R., Tanaka, Y., Furst, D. E., Yamanaka, H., Vasyutin, I., Kaviarasu, T., Korneva, E., Koloda, D., Takeuchi, T. WILEY. 2016

  View details for Web of Science ID 000417143402414

• Effects of Baseline Patient Characteristics on Baricitinib Efficacy in Patients with Rheumatoid Arthritis Kremer, J. M., Genovese, M. C., Muram, D., Zhong, J., Alam, J., Schiff, M. WILEY. 2016

  View details for Web of Science ID 000417143404261

• ABT-122, a Tnf- and IL-17-Targeted Dual Variable Domain (DVD)-Ig (TM) in Rheumatoid Arthritis Patients with Inadequate Response to Methotrexate: Results from a Phase 2 Trial Genovese, M. C., Weinblatt, M., Aelion, J. A., Mansikka, H. T., Peloso, P. M., Chen, K., Li, Y., Othman, A. A., Khatri, A., Khan, N. S., Padley, R. J. WILEY. 2016

  View details for Web of Science ID 000417143401055

• Safety and Efficacy of ABT-122, a TNF and IL-17-Targeted Dual Variable Domain (DVD)-Ig (TM), in Psoriatic Arthritis Patients with Inadequate Response to Methotrexate: Results from a Phase 2 Trial Mease, P. J., Genovese, M. C., Weinblatt, M., Peloso, P. M., Chen, K., Li, Y., Mansikka, H. T., Khatri, A., Othman, A. A., Wishart, N., Liu, J., Padley, R. J. WILEY. 2016

  View details for Web of Science ID 000417143401362

• Efficacy after Transition to SB5 from Reference Adalimumab (Humira (R)) Vs. Continuation of SB5 or Reference Adalimumab By Antibodies Developed after Transition from a SB5 Phase III Study Genovese, M. C., Weinblatt, M., Keystone, E. C., Baranauskaite, A., Cheong, S., Ghil, J. WILEY. 2016

  View details for Web of Science ID 000417143401028

• Dual Cytokine Inhibition with ABT-122, a Tnf- and IL-17-Targeted Dual Variable Domain Immunoglobulin (DVD-Ig (TM)): Results from a 24-Week Open-Label Extension Study in Patients with Rheumatoid Arthritis Genovese, M. C., Weinblatt, M., Mansikka, H. T., Peloso, P. M., Chen, K., Li, Y., Liu, J., Padley, R. J. WILEY. 2016

  View details for Web of Science ID 000417143405348

• Clinical and Radiographic Outcomes after 3 Years of Sarilumab in Patients with Rheumatoid Arthritis van der Heijde, D., van Adelsberg, J., van Hoogstraten, H., Iglesias-Rodriguez, M., Mangan, E., Graham, N., Dukovic, D., Spindler, A., Genovese, M. C. WILEY. 2016

  View details for Web of Science ID 000417143402449

• Pooled Safety and Efficacy of Sarilumab in Rheumatoid Arthritis Patients 65 Years of Age and Older Fleischmann, R., Genovese, M. C., van Adelsberg, J., Mangan, E., Iglesias-Rodriguez, M., Dukovic, D., Huizinga, T. J. WILEY. 2016

  View details for Web of Science ID 000417143402421

• Sarilumab Dose Reduction in an Open-Label Extension Study in RA Patients Genovese, M. C., Fay, J., Parrino, J., Beyer, D., Iglesias-Rodriguez, M., Graham, N., Boddy, A., Simon, J., Martincova, R., Burmester, G. R. WILEY. 2016

  View details for Web of Science ID 000417143402447

• Switching from adalimumab to tofacitinib in the treatment of patients with rheumatoid arthritis ARTHRITIS RESEARCH & THERAPY Genovese, M. C., Van Vollenhoven, R. F., Wilkinson, B., Wang, L., Zwillich, S. H., Gruben, D., Biswas, P., Riese, R., Takiya, L., Jones, T. V. 2016; 18

  Abstract

  Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). The aim of this study was to explore the safety and efficacy of open-label tofacitinib following blinded treatment with adalimumab or tofacitinib for moderate to severe RA.Analyses included patients treated with adalimumab 40 mg once every 2 weeks or tofacitinib 10 mg twice daily (BID) with background methotrexate (MTX) in a 12-month randomized study (NCT00853385), who subsequently received tofacitinib 10 mg BID (with/without background MTX) in an open-label extension (NCT00413699). Patients with treatment-related serious adverse events (AEs) and serious or recurrent infections in the index study were excluded from the extension study. Exposure-adjusted incidence rates of safety-related events were assessed in 3-month and 12-month periods in the year before and in the year after switching. Efficacy was assessed 3 months before, at the time of, and 3 months after switching.There were 233 (107 adalimumab to tofacitinib 10 mg BID, 126 blinded to open-label tofacitinib 10 mg BID) patients included in these analyses. Patients in both treatment sequences had similar incidence rates (per 100 patient-years) of discontinuation due to AEs, serious AEs, and serious infections in the year before and in the year after switching. Incidence rates of AEs were increased in the first 3 months after switching compared with the last 3 months before switching in both treatment groups. Switching from either blinded adalimumab or tofacitinib to open-label tofacitinib resulted in numerically higher incidence of responders for signs and symptoms of disease and improved physical function.Treatment can be directly switched from adalimumab to tofacitinib. A similar safety and efficacy profile was seen when patients received open-label tofacitinib after receiving either blinded adalimumab or tofacitinib.ClinicalTrials.gov Identifiers: NCT00853385 , registered 27 February 2009; NCT00413699 , registered 18 December 2006.

  View details for DOI 10.1186/s13075-016-1049-3

  View details for Web of Science ID 000378589700001

  View details for PubMedID 27334658

  View details for PubMedCentralID PMC4918072

• Baricitinib, an Oral Janus Kinase (JAK) 1/JAK2 Inhibitor, in Patients with Active Rheumatoid Arthritis (RA) and an Inadequate Response to TNF Inhibitors: Results of the Phase 3 RA-BEACON Study Genovese, M., Kremer, J., Zamani, O., Ludivico, C., Krogulec, M., Xie, L., Beattie, S., Koch, A., Cardillo, T., Rooney, T., Macias, W., Schlichting, D., Smolen, J., Bookman, A. J RHEUMATOL PUBL CO. 2016: 1188

  View details for Web of Science ID 000380879100134

• Clinical and Radiographic Efficacy of Sarilumab Plus Methotrexate in Biologic-Experienced and Biologic-Naive Patients with Rheumatoid Arthritis in a Phase 3, Randomized, Double-blind, Placebo-Controlled Study Fiore, S., Genovese, M., Fan, C., Decktor, D., Fleischmann, R. J RHEUMATOL PUBL CO. 2016: 1217

  View details for Web of Science ID 000380879100214

• Antibody response to pneumococcal and influenza vaccination in patients with rheumatoid arthritis receiving abatacept BMC MUSCULOSKELETAL DISORDERS Alten, R., Bingham, C. O., Cohen, S. B., Curtis, J. R., Kelly, S., Wong, D., Genovese, M. C. 2016; 17

  Abstract

  Patients with rheumatoid arthritis (RA), including those treated with biologics, are at increased risk of some vaccine-preventable infections. We evaluated the antibody response to standard 23-valent pneumococcal polysaccharide vaccine (PPSV23) and the 2011-2012 trivalent seasonal influenza vaccine in adults with RA receiving subcutaneous (SC) abatacept and background disease-modifying anti-rheumatic drugs (DMARDs).Two multicenter, open-label sub-studies enrolled patients from the ACQUIRE (pneumococcal and influenza) and ATTUNE (pneumococcal) studies at any point during their SC abatacept treatment cycle following completion of ≥3 months' SC abatacept. All patients received fixed-dose abatacept 125 mg/week with background DMARDs. A pre-vaccination blood sample was taken, and after 28 ± 3 days a final post-vaccination sample was collected. The primary endpoint was the proportion of patients achieving an immunologic response to the vaccine at Day 28 among patients without a protective antibody level to the vaccine antigens at baseline (pneumococcal: defined as ≥2-fold increase in post-vaccination titers to ≥3 of 5 antigens and protective antibody level of ≥1.6 μg/mL to ≥3 of 5 antigens; influenza: defined as ≥4-fold increase in post-vaccination titers to ≥2 of 3 antigens and protective antibody level of ≥1:40 to ≥2 of 3 antigens). Safety and tolerability were evaluated throughout the sub-studies.Pre- and post-vaccination titers were available for 113/125 and 186/191 enrolled patients receiving the PPSV23 and influenza vaccine, respectively. Among vaccinated patients, 47/113 pneumococcal and 121/186 influenza patients were without protective antibody levels at baseline. Among patients with available data, 73.9 % (34/46) and 61.3 % (73/119) met the primary endpoint and achieved an immunologic response to PPSV23 or influenza vaccine, respectively. In patients with pre- and post-vaccination data available, 83.9 % in the pneumococcal study demonstrated protective antibody levels with PPSV23 (titer ≥1.6 μg/mL to ≥3 of 5 antigens), and 81.2 % in the influenza study achieved protective antibody levels (titer ≥1:40 to ≥2 of 3 antigens) at Day 28 post-vaccination. Vaccines were well tolerated with SC abatacept with background DMARDs.In these sub-studies, patients with RA receiving SC abatacept and background DMARDs were able to mount an appropriate immune response to pneumococcal and influenza vaccines.NCT00559585 (registered 15 November 2007) and NCT00663702 (registered 18 April 2008).

  View details for DOI 10.1186/s12891-016-1082-z

  View details for PubMedID 27229685

• Effects of the oral Janus kinase inhibitor tofacitinib on patient-reported outcomes in patients with active rheumatoid arthritis: results of two Phase 2 randomised controlled trials CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Wallenstein, G. V., Kanik, K. S., Wilkinson, B., Cohen, S., Cutolo, M., Fleischmann, R., Genovese, M. C., Gomez Reino, J., Gruben, D., Kremer, J., Krishnaswami, S., Lee, E. B., Pascual-Ramos, V., Strand, V., Zwillich, S. H. 2016; 34 (3): 430-442

  Abstract

  Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here we investigated the effects of tofacitinib on patient-reported outcomes (PRO) in patients with active RA.Two, 6-month, double-blind, placebo-controlled Phase 2b studies were performed. The combination study evaluated patients with inadequate response to methotrexate who received tofacitinib 1-15 mg twice daily (BID), 20 mg once daily or placebo, on background methotrexate. In the monotherapy study, patients with inadequate response to disease-modifying anti-rheumatic drugs received tofacitinib 1-15 mg BID, adalimumab 40 mg once every other week or placebo. PROs measured were: Patient's Assessment of Arthritis Pain (PAAP), Patient's Assessment of Disease Activity, HAQ-DI, FACIT-F and SF-36.In the combination study (n=507), significant improvements (p<0.05) versus placebo were observed at Week 12 in PAAP (visual analogue scale) and HAQ-DI for all tofacitinib groups. In the monotherapy study (n=384), significant improvements in PAAP were observed at Week 12 for tofacitinib 5, 10 and 15 mg BID, and in HAQ-DI for tofacitinib 3, 5, 10 and 15 mg BID. Significant improvements versus placebo were seen at Week 2 in PAAP (both studies) and HAQ‑DI (monotherapy study) with tofacitinib, and were maintained throughout each study. In both studies, improvements in several domains of the SF-36 in the tofacitinib groups were observed at Weeks 12 and 24.In patients with active RA, tofacitinib, either in combination with methotrexate or as monotherapy, demonstrated rapid and sustained improvement in pain, physical functioning and health-related quality of life.

  View details for Web of Science ID 000376977900009

• Effects of the oral Janus kinase inhibitor tofacitinib on patient-reported outcomes in patients with active rheumatoid arthritis: results of two Phase 2 randomised controlled trials. Clinical and experimental rheumatology Wallenstein, G. V., Kanik, K. S., Wilkinson, B., Cohen, S., Cutolo, M., Fleishmann, R., Genovese, M. C., Gomez reino, J., Gruben, D., Kremer, J., Krishnaswami, S., Lee, E. B., Pascual-Ramos, V., Strand, V., Zwillich, S. H. 2016; 34 (3): 430-442

  Abstract

  Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Here we investigated the effects of tofacitinib on patient-reported outcomes (PRO) in patients with active RA.Two, 6-month, double-blind, placebo-controlled Phase 2b studies were performed. The combination study evaluated patients with inadequate response to methotrexate who received tofacitinib 1-15 mg twice daily (BID), 20 mg once daily or placebo, on background methotrexate. In the monotherapy study, patients with inadequate response to disease-modifying anti-rheumatic drugs received tofacitinib 1-15 mg BID, adalimumab 40 mg once every other week or placebo. PROs measured were: Patient's Assessment of Arthritis Pain (PAAP), Patient's Assessment of Disease Activity, HAQ-DI, FACIT-F and SF-36.In the combination study (n=507), significant improvements (p<0.05) versus placebo were observed at Week 12 in PAAP (visual analogue scale) and HAQ-DI for all tofacitinib groups. In the monotherapy study (n=384), significant improvements in PAAP were observed at Week 12 for tofacitinib 5, 10 and 15 mg BID, and in HAQ-DI for tofacitinib 3, 5, 10 and 15 mg BID. Significant improvements versus placebo were seen at Week 2 in PAAP (both studies) and HAQ‑DI (monotherapy study) with tofacitinib, and were maintained throughout each study. In both studies, improvements in several domains of the SF-36 in the tofacitinib groups were observed at Weeks 12 and 24.In patients with active RA, tofacitinib, either in combination with methotrexate or as monotherapy, demonstrated rapid and sustained improvement in pain, physical functioning and health-related quality of life.

  View details for PubMedID 27156561

• SARILUMAB DOSE REDUCTION TO MANAGE LABORATORY ABNORMALITIES IN AN OPEN-LABEL EXTENSION STUDY IN RA PATIENTS Burmester, G. R., Garg, A., Van Hoogstraten, H., Graham, N., Boddy, A., Parrino, J., Genovese, M. C. WILEY-BLACKWELL. 2016: 40–41

  View details for Web of Science ID 000375046500119

• EFFICACY AND SAFETY OF SARILUMAB PLUS METHOTREXATE IN PATIENTS WITH RHEUMATOID ARTHRITIS USING BIOLOGICS AND IN THOSE WHO ARE BIOLOGIC-NAIVE Fleischmann, R., Genovese, M., Fan, C., Fiore, S., Decktor, D. LIPPINCOTT WILLIAMS & WILKINS. 2016: 122

  View details for Web of Science ID 000373236400040

• IMMUNOGENICITY OF SUBCUTANEOUS AND INTRAVENOUS TOCILIZUMAB AS MONOTHERAPY OR IN COMBINATION WITH DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS IN RHEUMATOID ARTHRITIS Genovese, M. C., Ogata, A., Nomura, A., Bao, M., Hitraya, E., Lacey, S., Burmester, G. R. OXFORD UNIV PRESS. 2016: 92–93

  View details for Web of Science ID 000376656000242

• Baricitinib in Patients with Refractory Rheumatoid Arthritis NEW ENGLAND JOURNAL OF MEDICINE Genovese, M. C., Kremer, J., Zamani, O., Ludivico, C., Krogulec, M., Xie, L., Beattie, S. D., Koch, A. E., Cardillo, T. E., Rooney, T. P., Macias, W. L., de Bono, S., Schlichting, D. E., Smolen, J. S. 2016; 374 (13): 1243-1252

  Abstract

  In phase 2 studies, baricitinib, an oral Janus kinase 1 and 2 inhibitor, reduced disease activity in patients with rheumatoid arthritis who had not previously received treatment with biologic disease-modifying antirheumatic drugs (DMARDs).In this phase 3 study involving 527 patients with an inadequate response to or unacceptable side effects associated with one or more tumor necrosis factor inhibitors, other biologic DMARDs, or both, we randomly assigned the patients in a 1:1:1 ratio to baricitinib at a dose of 2 or 4 mg daily or placebo for 24 weeks. End points, tested hierarchically at week 12 to control type 1 error, were the American College of Rheumatology 20% (ACR20) response (primary end point), the Health Assessment Questionnaire-Disability Index (HAQ-DI) score, the 28-joint Disease Activity Score based on C-reactive protein level (DAS28-CRP), and a Simplified Disease Activity Index (SDAI) score of 3.3 or less (on a scale of 0.1 to 86.0, with a score of 3.3 or less indicating remission). Comparisons with placebo were made first with the 4-mg dose of baricitinib and then with the 2-mg dose.Significantly more patients receiving baricitinib at the 4-mg dose than those receiving placebo had an ACR20 response at week 12 (55% vs. 27%, P<0.001). Differences between the higher-dose baricitinib group and the placebo group were also significant for the HAQ-DI score and the DAS28-CRP but not for an SDAI score of 3.3 or less. Adverse-event rates through 24 weeks were higher for patients receiving the 2-mg dose of baricitinib and those receiving the 4-mg dose than for patients receiving placebo (71% and 77%, respectively, vs. 64%), including infections (44% and 40%, vs. 31%). The rates of serious adverse events were 4%, 10%, and 7% in the three groups, respectively. Two nonmelanoma skin cancers and two major adverse cardiovascular events, including a fatal stroke, occurred in the higher-dose group. Baricitinib was associated with a small reduction in neutrophil levels and increases in serum creatinine and low-density lipoprotein cholesterol levels.In patients with rheumatoid arthritis and an inadequate response to biologic DMARDs, baricitinib at a daily dose of 4 mg was associated with clinical improvement at 12 weeks. (Funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01721044.).

  View details for DOI 10.1056/NEJMoa1507247

  View details for Web of Science ID 000373085500007

  View details for PubMedID 27028914

• Safety and Efficacy of Open-label Subcutaneous Ixekizumab Treatment for 48 Weeks in a Phase II Study in Biologic-naive and TNF-IR Patients with Rheumatoid Arthritis. journal of rheumatology Genovese, M. C., Braun, D. K., Erickson, J. S., Berclaz, P., Banerjee, S., Heffernan, M. P., Carlier, H. 2016; 43 (2): 289-297

  Abstract

  To evaluate ixekizumab, an anti-interleukin 17A monoclonal antibody, for safety and effectiveness through 64 weeks in biologic-naive and tumor necrosis factor-inadequate responder (TNF-IR) patients with rheumatoid arthritis.Patients completing the 16-week double-blind period of a phase II study were eligible to enter the open-label extension (OLE) for an additional 48 weeks of ixekizumab treatment. After a treatment hiatus between weeks 10 to 16, 232 biologic-naive and 158 TNF-IR patients entered the OLE with all patients receiving 160 mg ixekizumab at weeks 16, 18, and 20, and then every 4 weeks through Week 64.A total of 201 (87%) biologic-naive and 99 (62%) TNF-IR patients completed the OLE. Treatment-emergent adverse events (AE) occurred in 168 (72%) biologic-naive and 115 (73%) TNF-IR patients during the OLE. Most AE were mild to moderate in severity and did not lead to study discontinuation. Serious AE (SAE) occurred in 17 (7%) biologic-naive patients, including 5 (2%) serious infections and 2 (1%) deaths. SAE occurred in 18 (11%) TNF-IR patients, including 4 (3%) serious infections and 1 (1%) death. No mycobacterial or invasive fungal infections were reported. Clinical responses [American College of Rheumatology (ACR) 20, ACR50, ACR70, and 28-joint Disease Activity Score with C-reactive protein] observed at Week 16 were maintained or improved through Week 64.Ixekizumab was well tolerated, and safety findings in the OLE were consistent overall with those in the double-blind period of this study. Clinical improvements observed with ixekizumab through Week 16 were maintained or improved in patients participating in the OLE through Week 64.NCT00966875.

  View details for DOI 10.3899/jrheum.140831

  View details for PubMedID 26669919

• Improvement in Psoriasis Signs and Symptoms Assessed by the Psoriasis Symptom Inventory with Brodalumab Treatment in Patients with Psoriatic Arthritis. journal of rheumatology Mease, P. J., Genovese, M. C., Mutebi, A., Viswanathan, H. N., Chau, D., Feng, J., Erondu, N., Nirula, A. 2016; 43 (2): 343-349

  Abstract

  To evaluate the effect of brodalumab on psoriasis signs and symptoms assessed by the Psoriasis Symptom Inventory (PSI) in patients with psoriatic arthritis (PsA).This prespecified analysis of a phase II study (NCT01516957) evaluated patients with active PsA and psoriasis-affected body surface area ≥ 3%, randomized to brodalumab (140 or 280 mg) or placebo every 2 weeks (Q2W) for 12 weeks with loading dose at Week 1. At Week 12, patients entering an open-label extension received brodalumab 280 mg Q2W. The PSI measures 8 psoriasis signs and symptoms: itch, redness, scaling, burning, stinging, cracking, flaking, and pain. PSI response is defined as total PSI ≤ 8 (range 0-32), each item ≤ 1 (range 0-4). PSI scores were assessed at weeks 12 and 24.There were 107 eligible patients. At Week 12, mean improvement in PSI scores was 7.8, 11.2, and 1.5 in brodalumab 140 mg, 280 mg, and placebo groups, respectively; by Week 24, improvement was 10.2, 12.4, and 11.7. At Week 12, 75.0%, 81.8%, and 16.7% of patients receiving brodalumab 140 mg, 280 mg, and placebo, respectively, achieved PSI response; improvement was sustained through Week 24, when 83.9% of prior placebo recipients achieved response. At Week 12, 25.0%, 36.4%, and 2.8% of patients receiving brodalumab 140 mg, 280 mg, and placebo, respectively, achieved PSI 0. Percentages improved through Week 24: 40.0% brodalumab 140 mg, 42.9% brodalumab 280 mg, and 48.4% placebo.Significantly more brodalumab-treated patients with PsA achieved patient-reported improvements in psoriasis signs and symptoms than did those receiving placebo. Improvements were comparable between brodalumab groups.

  View details for DOI 10.3899/jrheum.150182

  View details for PubMedID 26773108

• Safety and Efficacy of Subcutaneous Golimumab in Patients with Active Rheumatoid Arthritis despite Methotrexate Therapy: Final 5-year Results of the GO-FORWARD Trial. journal of rheumatology Keystone, E. C., Genovese, M. C., Hall, S., Bae, S., Han, C., Gathany, T. A., Xu, S., Zhou, Y., Leu, J. H., Hsia, E. C. 2016; 43 (2): 298-306

  Abstract

  To evaluate the safety and efficacy of golimumab (GOL), a human antitumor necrosis factor antibody, in patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) therapy through 5 years in the GO-FORWARD trial.Patients with active RA despite MTX therapy were randomly assigned to receive placebo + MTX (Group 1), GOL 100 mg + placebo (Group 2), GOL 50 mg + MTX (Group 3), or GOL 100 mg + MTX (Group 4). Patients in groups 1, 2, and 3 with inadequate response could enter early escape at Week 16 to GOL 50 mg + MTX or GOL 100 mg + MTX, and all remaining Group 1 patients crossed over to GOL 50 mg + MTX at Week 24. The blind was maintained through the 52-week database lock, after which treatment adjustments were permitted. Adverse events (AE) were monitored through Week 268. Efficacy was evaluated using the American College of Rheumatology (ACR) 20/50/70 responses and a 28-joint Disease Activity Score using C-reactive protein (DAS28-CRP). Response rates at Week 256 were analyzed by an intent-to-treat analysis.A total of 444 patients were randomized, and 313 received GOL through Week 252; 301 patients completed the safety followup through Week 268. Infections were the most common type of AE; 172 patients (39.6%) had ≥ 1 serious AE. No unexpected safety signals were observed. At Week 256, ACR20/50/70 responses were achieved by 63.1%, 40.8%, and 24.1%, respectively, of all randomized patients. About 78% of all patients achieved a good or moderate DAS28-CRP response.Improvements in the signs and symptoms of RA were maintained through 5 years. AE through 5 years were consistent with earlier reports of the GO-FORWARD trial; no apparent increased risk was observed over time.

  View details for DOI 10.3899/jrheum.150712

  View details for PubMedID 26669912

• Association of HLA-DRB1 alleles with clinical responses to the anti-interleukin-17A monoclonal antibody secukinumab in active rheumatoid arthritis RHEUMATOLOGY Burmester, G. R., Durez, P., Shestakova, G., Genovese, M. C., Schulze-Koops, H., Li, Y., Wang, Y. A., Lewitzky, S., Koroleva, I., Berneis, A. A., Lee, D. M., Hueber, W. 2016; 55 (1): 49-55

  Abstract

  To assess whether preliminary findings of associations between the HLA-DRB1*04 and HLA-DRB1* shared epitope (SE) allelic groups and response to the anti-IL-17A mAb secukinumab in RA were reproducible in an independent RA cohort.Biologic-naïve subjects (n = 100) with RA by 2010 criteria with tender/swollen joint counts (each ≥6) and high-sensitivity CRP (hsCRP) >10 mg/l were randomized 2:1 to secukinumab 10 mg/kg i.v. or placebo every 2 weeks until week 10. Potential associations with treatment response to secukinumab at week 12 (DAS28-CRP change from baseline by analysis of covariance, ACR20 response rate by logistic regression) were assessed for HLA-DRB1*04 (primary end point), HLA-DRB1*SE and HLA-DRB1 position 11 V/L (HLA-DRB1*pos11 V/L) allelic groups, and baseline levels of hsCRP, RF and anti-CCP.Secukinumab was significantly more effective than placebo in reducing DAS28-CRP (-2.41 vs -0.71; P < 0.0001) and producing ACR20 responses (87.1% vs 25.0%; P < 0.0001) at week 12. The HLA-DRB1*04 allelic group was not significantly related to secukinumab response vs placebo. For change from baseline in DAS28-CRP, HLA-DRB1*SE (P = 0.003) and HLA-DRB1*pos11 V/L (P = 0.002) allelic groups were associated with positive treatment response. Higher RF levels, but not anti-CCP positivity, were significantly associated with DAS28-CRP reductions (P = 0.015) and ACR20 (P = 0.008) responses. Secukinumab was well tolerated.Secukinumab significantly reduced signs and symptoms of RA vs placebo. As the HLA-DRB1*SE and HLA-DRB1*pos11 V/L results were driven by lack of placebo response in carriers, the hypothesis of clinical utility for HLA-DRB1* allelic groups in RA anti-IL-17A short-term response prediction could not be corroborated.ClinicalTrials.gov; https://clinicaltrials.gov/; NCT01426789.

  View details for DOI 10.1093/rheumatology/kev258

  View details for PubMedID 26268815

• VX-509 (Decernotinib), an Oral Selective JAK-3 Inhibitor, in Combination With Methotrexate in Patients With Rheumatoid Arthritis. Arthritis & rheumatology (Hoboken, N.J.) Genovese, M. C., van Vollenhoven, R. F., Pacheco-Tena, C., Zhang, Y., Kinnman, N. 2016; 68 (1): 46-55

  Abstract

  To assess the efficacy and safety of decernotinib (VX-509), an oral selective inhibitor of JAK-3, in patients with rheumatoid arthritis (RA) in whom the response to methotrexate treatment was inadequate.In this 24-week, double-blind, randomized phase IIb study, 358 patients with active RA received either placebo (n = 71) or VX-509 at dosages of 100 mg/day (n = 71), 150 mg/day (n = 72), 200 mg/day (n = 72), or 100 mg twice daily (n = 72). Primary measures of efficacy at week 12 were the response rate according to the American College of Rheumatology 20% improvement criteria (ACR20) and change from baseline in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP).At week 12, the ACR20 response rates were 46.5%, 66.7%, 56.9%, and 68.1% in the groups receiving VX-509 at dosages of 100 mg/day, 150 mg/day, 200 mg/day, and 100 mg twice daily, respectively, and 18.3% in the placebo group (P < 0.001 for all comparisons). At week 12, the mean change from baseline in the DAS28-CRP was significantly greater in each VX-509 group compared with the placebo group (P < 0.001). Improvements were maintained at week 24, as shown by the ACR20, ACR50, and ACR70 response rates and mean change from baseline in the DAS28-CRP. The most common adverse event in the VX-509 group was headache (8.7%), and elevated levels of transaminases, lipoproteins, and creatinine were observed.VX-509 significantly improved the signs and symptoms of RA at weeks 12 and 24 compared with the placebo group when it was administered in combination with methotrexate. Safety signals included infection and increases in liver transaminase and lipid levels.

  View details for DOI 10.1002/art.39473

  View details for PubMedID 26473751

• VX-509 (Decernotinib), an Oral Selective JAK-3 Inhibitor, in Combination With Methotrexate in Patients With Rheumatoid Arthritis ARTHRITIS & RHEUMATOLOGY Genovese, M. C., Van Vollenhoven, R. F., Pacheco-Tena, C., Zhang, Y., Kinnman, N. 2016; 68 (1): 46-55

  Abstract

  To assess the efficacy and safety of decernotinib (VX-509), an oral selective inhibitor of JAK-3, in patients with rheumatoid arthritis (RA) in whom the response to methotrexate treatment was inadequate.In this 24-week, double-blind, randomized phase IIb study, 358 patients with active RA received either placebo (n = 71) or VX-509 at dosages of 100 mg/day (n = 71), 150 mg/day (n = 72), 200 mg/day (n = 72), or 100 mg twice daily (n = 72). Primary measures of efficacy at week 12 were the response rate according to the American College of Rheumatology 20% improvement criteria (ACR20) and change from baseline in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP).At week 12, the ACR20 response rates were 46.5%, 66.7%, 56.9%, and 68.1% in the groups receiving VX-509 at dosages of 100 mg/day, 150 mg/day, 200 mg/day, and 100 mg twice daily, respectively, and 18.3% in the placebo group (P < 0.001 for all comparisons). At week 12, the mean change from baseline in the DAS28-CRP was significantly greater in each VX-509 group compared with the placebo group (P < 0.001). Improvements were maintained at week 24, as shown by the ACR20, ACR50, and ACR70 response rates and mean change from baseline in the DAS28-CRP. The most common adverse event in the VX-509 group was headache (8.7%), and elevated levels of transaminases, lipoproteins, and creatinine were observed.VX-509 significantly improved the signs and symptoms of RA at weeks 12 and 24 compared with the placebo group when it was administered in combination with methotrexate. Safety signals included infection and increases in liver transaminase and lipid levels.

  View details for DOI 10.1002/art.39473

  View details for Web of Science ID 000367353900005

• Sarilumab plus methotrexate improves patient-reported outcomes in patients with active rheumatoid arthritis and inadequate responses to methotrexate: results of a phase III trial. Arthritis research & therapy Strand, V., Kosinski, M., Chen, C., Joseph, G., Rendas-Baum, R., Graham, N. M., van Hoogstraten, H., Bayliss, M., Fan, C., Huizinga, T., Genovese, M. C. 2016; 18: 198-?

  Abstract

  Sarilumab is a human monoclonal antibody directed against the alpha subunit of the interleukin-6 receptor complex. In the MOBILITY phase III randomized controlled trial (RCT), sarilumab + methotrexate (MTX) treatment resulted in clinical improvements at 24 weeks that were maintained at 52 weeks in adults with rheumatoid arthritis (RA), who have inadequate response to MTX (MTX-IR). These analyses indicate the effects of sarilumab + MTX versus placebo on patient-reported outcomes (PROs) in this RCT.Patients (n = 1197) were randomized to receive placebo, sarilumab 150 or 200 mg subcutaneously + MTX every 2 weeks for 52 weeks; after 16 weeks, patients without ≥20 % improvement from baseline in swollen or tender joint counts on two consecutive assessments were offered open-label treatment. PROs included patient global assessment of disease activity (PtGA), pain, health assessment questionnaire disability index (HAQ-DI), Short Form-36 Health Survey (SF-36), and functional assessment of chronic illness therapy-fatigue (FACIT-F). Changes from baseline at weeks 24 and 52 were analyzed using a mixed model for repeated measures. Post hoc analyses included percentages of patients reporting improvements equal to or greater than minimal clinically important differences (MCID) and normative values in the FACIT-F and SF-36. Pearson correlation between observed PRO scores and clinical measures of disease activity was tested at week 24.Both doses of sarilumab + MTX vs placebo + MTX resulted in improvement from baseline by week 24 in PtGA, pain, HAQ-DI, SF-36 and FACIT-F scores (p < 0.0001) that was clinically meaningful, and persisted until week 52. In post hoc analyses, the percentages of patients with improvement equal to or greater than the MCID across all PROs were greater with sarilumab than placebo (p < 0.05), with differences ranging from 11.6 to 26.2 %, as were those reporting equal to or greater than normative scores.In this RCT in patients with MTX-IR RA, sarilumab + MTX resulted in sustained improvement in PROs that were clinically meaningful, greater than placebo + MTX, and complement the previously reported clinical efficacy and safety of sarilumab.ClinicalTrials.gov. NCT01061736 . February 2, 2010.

  View details for DOI 10.1186/s13075-016-1096-9

  View details for PubMedID 27600829

• Reliability and Validity of the Psoriasis Symptom Inventory in Patients With Psoriatic Arthritis ARTHRITIS CARE & RESEARCH Wilson, H. D., Mutebi, A., Revicki, D. A., Mease, P. J., Genovese, M. C., Erondu, N., Nirula, A., Yuan, F. J., Viswanathan, H. N. 2015; 67 (12): 1750-1756

  Abstract

  To evaluate the measurement properties of the Psoriasis Symptom Inventory (PSI) in psoriatic arthritis (PsA).The PSI is an 8-item, patient-reported outcome measure of the severity of psoriasis signs and symptoms. This was a secondary analysis of pooled data from a phase II study evaluating the efficacy of brodalumab in patients with PsA. Unidimensionality and item evaluation were assessed using factor and Rasch analyses. Reliability was assessed using Cronbach's alpha (internal consistency) and intraclass correlation coefficients (ICCs) for PSI scores in patients with stable disease (test-retest). Construct validity was evaluated by correlations between PSI scores and body surface area (BSA) affected by psoriasis and selected Short Form 36 (SF-36) health survey domains. Known-groups validity was evaluated based on BSA severity categories, and the ability to detect change was evaluated based on improvement in the subject's global assessment (SGA).The analysis sample (n = 154) was 93.5% white and 63.0% female. The mean ± SD baseline affected BSA was 10.4% ± 15.6%, and age was 52.2 ± 11.5 years. The PSI demonstrated unidimensionality, with good item fit and correctly ordered categories, excellent internal consistency (α = 0.95), good test-retest reliability (total score ICC 0.70; item ICCs range 0.67-0.81), convergent validity based on moderate correlations with BSA (r = 0.50), discriminant validity based on small baseline correlations (r <-0.3) with the SF-36 domains (role-physical, role-emotional, vitality), known groups validity based on significant differences between BSA groups, and responsiveness based on SGA improvements (P < 0.05).The PSI demonstrated excellent test-retest and internal consistency reliability and good construct validity in measuring psoriasis signs and symptoms severity in PsA.

  View details for DOI 10.1002/acr.22653

  View details for Web of Science ID 000367681900016

• Reliability and Validity of the Psoriasis Symptom Inventory in Patients With Psoriatic Arthritis. Arthritis care & research Wilson, H. D., Mutebi, A., Revicki, D. A., Mease, P. J., Genovese, M. C., Erondu, N., Nirula, A., Yuan, F. J., Viswanathan, H. N. 2015; 67 (12): 1750-6

  Abstract

  To evaluate the measurement properties of the Psoriasis Symptom Inventory (PSI) in psoriatic arthritis (PsA).The PSI is an 8-item, patient-reported outcome measure of the severity of psoriasis signs and symptoms. This was a secondary analysis of pooled data from a phase II study evaluating the efficacy of brodalumab in patients with PsA. Unidimensionality and item evaluation were assessed using factor and Rasch analyses. Reliability was assessed using Cronbach's alpha (internal consistency) and intraclass correlation coefficients (ICCs) for PSI scores in patients with stable disease (test-retest). Construct validity was evaluated by correlations between PSI scores and body surface area (BSA) affected by psoriasis and selected Short Form 36 (SF-36) health survey domains. Known-groups validity was evaluated based on BSA severity categories, and the ability to detect change was evaluated based on improvement in the subject's global assessment (SGA).The analysis sample (n = 154) was 93.5% white and 63.0% female. The mean ± SD baseline affected BSA was 10.4% ± 15.6%, and age was 52.2 ± 11.5 years. The PSI demonstrated unidimensionality, with good item fit and correctly ordered categories, excellent internal consistency (α = 0.95), good test-retest reliability (total score ICC 0.70; item ICCs range 0.67-0.81), convergent validity based on moderate correlations with BSA (r = 0.50), discriminant validity based on small baseline correlations (r <-0.3) with the SF-36 domains (role-physical, role-emotional, vitality), known groups validity based on significant differences between BSA groups, and responsiveness based on SGA improvements (P < 0.05).The PSI demonstrated excellent test-retest and internal consistency reliability and good construct validity in measuring psoriasis signs and symptoms severity in PsA.

  View details for DOI 10.1002/acr.22653

  View details for PubMedID 26206134

• OSKIRA-4: a phase IIb randomised, placebo-controlled study of the efficacy and safety of fostamatinib monotherapy ANNALS OF THE RHEUMATIC DISEASES Taylor, P. C., Genovese, M. C., Greenwood, M., Ho, M., Nasonov, E., Oemar, B., Stoilov, R., Vencovsky, J., Weinblatt, M. 2015; 74 (12): 2123-2129

  Abstract

  OSKIRA-4 evaluated the efficacy of fostamatinib monotherapy versus placebo on the signs and symptoms of rheumatoid arthritis over 6 weeks by Disease Activity Score C reactive protein (DAS-28(CRP)) and assessed non-inferiority to adalimumab monotherapy at Week 24 by DAS-28(CRP).Overall, 279 patients not currently taking disease-modifying antirheumatic drugs were randomised to: (A) fostamatinib 100 mg twice daily for 24 weeks plus placebo injection every 2 weeks (PBOI); (B) fostamatinib 100 mg twice daily for 4 weeks, then 150 mg once daily up to Week 24, plus PBOI; (C) fostamatinib 100 mg twice daily for 4 weeks, then 100 mg once daily up to Week 24, plus PBOI; (D) adalimumab 40 mg every 2 weeks for 24 weeks, plus oral placebo twice daily; or (E) oral placebo twice daily for 6 weeks, plus PBOI, then a switch to arm A or B.Fostamatinib demonstrated a significant improvement in DAS-28(CRP) score from baseline versus placebo at Week 6 for arms A and B, but not C. Fostamatinib was significantly less effective than adalimumab at Week 24 based on DAS-28(CRP). Adverse events observed with fostamatinib treatment were consistent with those reported in previous studies, including hypertension and diarrhoea.Fostamatinib demonstrated efficacy as monotherapy, showing superior DAS-28(CRP) score changes between baseline and 6 weeks when compared with placebo in treatment arms A and B. However, all fostamatinib regimens demonstrated inferior responses compared with adalimumab at Week 24.Clinicaltrials.gov: NCT01264770.

  View details for DOI 10.1136/annrheumdis-2014-205361

  View details for Web of Science ID 000365846400012

  View details for PubMedID 25074688

• Switching from Intravenous to Subcutaneous Formulation of Abatacept: Different Results in a Series of 21 Patients JOURNAL OF RHEUMATOLOGY Genovese, M. 2015; 42 (10): 1994

  View details for PubMedID 26429208

• The Clinical Efficacy and Safety of Baminercept, a Lymphotoxin-Beta Receptor Fusion Protein, in Primary Sjogren's Syndrome: Results from a Randomized, Double-Blind, Placebo-Controlled Phase II Trial St Clair, E., Baer, A. N., Noaiseh, G., Parke, A., Coca, A., Utset, T., Genovese, M. C., Wallace, D. J., McNamara, J., Boyle, K., Keyes-Elstein, L., Franchimont, N., James, J. A., Autoimmunity Ctr Excellence WILEY-BLACKWELL. 2015

  View details for Web of Science ID 000370860204752

• Sarilumab Dose Reduction to Manage Laboratory Abnormalities in an Open-Label Extension Study in RA Patients Burmester, G., Garg, A., van Hoogstraten, H., Graham, N., Boddy, A., Parrino, J., Genovese, M. C. WILEY-BLACKWELL. 2015

  View details for Web of Science ID 000370860204313

• Telomere Damage in Rheumatoid Arthritis Li, Y., Ju, J., Bush, T. M., Genovese, M. C., Goronzy, J., Weyand, C. M. WILEY-BLACKWELL. 2015

  View details for Web of Science ID 000370860203013

• Two-Year Clinical Response to Brodalumab, an Anti-Interleukin-17 Receptor Antibody, in Patients with Psoriatic Arthritis Genovese, M. C., Mease, P. J., Greenwald, M., Ritchlin, C. T., Beaulieu, A., Deodhar, A. A., Newmark, R., Feng, J., Erondu, N., Nirula, A. WILEY-BLACKWELL. 2015

  View details for Web of Science ID 000370860204422

• Characterization of Changes in Lymphocyte Subsets in Baricitinib-Treated Patients with Rheumatoid Arthritis in Two Phase 3 Studies Emery, P., McInnes, I., Genovese, M. C., Smolen, J. S., Kremer, J., Dougados, M., Schlichting, D. E., Rooney, T., Issa, M., de Bono, S., Macias, W. L., Rogai, V., Zuckerman, S. H., Taylor, P. C. WILEY-BLACKWELL. 2015

  View details for Web of Science ID 000370860202311

• Responder Rates and Numbers Needed to Treat Based on Clinically Meaningful Improvements in Patient Reported Outcomes (PROs) Including Health-Related Quality of Life (HRQoL) after Sarilumab Treatment during a Phase III Randomized Controlled Trial (RCT) Strand, V., Rendas-Baum, R., Joseph, G. J., Chen, C., van Hoogstraten, H., Huizinga, T. J., Genovese, M. C. WILEY-BLACKWELL. 2015

  View details for Web of Science ID 000370860203717

• Immunogenicity of Subcutaneous and Intravenous Tocilizumab As Monotherapy or in Combination with Dmards Genovese, M. C., Ogata, A., Nomura, A., Bao, M., Hitraya, E., Lacey, S., Burmester, G. WILEY-BLACKWELL. 2015

  View details for Web of Science ID 000370860204663

• Previous Biologic Disease-Modifying Antirheumatic Drug (bDMARD) Exposure and Efficacy and Safety Analysis from a Phase 3 Study of Baricitinib in Patients with Rheumatoid Arthritis and an Inadequate Response to Tumor Necrosis Factor Inhibitors Genovese, M. C., Kremer, J. M., Kartman, C., Schlichting, D. E., Xie, L., Carmack, T., Macias, W. L., Smolen, J. S. WILEY-BLACKWELL. 2015

  View details for Web of Science ID 000370860202310

• Randomized, Double-Blind, Phase 3 Study of Efficacy and Safety of ABP 501 Compared with Adalimumab in Subjects with Moderate to Severe Rheumatoid Arthritis Cohen, S. B., Genovese, M. C., Choy, E. H., Perez-Ruiz, F., Pablos, J. L., Zhang, N., Kaur, P. WILEY-BLACKWELL. 2015

  View details for Web of Science ID 000370860203460

• Response to Baricitinib at 4 Weeks Predicts Response at 12 and 24 Weeks in Patients with Rheumatoid Arthritis: Results from Two Phase 3 Studies Kremer, J., Dougados, M., Genovese, M. C., Emery, P., Yang, L., de Bono, S., Holzkaemper, T., Iikuni, N., Schlichting, D. E., Smolen, J. S. WILEY-BLACKWELL. 2015

  View details for Web of Science ID 000370860202314

• Results from a Phase IIA Parallel Group Study of JNJ-40346527, an Oral CSF-1R Inhibitor, in Patients with Active Rheumatoid Arthritis despite Disease-modifying Antirheumatic Drug Therapy. journal of rheumatology Genovese, M. C., Hsia, E., Belkowski, S. M., Chien, C., Masterson, T., Thurmond, R. L., Manthey, C. L., Yan, X. D., Ge, T., Franks, C., Greenspan, A. 2015; 42 (10): 1752-1760

  Abstract

  To assess the efficacy and safety of JNJ-40346527, a selective inhibitor of colony-stimulating factor-1 (CSF-1) receptor kinase that acts to inhibit macrophage survival, proliferation, and differentiation in patients with active rheumatoid arthritis (RA) despite disease-modifying antirheumatic drug (DMARD) therapy.In this randomized, double-blind, placebo-controlled, parallel group study, adults were randomized (2:1) to receive oral JNJ-40346527 100 mg or placebo twice daily through Week 12. Patients with RA had disease activity [≥ 6 swollen/≥ 6 tender joints, C-reactive protein (CRP) ≥ 0.8 mg/dl] despite DMARD therapy for ≥ 6 months. The primary endpoint was change from baseline at Week 12 in the 28-joint Disease Activity Score with CRP (DAS28-CRP). Pharmacokinetic/pharmacodynamic analyses were also performed, and safety was assessed through Week 16.Ninety-five patients were treated (63 JNJ-40346527, 32 placebo); 8 patients discontinued treatment (6 JNJ-40346527, 2 placebo) through Week 12. Mean improvements in DAS28-CRP from baseline to Week 12 were 1.15 for the JNJ-40346527 group and 1.42 for the placebo group (p = 0.30); thus, a statistically significant difference was not observed for the primary endpoint. Pharmacokinetic exposure to JNJ-40346527 and its active metabolites was above the projected concentration needed for pharmacologic activity, and effective target engagement and proof of activity were demonstrated by increased levels of CSF-1 and decreased CD16+ monocytes in JNJ-40346527-treated, but not placebo-treated, patients. Thirty-seven (58.7%) JNJ-40346527-treated and 16 (50.0%) placebo-treated patients reported ≥ 1 adverse event (AE); 1 (1.6%) JNJ-40346527-treated and 3 (9.4%) placebo-treated patients reported ≥ 1 serious AE.Although adequate exposure and effective peripheral target engagement were evident, JNJ-40346527 efficacy was not observed in patients with DMARD-refractory active RA. ClinicalTrials.gov identifier: NCT01597739. EudraCT Number: 2011-004529-28.

  View details for DOI 10.3899/jrheum.141580

  View details for PubMedID 26233509

• Efficacy of Sarilumab Plus Methotrexate in Achieving Clinical Remission, Using 4 Different Definitions, in Patients with Active, Moderate-to-Severe Rheumatoid Arthritis in a Phase 3 Study Genovese, M. C., Stanislav, M., van Hoogstraten, H., Martincova, R., Fan, C., van Adelsberg, J. WILEY-BLACKWELL. 2015

  View details for Web of Science ID 000370860204321

• Safety and Efficacy of Baricitinib through 128 Weeks in an Open-Label, Long- Term Extension Study in Patients with Rheumatoid Arthritis Magloire, A., Keystone, E., Taylor, P., Genovese, M., Schlichting, D., de la Torre, I., Beattie, S., Rooney, T. E M H SWISS MEDICAL PUBLISHERS LTD. 2015: 4S–5S

  View details for Web of Science ID 000447700900009

• Increases in Serum Cholesterol with Baricitinib Treatment are Associated with Favorable Changes in Apolipoprotein Content and with Improvement in DAS28-CRP in Patients with Rheumatoid Arthritis Magloire, A., Kremer, J., Genovese, M. C., Keystone, E., Taylor, P., Zuckerman, S. H., Schlichting, D. E., Nantz, E., Beattie, S. D., Macias, W. L. E M H SWISS MEDICAL PUBLISHERS LTD. 2015: 4S

  View details for Web of Science ID 000447700900008

• Efficacy and Safety of Tabalumab, an Anti-B-Cell-Activating Factor Monoclonal Antibody, in a Heterogeneous Rheumatoid Arthritis Population Results From a Randomized, Placebo-Controlled, Phase 3 Trial (FLEX-O) JCR-JOURNAL OF CLINICAL RHEUMATOLOGY Genovese, M. C., Silverman, G. J., Emery, P., Gupta, R. C., Gill, A., Veenhuizen, M., Xie, L., Komocsar, W. J., Berclaz, P., Lee, C. 2015; 21 (5): 231-238

  Abstract

  The efficacy and safety of 2 different dosing regimens of tabalumab, a monoclonal antibody that neutralizes membrane-bound and soluble B-cell-activating factor (BAFF), were evaluated in patients with rheumatoid arthritis.In this phase 3, multicenter, randomized study, 1004 patients (intention-to-treat population) received subcutaneous 120 mg tabalumab every 4 weeks (120/Q4W), 90 mg tabalumab every 2 weeks (90/Q2W), or placebo over 24 weeks. At baseline, a loading dose double the planned dose (ie, 240 mg, 180 mg, or placebo) was administered. Efficacy analyses were based on a prespecified subset of patients with 5 or more of 68 tender and 5 or more of 66 swollen joints at baseline (efficacy population, n = 849). The primary efficacy end point was ACR20 (20% improvement in American College of Rheumatology criteria) response at week 24.At week 24, there were no differences in ACR20 response rates (120/Q4W = 34.4%, 90/Q2W = 33.5%, placebo = 31.5%) or any other measures of efficacy across the treatment groups. Discontinuations due to adverse events (AE) were 3.4%, 2.7%, and 4.0%; incidence of treatment-emergent AEs were 64.1%, 58.2%, and 58.8%, with 23.2%, 25.9%, and 22.0% treatment-emergent infections; and incidence rates of serious AEs were 3.7%, 2.2%, and 2.8% with 1.1%, 0.3%, and 0.7% serious infections in the 120/Q4W, 90/Q2W, and placebo groups, respectively. Three deaths were reported (120/Q4W, n = 2; 90/Q2W, n = 1). Each tabalumab group had significant decreases versus placebo in CD3-CD20 B cells (P ≤ 0.05) and in serum immunoglobulins (P ≤ 0.001).Although tabalumab administration resulted in biologic activity, as demonstrated by changes in B cells and immunoglobulins, targeting BAFF-dependent pathways alone is not sufficient to significantly reduce rheumatoid arthritis disease activity.

  View details for DOI 10.1097/RHU.0000000000000276

  View details for Web of Science ID 000359829100001

  View details for PubMedID 26203826

• Apremilast in Patients With Active Rheumatoid Arthritis: A Phase II, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study ARTHRITIS & RHEUMATOLOGY Genovese, M. C., Jarosova, K., Cieslak, D., Alper, J., Kivitz, A., Hough, D. R., Maes, P., Pineda, L., Chen, M., Zaidi, F. 2015; 67 (7): 1703-1710

  Abstract

  To study the efficacy/safety of apremilast, an oral phosphodiesterase 4 inhibitor, compared with placebo in patients with active rheumatoid arthritis (RA) who had an inadequate response to methotrexate (MTX).Patients were randomized 1:1:1 to receive placebo, apremilast 20 mg twice a day, or apremilast 30 mg twice a day. Patients whose swollen and tender joint counts had not improved by ≥20% were considered nonresponders at week 16 and were required to enter the protocol-defined early escape. At week 24, patients were transitioned in a blinded manner to receive apremilast 20 mg twice a day if they were initially randomized to receive placebo. Patients who were not initially randomized to receive placebo continued to receive their target apremilast dose. Patients were required to take a stable dose of MTX (7.5-25 mg/week) throughout the study. Magnetic resonance imaging (MRI) was performed in a subset of patients.A total of 237 patients who were receiving MTX therapy were randomized and received ≥1 dose of study medication. At week 16, similar proportions of patients receiving placebo (35%), apremilast 20 mg twice a day (28%), and apremilast 30 mg twice a day (34%) met the American College of Rheumatology criteria for 20% improvement in disease activity (the primary efficacy end point). In the MRI substudy, mean change from baseline in total joint damage scores according to the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring system was generally similar with either apremilast dose at week 16. At week 52, no trends were noted for clinical end points by treatment group. Both apremilast doses were generally well tolerated.Apremilast efficacy was not demonstrated in patients who had active RA despite stable MTX therapy.

  View details for DOI 10.1002/art.39120

  View details for Web of Science ID 000357013500004

  View details for PubMedID 25779750

• Increases in Serum Cholesterol with Baricitinib Treatment are Associated with Favorable Changes in Apolipoprotein Content and with Improvement in DAS28-CRP in Patients with Rheumatoid Arthritis Kremer, J., Genovese, M., Keystone, E., Taylor, P., Zuckerman, S., Schlichting, D., Nantz, E., Beattie, S., Macias, W. J RHEUMATOL PUBL CO. 2015: 1291

  View details for Web of Science ID 000357280700111

• Safety and Efficacy of Baricitinib through 128 Weeks in an Open-Label, Long-Term Extension Study in Patients with Rheumatoid Arthritis Keystone, E., Taylor, P., Genovese, M., Schlichting, D., de la Torre, I., Beattie, S., Rooney, T. J RHEUMATOL PUBL CO. 2015: 1292

  View details for Web of Science ID 000357280700113

• Gene expression changes reflect clinical response in a placebo-controlled randomized trial of abatacept in patients with diffuse cutaneous systemic sclerosis ARTHRITIS RESEARCH & THERAPY Chakravarty, E. F., Martyanov, V., Fiorentino, D., Wood, T. A., Haddon, D. J., Jarrell, J. A., Utz, P. J., Genovese, M. C., Whitfield, M. L., Chung, L. 2015; 17

  Abstract

  Systemic sclerosis is an autoimmune disease characterized by inflammation and fibrosis of the skin and internal organs. We sought to assess the clinical and molecular effects associated with response to intravenous abatacept in patients with diffuse cutaneous systemic.Adult diffuse cutaneous systemic sclerosis patients were randomized in a 2:1 double-blinded fashion to receive abatacept or placebo over 24 weeks. Primary outcomes were safety and the change in modified Rodnan Skin Score (mRSS) at week 24 compared with baseline. Improvers were defined as patients with a decrease in mRSS of ≥30% post-treatment compared to baseline. Skin biopsies were obtained for differential gene expression and pathway enrichment analyses and intrinsic gene expression subset assignment.Ten subjects were randomized to abatacept (n = 7) or placebo (n = 3). Disease duration from first non-Raynaud's symptom was significantly longer (8.8 ± 3.8 years vs. 2.4 ± 1.6 years, p = 0.004) and median mRSS was higher (30 vs. 22, p = 0.05) in the placebo compared to abatacept group. Adverse events were similar in the two groups. Five out of seven patients (71%) randomized to abatacept and one out of three patients (33%) randomized to placebo experienced ≥30% improvement in skin score. Subjects receiving abatacept showed a trend toward improvement in mRSS at week 24 (-8.6 ± 7.5, p = 0.0625) while those in the placebo group did not (-2.3 ± 15, p = 0.75). After adjusting for disease duration, mRSS significantly improved in the abatacept compared with the placebo group (abatacept vs. placebo mRSS decrease estimate -9.8, 95% confidence interval -16.7 to -3.0, p = 0.0114). In the abatacept group, the patients in the inflammatory intrinsic subset showed a trend toward greater improvement in skin score at 24 weeks compared with the patients in the normal-like intrinsic subset (-13.5 ± 3.1 vs. -4.5 ± 6.4, p = 0.067). Abatacept resulted in decreased CD28 co-stimulatory gene expression in improvers consistent with its mechanism of action. Improvers mapped to the inflammatory intrinsic subset and showed decreased gene expression in inflammatory pathways, while non-improver and placebos showed stable or reverse gene expression over 24 weeks.Clinical improvement following abatacept therapy was associated with modulation of inflammatory pathways in skin.ClinicalTrials.gov NCT00442611. Registered 1 March 2007.

  View details for DOI 10.1186/s13075-015-0669-3

  View details for Web of Science ID 000357069900001

  View details for PubMedID 26071192

  View details for PubMedCentralID PMC4487200

• Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate Results of a Phase III Study ARTHRITIS & RHEUMATOLOGY Genovese, M. C., Fleischmann, R., Kivitz, A. J., Rell-Bakalarska, M., Martincova, R., Fiore, S., Rohane, P., van Hoogstraten, H., Garg, A., Fan, C., van Adelsberg, J., Weinstein, S. P., Graham, N. M., Stahl, N., Yancopoulos, G. D., Huizinga, T. W., van der Heijde, D. 2015; 67 (6): 1424-1437

  Abstract

  To evaluate the efficacy and safety of sarilumab in combination with methotrexate (MTX) for the treatment of rheumatoid arthritis (RA).Adults with moderate-to-severe RA and an inadequate response to MTX were randomized (1:1:1) to receive sarilumab (doses of 150 mg or 200 mg) or placebo every 2 weeks in conjunction with weekly MTX for 52 weeks. Co-primary end points were the proportion of patients achieving American College of Rheumatology 20% (ACR20) improvement responses at week 24, change from baseline in the Health Assessment Questionnaire (HAQ) disability index (DI) at week 16, and change from baseline in the modified Sharp/van der Heijde score (SHS) of radiographic damage at week 52.Baseline characteristics were similar among the groups. For all 3 co-primary end points, the sarilumab 150 mg and 200 mg groups demonstrated statistically significant improvements as compared with the placebo group (ACR20 response rate at week 24, 58.0%, 66.4%, and 33.4%, respectively [P < 0.0001]; least squares mean change in HAQ DI at week 16, -0.53, -0.55, and -0.29, respectively [P < 0.0001]; and mean change in SHS at week 52, 0.90, 0.25, and 2.78, respectively [P < 0.0001]). The most common treatment-emergent adverse event was infection. In the sarilumab 150 mg, sarilumab 200 mg, and placebo groups, the incidence of serious infections was 2.6%, 4.0%, and 2.3%, respectively. Elevations in alanine aminotransferase levels >3-fold the upper limit of normal occurred in 9.5%, 8.0%, and 2.1% of patients, respectively; in 24 patients, this led to discontinuation of treatment. Elevated total cholesterol levels were observed in 36.8%, 43.0%, and 18.3% of patients, respectively. In patients receiving 150 mg and 200 mg sarilumab, neutrophil counts of 0.5 to <1.0 × 10(9) /liter were observed in 5.1% and 7.8% of patients, respectively, while neutrophil counts of <0.5 × 10(9) /liter were observed in 0.9% and 0.7% of patients, respectively; none of the patients receiving placebo experienced changes in neutrophil counts.In RA patients treated with sarilumab (150 mg or 200 mg every 2 weeks) in combination with MTX, both doses provided sustained clinical efficacy, as shown by significant improvements in symptomatic, functional, and radiographic outcomes. Sarilumab was generally well tolerated. The adverse events observed in this study were consistent with the effects of interleukin-6 signaling blockade.

  View details for DOI 10.1002/art.39093

  View details for Web of Science ID 000355328400005

  View details for PubMedID 25733246

• Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate: Results of a Phase III Study. Arthritis & rheumatology Genovese, M. C., Fleischmann, R., Kivitz, A. J., Rell-Bakalarska, M., Martincova, R., Fiore, S., Rohane, P., van Hoogstraten, H., Garg, A., Fan, C., van Adelsberg, J., Weinstein, S. P., Graham, N. M., Stahl, N., Yancopoulos, G. D., Huizinga, T. W., van der Heijde, D. 2015; 67 (6): 1424-1437

  Abstract

  To evaluate the efficacy and safety of sarilumab in combination with methotrexate (MTX) for the treatment of rheumatoid arthritis (RA).Adults with moderate-to-severe RA and an inadequate response to MTX were randomized (1:1:1) to receive sarilumab (doses of 150 mg or 200 mg) or placebo every 2 weeks in conjunction with weekly MTX for 52 weeks. Co-primary end points were the proportion of patients achieving American College of Rheumatology 20% (ACR20) improvement responses at week 24, change from baseline in the Health Assessment Questionnaire (HAQ) disability index (DI) at week 16, and change from baseline in the modified Sharp/van der Heijde score (SHS) of radiographic damage at week 52.Baseline characteristics were similar among the groups. For all 3 co-primary end points, the sarilumab 150 mg and 200 mg groups demonstrated statistically significant improvements as compared with the placebo group (ACR20 response rate at week 24, 58.0%, 66.4%, and 33.4%, respectively [P < 0.0001]; least squares mean change in HAQ DI at week 16, -0.53, -0.55, and -0.29, respectively [P < 0.0001]; and mean change in SHS at week 52, 0.90, 0.25, and 2.78, respectively [P < 0.0001]). The most common treatment-emergent adverse event was infection. In the sarilumab 150 mg, sarilumab 200 mg, and placebo groups, the incidence of serious infections was 2.6%, 4.0%, and 2.3%, respectively. Elevations in alanine aminotransferase levels >3-fold the upper limit of normal occurred in 9.5%, 8.0%, and 2.1% of patients, respectively; in 24 patients, this led to discontinuation of treatment. Elevated total cholesterol levels were observed in 36.8%, 43.0%, and 18.3% of patients, respectively. In patients receiving 150 mg and 200 mg sarilumab, neutrophil counts of 0.5 to <1.0 × 10(9) /liter were observed in 5.1% and 7.8% of patients, respectively, while neutrophil counts of <0.5 × 10(9) /liter were observed in 0.9% and 0.7% of patients, respectively; none of the patients receiving placebo experienced changes in neutrophil counts.In RA patients treated with sarilumab (150 mg or 200 mg every 2 weeks) in combination with MTX, both doses provided sustained clinical efficacy, as shown by significant improvements in symptomatic, functional, and radiographic outcomes. Sarilumab was generally well tolerated. The adverse events observed in this study were consistent with the effects of interleukin-6 signaling blockade.

  View details for DOI 10.1002/art.39093

  View details for PubMedID 25733246

• Mass cytometry as a platform for the discovery of cellular biomarkers to guide effective rheumatic disease therapy ARTHRITIS RESEARCH & THERAPY Nair, N., Mei, H. E., Chen, S., Hale, M., Nolan, G. P., Maecker, H. T., Genovese, M., Fathman, C. G., Whiting, C. C. 2015; 17

  Abstract

  The development of biomarkers for autoimmune diseases has been hampered by a lack of understanding of disease etiopathogenesis and of the mechanisms underlying the induction and maintenance of inflammation, which involves complex activation dynamics of diverse cell types. The heterogeneous nature and suboptimal clinical response to treatment observed in many autoimmune syndromes highlight the need to develop improved strategies to predict patient outcome to therapy and personalize patient care. Mass cytometry, using CyTOF®, is an advanced technology that facilitates multiparametric, phenotypic analysis of immune cells at single-cell resolution. In this review, we outline the capabilities of mass cytometry and illustrate the potential of this technology to enhance the discovery of cellular biomarkers for rheumatoid arthritis, a prototypical autoimmune disease.

  View details for DOI 10.1186/s13075-015-0644-z

  View details for Web of Science ID 000354850500001

  View details for PubMedID 25981462

  View details for PubMedCentralID PMC4436107

• Results of a proof of concept, double-blind, randomized trial of a second generation antisense oligonucleotide targeting high-sensitivity C-reactive protein (hs-CRP) in rheumatoid arthritis ARTHRITIS RESEARCH & THERAPY Warren, M. S., Hughes, S. G., Singleton, W., Yamashita, M., Genovese, M. C. 2015; 17: 80

  Abstract

  This randomized, double-blind, phase II study evaluated the pharmacodynamics, safety and tolerability of ISIS 329993 (ISIS-CRPRx), an antisense oligonucleotide, in patients with active rheumatoid arthritis (RA).Patients with active RA of at least six months duration were randomized into three cohorts to receive ISIS-CRPRx (100 mg, 200 mg or 400 mg) or placebo (3 active:1 placebo within each cohort) via subcutaneous (SC) injection on Days 1, 3, 5 and 8 and then once weekly for the next 11 weeks. The effects of study treatment on high-sensitivity C-reactive protein (hs-CRP) level were evaluated. An exploratory analysis on disease activity was assessed via the American College of Rheumatology 20% improvement criteria (ACR20). Safety was evaluated via adverse events and laboratory measures.Fifty-one patients received one of the following treatments: ISIS-CRPRx 100 mg, n = 12; 200 mg, n = 13, 400 mg, n = 14; placebo n = 12. In the ISIS-CRPRx treatment groups there were dose-dependent reductions in hs-CRP. At Day 36 the mean percent change from baseline was: placebo: -14.4%; ISIS-CRPRx 100 mg: -19.5%; 200 mg: -56.6% and 400 mg: -76.7%, (P = 0.0015 placebo compared to 400 mg). There were no differences between treatment groups and placebo in the ACR20 at Day 36 or Day 92. There were no serious infections and no elevations in liver function tests, lipids, creatinine or other lab abnormalities related to ISIS-CRPRx.In this study, ISIS-CRPRx selectively reduced hs-CRP in a dose-dependent manner, and was well-tolerated in patients with RA. Its utility as a therapy in RA remains unclear.Clinicaltrials.gov NCT01414101 . Registered 21 July 2011.

  View details for PubMedID 25885521

  View details for PubMedCentralID PMC4415222

• Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate ANNALS OF THE RHEUMATIC DISEASES Keystone, E. C., Taylor, P. C., Drescher, E., Schlichting, D. E., Beattie, S. D., Berclaz, P., Lee, C. H., Fidelus-Gort, R. K., Luchi, M. E., Rooney, T. P., Macias, W. L., Genovese, M. C. 2015; 74 (2): 333-340

  Abstract

  To investigate baricitinib (LY3009104, formerly INCB028050), a novel, oral inhibitor of JAK1/JAK2 in patients with moderate to severe rheumatoid arthritis (RA) despite treatment with methotrexate.In this phase IIb study, 301 patients were randomised 2:1:1:1:1 to receive once daily doses of placebo or 1, 2, 4 or 8 mg baricitinib for 12 weeks. Patients assigned to 2, 4 and 8 mg baricitinib continued blinded treatment for an additional 12 weeks. Patients assigned to placebo or 1 mg baricitinib were reassigned to 2 mg twice daily or 4 mg once daily baricitinib between weeks 12-24. The primary endpoint was the proportion of patients in the combined 4 and 8 mg groups achieving an American College of Rheumatology 20% (ACR20) response versus placebo at week 12.Significantly more patients in the combined baricitinib 4 and 8 mg groups compared with placebo achieved an ACR20 response at week 12 (76% vs 41%, p<0.001). At week 12, significant differences versus placebo were also observed in patients achieving ACR50, ACR70 and remission as measured by Disease Activity Score for 28-joint counts, Clinical Disease Activity Index and Simplified Disease Activity Index. Patients receiving 2, 4, or 8 mg baricitinib maintained or improved in all measures through 24 weeks. Similar proportions of patients experienced at least one adverse event in the placebo and baricitinib groups. Serious infections developed in three patients receiving baricitinib. No cases of tuberculosis, herpes zoster, opportunistic infections or deaths were reported. Dose-dependent decreases in haemoglobin were observed with baricitinib.Baricitinib improved the signs and symptoms of RA in methotrexate inadequate responders with active disease. Baricitinib was well tolerated with no unexpected safety findings through week 24.NCT01185353.

  View details for DOI 10.1136/annrheumdis-2014-206478

  View details for Web of Science ID 000347458300004

  View details for PubMedID 25431052

  View details for PubMedCentralID PMC4316868

• Gene expression changes reflect clinical response in a placebo-controlled randomized trial of abatacept in patients with diffuse cutaneous systemic sclerosis. Arthritis research & therapy Chakravarty, E. F., Martyanov, V., Fiorentino, D., Wood, T. A., Haddon, D. J., Jarrell, J. A., Utz, P. J., Genovese, M. C., Whitfield, M. L., Chung, L. 2015; 17: 159-?

  Abstract

  Systemic sclerosis is an autoimmune disease characterized by inflammation and fibrosis of the skin and internal organs. We sought to assess the clinical and molecular effects associated with response to intravenous abatacept in patients with diffuse cutaneous systemic.Adult diffuse cutaneous systemic sclerosis patients were randomized in a 2:1 double-blinded fashion to receive abatacept or placebo over 24 weeks. Primary outcomes were safety and the change in modified Rodnan Skin Score (mRSS) at week 24 compared with baseline. Improvers were defined as patients with a decrease in mRSS of ≥30% post-treatment compared to baseline. Skin biopsies were obtained for differential gene expression and pathway enrichment analyses and intrinsic gene expression subset assignment.Ten subjects were randomized to abatacept (n = 7) or placebo (n = 3). Disease duration from first non-Raynaud's symptom was significantly longer (8.8 ± 3.8 years vs. 2.4 ± 1.6 years, p = 0.004) and median mRSS was higher (30 vs. 22, p = 0.05) in the placebo compared to abatacept group. Adverse events were similar in the two groups. Five out of seven patients (71%) randomized to abatacept and one out of three patients (33%) randomized to placebo experienced ≥30% improvement in skin score. Subjects receiving abatacept showed a trend toward improvement in mRSS at week 24 (-8.6 ± 7.5, p = 0.0625) while those in the placebo group did not (-2.3 ± 15, p = 0.75). After adjusting for disease duration, mRSS significantly improved in the abatacept compared with the placebo group (abatacept vs. placebo mRSS decrease estimate -9.8, 95% confidence interval -16.7 to -3.0, p = 0.0114). In the abatacept group, the patients in the inflammatory intrinsic subset showed a trend toward greater improvement in skin score at 24 weeks compared with the patients in the normal-like intrinsic subset (-13.5 ± 3.1 vs. -4.5 ± 6.4, p = 0.067). Abatacept resulted in decreased CD28 co-stimulatory gene expression in improvers consistent with its mechanism of action. Improvers mapped to the inflammatory intrinsic subset and showed decreased gene expression in inflammatory pathways, while non-improver and placebos showed stable or reverse gene expression over 24 weeks.Clinical improvement following abatacept therapy was associated with modulation of inflammatory pathways in skin.ClinicalTrials.gov NCT00442611. Registered 1 March 2007.

  View details for DOI 10.1186/s13075-015-0669-3

  View details for PubMedID 26071192

  View details for PubMedCentralID PMC4487200

• Mass cytometry as a platform for the discovery of cellular biomarkers to guide effective rheumatic disease therapy. Arthritis research & therapy Nair, N., Mei, H. E., Chen, S., Hale, M., Nolan, G. P., Maecker, H. T., Genovese, M., Fathman, C. G., Whiting, C. C. 2015; 17: 127-?

  Abstract

  The development of biomarkers for autoimmune diseases has been hampered by a lack of understanding of disease etiopathogenesis and of the mechanisms underlying the induction and maintenance of inflammation, which involves complex activation dynamics of diverse cell types. The heterogeneous nature and suboptimal clinical response to treatment observed in many autoimmune syndromes highlight the need to develop improved strategies to predict patient outcome to therapy and personalize patient care. Mass cytometry, using CyTOF®, is an advanced technology that facilitates multiparametric, phenotypic analysis of immune cells at single-cell resolution. In this review, we outline the capabilities of mass cytometry and illustrate the potential of this technology to enhance the discovery of cellular biomarkers for rheumatoid arthritis, a prototypical autoimmune disease.

  View details for DOI 10.1186/s13075-015-0644-z

  View details for PubMedID 25981462

• Effects of Fostamatinib, an Oral Spleen Tyrosine Kinase Inhibitor, in Rheumatoid Arthritis Patients With an Inadequate Response to Methotrexate Results From a Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study ARTHRITIS & RHEUMATOLOGY Weinblatt, M. E., Genovese, M. C., Ho, M., Hollis, S., Rosiak-Jedrychowicz, K., Kavanaugh, A., Millson, D. S., Leon, G., Wang, M., van der Heijde, D. 2014; 66 (12): 3255-3264

  Abstract

  This phase III, 52-week study compared fostamatinib with placebo (for 24 weeks) in patients with active rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX) therapy.Patients taking MTX were randomized (1:1:1) to receive fostamatinib 100 mg twice daily for 52 weeks (group A), fostamatinib 100 mg twice daily for 4 weeks and then 150 mg once daily (group B), or placebo for 24 weeks and then fostamatinib 100 mg twice daily (group C). At week 24, the co-primary end points were change from baseline in the American College of Rheumatology 20% (ACR20) improvement response rates and change in the modified total Sharp/van der Heijde score of radiographic damage (SHS).In this study, 918 patients were randomized and received ≥1 dose of study drug (fostamatinib or placebo); the demographic and baseline clinical characteristics were well balanced. Following treatment with both fostamatinib regimens, a statistically significant difference in the ACR20 improvement response was achieved at week 24 as compared with that in patients receiving placebo (49.0% [group A] and 44.4%, [group B] versus 34.2%; P < 0.001 and P = 0.006, respectively), but there was no statistically significant difference in the SHS between either fostamatinib group and placebo (P = 0.25 and P = 0.17, respectively). The most common adverse events in patients in groups A, B, and C were hypertension (15.8%, 15.1%, and 3.9%, respectively) and diarrhea (13.9%, 15.1%, and 3.9%, respectively). Elevated blood pressure (≥140/90 mm Hg) occurred at ≥1 visit in 44.2%, 41.6%, and 19.3% of patients in each respective group.With the use of either fostamatinib regimen in patients with RA, statistically significant, but not clinically significant, improvements in the ACR20 improvement response over placebo were achieved at 24 weeks, whereas a significant difference in the SHS was not seen. The overall level of response to treatment with fostamatinib was lower than had been observed in the phase II program, but similar adverse events were reported.

  View details for DOI 10.1002/art.38851

  View details for Web of Science ID 000345571200002

  View details for PubMedID 25223724

• A Phase III, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Study of 2 Dosing Regimens of Fostamatinib in Patients with Rheumatoid Arthritis with an Inadequate Response to a Tumor Necrosis Factor-alpha Antagonist JOURNAL OF RHEUMATOLOGY Genovese, M. C., van der Heijde, D. M., Keystone, E. C., Spindler, A. J., Benhamou, C., Kavanaugh, A., Fudman, E., Lampl, K., O'Brien, C., Duffield, E. L., Poiley, J., Weinblatt, M. E. 2014; 41 (11): 2120-2128

  Abstract

  Our 24-week study (NCT01197755; OSKIRA-3) compared the efficacy and safety of fostamatinib versus placebo in patients taking background methotrexate treatment with active rheumatoid arthritis (RA) and an inadequate response to a single tumor necrosis factor-α antagonist.Adult patients were randomized (1:1:1) to fostamatinib [100 mg bid for 24 weeks (n=105; Group A)], or 100 mg bid for 4 weeks, then 150 mg qd (n=108; Group B), or to placebo (n=110; Group C) for 24 weeks. Nonresponders at Week 12 could enter a longterm extension study. The primary endpoint was the proportion of patients achieving an American College of Rheumatology 20% (ACR20) response at Week 24.Baseline characteristics were well balanced. Significantly more patients in fostamatinib Group A (36.2%; p=0.004), but not B (27.8%; p=0.168), achieved ACR20 at Week 24 versus placebo (21.1%). Frequently reported adverse events were diarrhea, hypertension, and headache. Elevated blood pressure (≥140/90 mm Hg) at ≥1 visit was observed in 46.7%, 51.9%, and 26.6% of patients, respectively. There were 2 deaths in the study, 1 in Group B and 1 in the placebo group.Fostamatinib 100 mg bid, but not fostamatinib 100 mg bid for 4 weeks then 150 mg qd, achieved statistical improvements in ACR20 at 24 weeks versus placebo. Because of efficacy and safety results from the phase III clinical program, the companies developing fostamatinib have decided not to study it further in RA at this time.

  View details for DOI 10.3899/jrheum.140238

  View details for Web of Science ID 000344598900008

• A phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study of 2 dosing regimens of fostamatinib in patients with rheumatoid arthritis with an inadequate response to a tumor necrosis factor-a antagonist. journal of rheumatology Genovese, M. C., van der Heijde, D. M., Keystone, E. C., Spindler, A. J., Benhamou, C., Kavanaugh, A., Fudman, E., Lampl, K., O'Brien, C., Duffield, E. L., Poiley, J., Weinblatt, M. E. 2014; 41 (11): 2120-2128

  Abstract

  Our 24-week study (NCT01197755; OSKIRA-3) compared the efficacy and safety of fostamatinib versus placebo in patients taking background methotrexate treatment with active rheumatoid arthritis (RA) and an inadequate response to a single tumor necrosis factor-α antagonist.Adult patients were randomized (1:1:1) to fostamatinib [100 mg bid for 24 weeks (n=105; Group A)], or 100 mg bid for 4 weeks, then 150 mg qd (n=108; Group B), or to placebo (n=110; Group C) for 24 weeks. Nonresponders at Week 12 could enter a longterm extension study. The primary endpoint was the proportion of patients achieving an American College of Rheumatology 20% (ACR20) response at Week 24.Baseline characteristics were well balanced. Significantly more patients in fostamatinib Group A (36.2%; p=0.004), but not B (27.8%; p=0.168), achieved ACR20 at Week 24 versus placebo (21.1%). Frequently reported adverse events were diarrhea, hypertension, and headache. Elevated blood pressure (≥140/90 mm Hg) at ≥1 visit was observed in 46.7%, 51.9%, and 26.6% of patients, respectively. There were 2 deaths in the study, 1 in Group B and 1 in the placebo group.Fostamatinib 100 mg bid, but not fostamatinib 100 mg bid for 4 weeks then 150 mg qd, achieved statistical improvements in ACR20 at 24 weeks versus placebo. Because of efficacy and safety results from the phase III clinical program, the companies developing fostamatinib have decided not to study it further in RA at this time.

  View details for DOI 10.3899/jrheum.140238

  View details for PubMedID 25225285

• Serum 14-3-3 eta is a Novel Marker that Complements Current Serological Measurements to Enhance Detection of Patients with Rheumatoid Arthritis JOURNAL OF RHEUMATOLOGY Maksymowych, W. P., Naides, S. J., Bykerk, V., Siminovitch, K. A., van Schaardenburg, D., Boers, M., Landewe, R., van der Heijde, D., Tak, P., Genovese, M. C., Weinblatt, M. E., Keystone, E. C., Zhukov, O. S., Abolhosn, R. W., Popov, J. M., Britsemmer, K., van Kuijk, A. W., Marotta, A. 2014; 41 (11): 2104-2113

  Abstract

  Serum 14-3-3η is a novel joint-derived proinflammatory mediator implicated in the pathogenesis of rheumatoid arthritis (RA). In our study, we assessed the diagnostic utility of 14-3-3η and its association with standard clinical and serological measures.A quantitative ELISA was used to assess 14-3-3η levels. Early (n=99) and established patients with RA (n=135) were compared to all controls (n=385), including healthy subjects (n=189). The sensitivity, specificity, positive and negative predictive values of 14-3-3η, and the likelihood ratios (LR) for RA were determined through receiver-operator curve analysis. The incremental value of adding 14-3-3η to anticitrullinated protein antibody (ACPA) and rheumatoid factor (RF) in diagnosing early and established RA was assessed.Serum 14-3-3η differentiated established patients with RA from healthy individuals and all controls (p<0.0001). A serum 14-3-3η cutoff of ≥0.19 ng/ml delivered a sensitivity and specificity of 77% and 93%, respectively, with corresponding LR positivity of 10.4. At this cutoff in early RA, 64% of patients with early RA were positive for 14-3-3η, with a corresponding specificity of 93% (LR+ of 8.6), while 59% and 57% were positive for ACPA or RF, respectively. When ACPA, RF, and 14-3-3η positivity were used in combination, 77 of the 99 patients (78%) with early RA were positive for any 1 of the 3 markers. Serum 14-3-3η did not correlate with C-reactive protein, erythrocyte sedimentation rate, or Disease Activity Score, but patients who were 14-3-3η-positive had significantly worse disease.Serum 14-3-3η is a novel RA mechanistic marker that is highly specific, associated with worse disease, and complements current markers, enabling a more accurate diagnosis of RA.

  View details for DOI 10.3899/jrheum.131446

  View details for Web of Science ID 000344598900006

  View details for PubMedID 25128504

• Clinical Response in Subjects with Psoriatic Arthritis Following One Year of Treatment with Brodalumab, an Anti-Interleukin-17 Receptor Antibody Genovese, M. C., Mease, P., Greenwald, M. W., Ritchlin, C. T., Beaulieu, A., Deodhar, A. A., Newmark, R., Feng, J., Erondu, N., Nirula, A. WILEY-BLACKWELL. 2014: S687

  View details for Web of Science ID 000344384903181

• Impact of Sarilumab on Health Related Quality of Life (HRQoL), Fatigue, and Sleep in Rheumatoid Arthritis Patients at Week 24-Results of a Phase 3, Randomized, Double-Blind, Placebo-Controlled, Multi-Center Study. Strand, V., Joseph, G., van Hoogstraten, H., Chen, C., Fan, C., Carita, P., Graham, N., Momtahen, T., Genovese, M. C. WILEY-BLACKWELL. 2014: S669–S670

  View details for Web of Science ID 000344384903146

• Comparable Efficacy with Sarilumab Plus Methotrexate in Biologic-Experienced and Biologic-Naive Patients with Moderate-to-Severe Rheumatoid Arthritis from a Phase 3, Randomized, Double-Blind, Placebo-Controlled, International Study. Fleischmann, R., Decktor, D. L., Fan, C., Van Hoogstraten, H., Genovese, M. C. WILEY-BLACKWELL. 2014: S1232–S1233

  View details for Web of Science ID 000344384906058

• Increases in Serum Cholesterol with Baricitinib Treatment Are Associated with Favorable Changes in Apolipoprotein Content and with Improvement in DAS28-CRP in Patients with Rheumatoid Arthritis Kremer, J. M., Genovese, M. C., Keystone, E. C., Taylor, P. C., Zuckerman, S. H., Schlichting, D. E., Nantz, E. P., Beattie, S. D., Macias, W. L. WILEY-BLACKWELL. 2014: S210

  View details for Web of Science ID 000344384901033

• A Profile of the Efficacy of Sarilumab Plus Methotrexate in Rheumatoid Arthritis Patients: Results of a 52-Week, Phase 3, Randomized, Double-Blind, Placebo-Controlled, International Study. Kavanaugh, A., Decktor, D. L., Fan, C., van Adelsberg, J., Martincova, R., Genovese, M. C. WILEY-BLACKWELL. 2014: S1233–S1234

  View details for Web of Science ID 000344384906059

• Impact of Golimumab on Physical Function and Employability of Patients with Rheumatoid Arthritis: 5-Year Data from 3 Phase III Clinical Trials Han, C., Keystone, E. C., Fleischmann, R., Smolen, J. S., Matteson, E. L., Emery, P., Genovese, M. C., Gathany, T. A., Hsia, E. C. WILEY-BLACKWELL. 2014: S1090

  View details for Web of Science ID 000344384905172

• A Phase 2b, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Dose-Finding, Multi-Center Study to Evaluate the Safety and Efficacy of ASP015K in Moderate to Severe Rheumatoid Arthritis Subjects Not on Concomitant Methotrexate. Genovese, M. C., Greenwald, M., Codding, C., Cardiel, M. H., Zubrzycka-Sienkiewicz, A., Kivitz, A. J., Wisseh, S., Shay, K., Garg, J. P. WILEY-BLACKWELL. 2014: S1234–S1235

  View details for Web of Science ID 000344384906061

• Reversibility of pharmacodynamic effects after short and long-term treatment with tofacitinib in patients with rheumatoid arthritis. Genovese, M. C., Kawabata, T. T., Soma, K., Menon, S., Clark, J. D., Hodge, J. A., Takiya, L., Riese, R., Krishnaswami, S. WILEY-BLACKWELL. 2014: E225–E226

  View details for Web of Science ID 000342916800144

• Safety and Efficacy of Baricitinib through 128 Weeks in an Open-Label, Long-Term Extension Study in Patients with Rheumatoid Arthritis. Keystone, E. C., Taylor, P. C., Genovese, M. C., Schlichting, D. E., De La Torre, I., Beattie, S. D., Rooney, T. WILEY-BLACKWELL. 2014: S1232

  View details for Web of Science ID 000344384906057

• Reliability and Construct Validity of the Psoriasis Symptom Inventory in Subjects with Psoriatic Arthritis. Mease, P., Genovese, M. C., Mutebi, A., Wilson, H., Revicki, D., Erondu, N., Nirula, A., Feng, J., Viswanathan, H. WILEY-BLACKWELL. 2014: S240

  View details for Web of Science ID 000344384901093

• Sarilumab, a fully human monoclonal antibody against IL-6R alpha in patients with rheumatoid arthritis and an inadequate response to methotrexate: efficacy and safety results from the randomised SARIL-RA-MOBILITY Part A trial ANNALS OF THE RHEUMATIC DISEASES Huizinga, T. W., Fleischmann, R. M., Jasson, M., Radin, A. R., van Adelsberg, J., Fiore, S., Huang, X., Yancopoulos, G. D., Stahl, N., Genovese, M. C. 2014; 73 (9): 1626-1634

  Abstract

  To evaluate safety and efficacy of weekly (qw) and every other week (q2w) dosing of sarilumab, a fully human anti-interleukin 6 receptor α (anti-IL-6Rα) monoclonal antibody, for moderate-to-severe rheumatoid arthritis (RA).In this dose-ranging study, patients (n=306) with active RA, despite methotrexate, were randomly assigned to placebo or one of five subcutaneous doses/regimens of sarilumab: 100 mg q2w, 150 mg q2w, 100 mg qw, 200 mg q2w, 150 mg qw for 12 weeks, plus methotrexate. The primary end point was ACR20 at Week 12. Secondary endpoints included ACR50, ACR70, Disease Activity Score in 28 joints (C reactive protein). Safety, pharmacokinetics, pharmacodynamics and efficacy in population subgroups were assessed.The proportion of patients achieving an ACR20 response compared with placebo was significantly higher for sarilumab 150 mg qw (72.0% vs 46.2%, multiplicity adjusted p=0.0203). Higher ACR20 responses were also attained with 150 mg q2w (67%; unadjusted (nominal) p=0.0363) and 200 mg q2w (65%; unadjusted p=0.0426) versus placebo. Sarilumab ≥150 mg q2w reduced C reactive protein, which did not return to baseline between dosing intervals. Infections were the most common adverse event; none were serious. Changes in laboratory values (neutropenia, transaminases and lipids) were consistent with reports with other IL-6Rα inhibitors.Sarilumab improved signs and symptoms of RA over 12 weeks in patients with moderate-to-severe RA with a safety profile similar to reports with other IL-6 inhibitors. Sarilumab 150 mg and sarilumab 200 mg q2w had the most favourable efficacy, safety and dosing convenience and are being further evaluated in Phase III.

  View details for DOI 10.1136/annrheumdis-2013-204405

  View details for Web of Science ID 000340723700012

  View details for PubMedID 24297381

  View details for PubMedCentralID PMC4145418

• Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a randomised Phase IIb study ANNALS OF THE RHEUMATIC DISEASES Genovese, M. C., Fleischmann, R., Furst, D., Janssen, N., Carter, J., Dasgupta, B., Bryson, J., Duncan, B., Zhu, W., Pitzalis, C., Durez, P., Kretsos, K. 2014; 73 (9): 1607-1615

  Abstract

  The aim of this 12-week Phase IIb study was to assess the efficacy and safety of olokizumab (OKZ), a humanised anti-IL6 monoclonal antibody, in patients with rheumatoid arthritis (RA) with moderate-to-severe disease activity who had previously failed tumour necrosis factor (TNF) inhibitor therapy. The dose-exposure-response relationship for OKZ was also investigated.Patients were randomised to one of nine treatment arms receiving placebo (PBO) or OKZ (60, 120 or 240 mg) every 4 weeks (Q4W) or every 2 weeks (Q2W), or 8 mg/kg tocilizumab (TCZ) Q4W. The primary endpoint was change from baseline in DAS28(C-reactive protein, CRP) at Week 12. Secondary efficacy endpoints were American College of Rheumatology 20 (ACR20), ACR50 and ACR70 response rates at Week 12. Exploratory analyses included comparisons of OKZ efficacy with TCZ.Across 221 randomised patients, OKZ treatment produced significantly greater reductions in DAS28(CRP) from baseline levels at Week 12, compared to PBO (p<0.001), at all the OKZ doses tested (60 mg OKZ p=0.0001, 120 and 240 mg OKZ p<0.0001). Additionally, ACR20 and ACR50 responses were numerically higher for OKZ than PBO (ACR20: PBO=17.1-29.9%, OKZ=32.5-60.7%; ACR50: PBO=1.3-4.9%, OKZ=11.5-33.2%). OKZ treatment, at several doses, demonstrated similar efficacy to TCZ across multiple endpoints. Most adverse events were mild or moderate and comparable between OKZ and TCZ treatment groups. Pharmacokinetic/pharmacodynamic modelling demonstrated a shallow dose/exposure response relationship in terms of percentage of patients with DAS28(CRP) <2.6.OKZ produced significantly greater reductions in DAS28(CRP) from baseline at Week 12 compared with PBO. Reported AEs were consistent with the safety profile expected of this class of drug, with no new safety signals identified.NCT01242488.

  View details for DOI 10.1136/annrheumdis-2013-204760

  View details for Web of Science ID 000340723700010

  View details for PubMedID 24641941

  View details for PubMedCentralID PMC4145439

• Long-Term Safety of Subcutaneous Abatacept in Rheumatoid Arthritis Integrated Analysis of Clinical Trial Data Representing More Than Four Years of Treatment ARTHRITIS & RHEUMATOLOGY Alten, R., Kaine, J., Keystone, E., Nash, P., Delaet, I., Genovese, M. C. 2014; 66 (8): 1987-1997

  Abstract

  To investigate the safety of long-term subcutaneous (SC) abatacept treatment using integrated clinical trial data obtained in patients with rheumatoid arthritis refractory to traditional disease-modifying antirheumatic drugs.Data from the double-blind and open-label phases of 5 clinical trials of SC abatacept were pooled. The overall and 6-month incidence rates were calculated as events per 100 patient-years of exposure.This analysis included 1,879 patients with 4,214.6 patient-years of exposure to SC abatacept. The mean ± SD length of exposure was 27.3 ± 9.1 months. The reported incidence rate of serious infections was 1.79 (95% confidence interval [95% CI] 1.42-2.24); the most frequent infections were pneumonia (incidence rate 0.36 [95% CI 0.22-0.59]), urinary tract infection (incidence rate 0.14 [95% CI 0.06-0.32]), and gastroenteritis (incidence rate 0.10 [95% CI 0.04-0.25]). Tuberculosis occurred rarely (incidence rate 0.09 [95% CI 0.04-0.25]). The reported incidence rate of malignancies was 1.32 (95% CI 1.01-1.72), and the most common was solid organ malignancy (incidence rate 0.69 [95% CI 0.48-0.99]). The incidence rate of autoimmune events was 1.37 (95% CI 1.06-1.78), and the most frequent events were psoriasis (incidence rate 0.33 [95% CI 0.20-0.56]) and Sjögren's syndrome (incidence rate 0.24 [95% CI 0.13-0.44]). The reported incidence rate of local injection site reactions was 1.72 (95% CI 1.36-2.17); these events occurred primarily during the first 6 months of treatment, and almost all were of mild or moderate intensity. The incidence rates of serious infections, malignancies, autoimmune events, and injection site reactions did not increase over time.Long-term treatment with SC abatacept was associated with low incidence rates of serious infections, malignancies, and autoimmune events and was well tolerated, with infrequent injection site reactions. These findings are consistent with those related to treatment with intravenous abatacept. Long-term treatment with SC abatacept did not lead to new safety signals over time.

  View details for DOI 10.1002/art.38687

  View details for Web of Science ID 000340375600005

  View details for PubMedID 24782324

• A Phase II Randomized Study of Subcutaneous Ixekizumab, an Anti-Interleukin-17 Monoclonal Antibody, in Rheumatoid Arthritis Patients Who Were Naive to Biologic Agents or Had an Inadequate Response to Tumor Necrosis Factor Inhibitors ARTHRITIS & RHEUMATOLOGY Genovese, M. C., Greenwald, M., Cho, C., Berman, A., Jin, L., Cameron, G. S., Benichou, O., Xie, L., Braun, D., Berclaz, P., Banerjee, S. 2014; 66 (7): 1693-1704

  Abstract

  To evaluate ixekizumab, an anti-interleukin-17A (anti-IL-17A) monoclonal antibody, in 2 populations of rheumatoid arthritis (RA) patients: biologics-naive patients and patients with an inadequate response to tumor necrosis factor (TNF) inhibitors.In this phase II, randomized, double-blind study, placebo or ixekizumab was administered subcutaneously to 260 biologics-naive patients and 188 patients with an inadequate response to TNF inhibitors at weeks 0, 1, 2, 4, 6, 8, and 10 with concomitant disease-modifying antirheumatic drugs. The primary objective was to determine the dose-response relationship of ixekizumab as measured by the proportion of biologics-naive patients meeting the American College of Rheumatology 20% improvement criteria (ACR20) at week 12.Using a logistic regression model defined a priori, a statistically significant dose-response relationship as measured by ACR20 response rates at week 12 was detected in biologics-naive patients (P = 0.031). For patients with an inadequate response to TNF inhibitors, ACR20 responses at week 12 were significantly better with ixekizumab than placebo (P < 0.05). Decreases in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP), Clinical Disease Activity Index (CDAI), and CRP level from baseline were observed at week 12 in the ixekizumab groups in both populations (P < 0.05 versus placebo). Onset of action was rapid in some dose groups in both populations, with improvements in the ACR20, DAS28-CRP, CRP levels, and CDAI observed by day 3 (P < 0.05). Adverse events occurred with similar frequencies overall in the ixekizumab and placebo groups. Infections were more frequent with ixekizumab than placebo (biologics-naive 25% versus 19%; inadequate responders to TNF inhibitors 27% versus 25%). No mycobacterial or invasive fungal infections were reported.Ixekizumab improved RA signs and symptoms in RA patients who were either naive to biologics treatment or had an inadequate response to TNF inhibitors. The safety profile was similar to that of other biologic agents, with no unexpected safety concerns.

  View details for DOI 10.1002/art.38617

  View details for PubMedID 24623718

• Long-Term Safety of Tocilizumab in Patients with Rheumatoid Arthritis following a Mean Treatment Duration of 3.9 Years Haraoui, B., Sebba, A., Rubbert-Roth, A., Scali, J., Alten, R., Kremer, J., Pitts, L., Vernon, E., van Vollenhoven, R., Genovese, M. J RHEUMATOL PUBL CO. 2014: 1508

  View details for Web of Science ID 000338923700166

• 12-and 24-Week Patient-Reported Outcomes from a Phase 2b Dose-Ranging Study of Baricitinib, an Oral Janus Kinase 1/Janus Kinase 2 Inhibitor, in Combination with Traditional Disease-Modifying Antirheumatic Drugs in Patients with Rheumatoid Arthritis Chalabi, Y., Smolen, J., Taylor, P., Genovese, M., Lee, C., Schlichting, D., Macias, W., Keystone, E. J RHEUMATOL PUBL CO. 2014: 1498–99

  View details for Web of Science ID 000338923700148

• Magnetic Resonance Imaging Substudy in a Phase 2b Dose-Ranging Study of Baricitinib, an Oral Janus Kinase 1/Janus Kinase 2 Inhibitor, in Combination with Traditional Disease-Modifying Antirheumatic Drugs in Patients with Rheumatoid Arthritis Chalabi, Y., Peterfy, C., Genovese, M., Emery, P., Taylor, P., Schlichting, D., Beattie, S., Macias, W., Keystone, E. J RHEUMATOL PUBL CO. 2014: 1506

  View details for Web of Science ID 000338923700162

• Baricitinib, an Oral Janus Kinase Inhibitor, in the Treatment of Rheumatoid Arthritis: 52 Week Safety and Efficacy in an Open-Label, Long-Term Extension Study Baker, M., Chalabi, Y., Genovese, M., Taylor, P., Schlichting, D., Beattie, S., Macias, W., Keystone, E. J RHEUMATOL PUBL CO. 2014: 1505

  View details for Web of Science ID 000338923700160

• Brodalumab, an Anti-IL17RA Monoclonal Antibody, in Psoriatic Arthritis NEW ENGLAND JOURNAL OF MEDICINE Mease, P. J., Genovese, M. C., Greenwald, M. W., Ritchlin, C. T., Beaulieu, A. D., Deodhar, A., Newmark, R., Feng, J., Erondu, N., Nirula, A. 2014; 370 (24): 2295-2306

  Abstract

  We assessed the efficacy and safety of brodalumab, a human monoclonal antibody against interleukin-17 receptor A (IL17RA), in a phase 2, randomized, double-blind, placebo-controlled study involving patients with psoriatic arthritis.We randomly assigned patients with active psoriatic arthritis to receive brodalumab (140 or 280 mg subcutaneously) or placebo on day 1 and at weeks 1, 2, 4, 6, 8, and 10. At week 12, patients who had not discontinued their participation in the study were offered open-label brodalumab (280 mg) every 2 weeks. The primary end point was 20% improvement in American College of Rheumatology response criteria (ACR 20) at week 12.Of the 168 patients who underwent randomization (57 in the brodalumab 140-mg group, 56 in the brodalumab 280-mg group, and 55 in the placebo group), 159 completed the double-blind phase and 134 completed 40 weeks of the open-label extension. At week 12, the brodalumab 140-mg and 280-mg groups had higher rates of ACR 20 than the placebo group (37% [P=0.03] and 39% [P=0.02], respectively, vs. 18%); they also had higher rates of 50% improvement (ACR 50) (14% [P=0.05] and 14% [P=0.05] vs. 4%). Rates of 70% improvement were not significantly higher in the brodalumab groups. Similar degrees of improvement were noted among patients who had received previous biologic therapy and those who had not received such therapy. At week 24, ACR 20 response rates in the brodalumab 140-mg and 280-mg groups were 51% and 64%, respectively, as compared with 44% among patients who switched from placebo to open-label brodalumab; responses were sustained through week 52. At week 12, serious adverse events had occurred in 3% of patients in the brodalumab groups and in 2% of those in the placebo group.Brodalumab significantly improved response rates among patients with psoriatic arthritis. Larger studies of longer duration are necessary to assess adverse events. (Funded by Amgen; ClinicalTrials.gov number, NCT01516957 .).

  View details for DOI 10.1056/NEJMoa1315231

  View details for PubMedID 24918373

• Subcutaneous Abatacept for the Treatment of Rheumatoid Arthritis: Longterm Data from the ACQUIRE Trial. journal of rheumatology Genovese, M. C., Tena, C. P., Covarrubias, A., Leon, G., Mysler, E., Keiserman, M., Valente, R., Nash, P., Simon-Campos, J. A., Box, J., Legerton, C. W., Nasonov, E., Durez, P., Delaet, I., Teng, J., Alten, R. 2014; 41 (4): 629-639

  Abstract

  Assess longterm tolerability, safety, and efficacy of subcutaneous (SC) abatacept (ABA) in methotrexate-refractory patients with rheumatoid arthritis (RA).The phase III, multinational Abatacept Comparison of Sub[QU]cutaneous Versus Intravenous in Inadequate Responders to MethotrexatE (ACQUIRE) trial comprised a 6-month, randomized, double-blind (DB) period, in which patients received intravenous (IV) or SC ABA, plus MTX, followed by an open-label, longterm extension (LTE), in which patients received SC ABA, 125 mg/week. Safety and efficacy from the LTE (∼3.5 yrs of exposure) are reported.Patients who completed the DB period (1372/1385, 99.1%) entered the LTE; 1134 patients (82.7%) kept taking the treatment at time of reporting. Mean (SD) was 31.9 months (6.8); median (range) exposure was 33.0 (8-44) months. Patients entering the LTE had longstanding, moderate-to-severe disease [mean 7.6 (7.9) yrs and DAS28 (C-reactive protein) 6.2 (0.9)]. Incidence rates (events/100 patient-yrs) were reported for serious adverse events (8.76, 95% CI 7.71, 9.95), infections (44.80, 95% CI 41.76, 48.01), serious infections (1.72, 95% CI 1.30, 2.27), malignancies (1.19, 95% CI 0.86, 1.66), and autoimmune events (1.31, 95% CI 0.95, 1.79). Twenty-seven patients (2%) experienced injection-site reactions; all except 1 were mild. American College of Rheumatology 20, 50, and 70 responses achieved during the DB period were maintained through the LTE, and on Day 981 were 80.2% (95% CI 77.2, 83.2), 63.5% (95% CI 58.2, 68.9), and 39.5% (95% CI 34.0, 44.9) for patients who kept taking SC ABA, and 80.0% (95% CI 77.0, 83.0), 63.2% (95% CI 57.8, 68.7), and 39.2% (95% CI 33.7, 44.7) for those who switched from IV to SC ABA.These findings support SC ABA as a well-tolerated and efficacious longterm treatment for patients with RA and inadequate response to MTX (ClinicalTrials.gov identifier NCT00559585).

  View details for DOI 10.3899/jrheum.130112

  View details for PubMedID 24584926

• SUSTAINED IMPROVEMENT IN HEALTH-RELATED QUALITY OF LIFE, WORK PRODUCTIVITY, EMPLOYABILITY AND REDUCED HEALTHCARE RESOURCE UTILIZATION OF PATIENTS WITH RHEUMATOID ARTHRITIS, PSORIATIC ARTHRITIS AND ANKYLOSING SPONDYLITIS TREATED WITH GOLIMUMAB: 5-YEAR RESULTS FROM THREE PHASE III STUDIES Han, C., Kavanaugh, A., Genovese, M. C., Deodhar, A., Hsu, B., Hsia, E. OXFORD UNIV PRESS. 2014: 74

  View details for Web of Science ID 000364513000224

• FINAL 5-YEAR SAFETY AND EFFICACY RESULTS OF A PHASE 3, RANDOMIZED PLACEBO-CONTROLLED TRIAL OF GOLIMUMAB IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS DESPITE Keystone, E., Genovese, M. C., Hall, S., Miranda, P. C., Bae, S., Han, C., Gathany, T., Zhou, Y., Xu, S., Hsia, E. C. OXFORD UNIV PRESS. 2014: 99

  View details for DOI 10.1093/rheumatology/keu101.031

  View details for Web of Science ID 000364513000284

• Prevalence and risk factors for Staphylococcus aureus colonization in individuals entering maximum-security prisons EPIDEMIOLOGY AND INFECTION Mukherjee, D. V., Herzig, C. T., Jeon, C. Y., Lee, C. J., Apa, Z. L., Genovese, M., Gage, D., Koenigsmann, C. J., Lowy, F. D., Larson, E. L. 2014; 142 (3): 484-493

  Abstract

  To assess the prevalence and risk factors for colonization with Staphylococcus aureus in inmates entering two maximum-security prisons in New York State, USA, inmates (N=830) were interviewed and anterior nares and oropharyngeal samples collected. Isolates were characterized using spa typing. Overall, 50·5% of women and 58·3% of men were colonized with S. aureus and 10·6% of women and 5·9% of men were colonized with MRSA at either or both body sites. Of MSSA isolates, the major subtypes were spa type 008 and 002. Overall, risk factors for S. aureus colonization varied by gender and were only found in women and included younger age, fair/poor self-reported general health, and longer length of prior incarceration. Prevalence of MRSA colonization was 8·2%, nearly 10 times greater than in the general population. Control of epidemic S. aureus in prisons should consider the constant introduction of strains by new inmates.

  View details for DOI 10.1017/S0950268813001544

  View details for Web of Science ID 000332937900005

  View details for PubMedID 23806331

  View details for PubMedCentralID PMC3874074

• BARICITINIB, AN ORAL JANUS KINASE INHIBITOR, IN THE TREATMENT OF RHEUMATOID ARTHRITIS: SAFETY AND EFFICACY IN AN OPEN-LABEL, LONG-TERM EXTENSION STUDY Taylor, P., Genovese, M., Keystone, E., Schlichting, D., Beattie, S., Macias, W. BMJ PUBLISHING GROUP. 2014: A31

  View details for DOI 10.1136/annrheumdis-2013-205124.71

  View details for Web of Science ID 000346248400072

• One-year Efficacy and Safety Results of Secukinumab in Patients With Rheumatoid Arthritis: Phase II, Dose-finding, Double-blind, Randomized, Placebo-controlled Study. journal of rheumatology Genovese, M. C., Durez, P., Richards, H. B., Supronik, J., Dokoupilova, E., Aelion, J. A., Lee, S., Codding, C. E., Kellner, H., Ikawa, T., Hugot, S., Ligozio, G., Mpofu, S. 2014; 41 (3): 414-421

  Abstract

  To evaluate the longer-term safety and efficacy of secukinumab, a fully human monoclonal antiinterleukin-17A antibody, in patients with rheumatoid arthritis.In this 52-week, double-blind, placebo-controlled (up to Week 20) study (NCT00928512), patients responding inadequately to disease-modifying antirheumatic drugs (DMARD) or biologics were randomized to receive monthly subcutaneous injections of secukinumab (25, 75, 150, or 300 mg), or placebo. The efficacy and safety results up to Week 20 have been reported previously. Here, efficacy results from Week 20 to 52 and safety results from Week 20 to 60 are presented.Of 237 patients randomized, 174 (73.4%) completed the study. Patients with improved American College of Rheumatology (ACR) and 28-joint Disease Activity Score (DAS28) C-reactive protein (CRP) responses at Week 16 sustained their responses through Week 52. In patients taking 150 mg of secukinumab, responses were improved through Week 52 (ACR50: Week 16 = 45%, Week 52 = 55%; DAS28-CRP ≤ 2.6: Week 16 = 25%, Week 52 = 40%). The rate of adverse events (AE) from weeks 20 to 60 was 64.8%, with most AE being mild to moderate in severity. The overall rate of infections was 31.9%, most being mild. The most predominant infection was nasopharyngitis, and was not associated with dose or concurrent neutropenia. Serious AE were reported in 21 patients (8.9%). There were 3 reports of malignancies (ovarian, lung, basal cell), and no deaths between weeks 20 and 60.Patients with active RA who failed to respond to DMARD and other biologics showed an improvement after longterm treatment with 150 mg of secukinumab. The frequency of AE remained stable over time and secukinumab had a consistent safety profile over 60 weeks.

  View details for DOI 10.3899/jrheum.130637

  View details for PubMedID 24429175

• Effect of golimumab on carotid atherosclerotic disease measures and cardiovascular events in inflammatory arthritides. Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases Wasko, M. C., Hsia, E. C., Kirkham, B., Touboul, P., Fleischmann, R., Genovese, M. C., Matteson, E. L., Lu, J., Xu, W., Rahman, M. U. 2014; 20 (1): 1-10

  Abstract

  The objective of this study was to assess the effect of golimumab on carotid ultrasound measures and cardiovascular serious adverse events (SAEs) in patients with inflammatory arthritides.An exploratory carotid artery ultrasound substudy was performed in the GO-BEFORE study of methotrexate (MTX)-naive rheumatoid arthritis patients, with ultrasounds performed at weeks 0, 24, and 52 to measure common carotid artery intima-media thickness, distensibility coefficient, interadventitial diameter, and plaque count. Cardiovascular SAEs reported over 2 years of follow-up were assessed in 5 golimumab phase 3 clinical trials of patients with rheumatoid arthritis (GO-BEFORE, GO-FORWARD, and GO-AFTER), psoriatic arthritis (GO-REVEAL), and ankylosing spondylitis (GO-RAISE). In GO-BEFORE and GO-FORWARD, patients received placebo + MTX, golimumab 50 mg + MTX, or golimumab 100 mg +/- MTX at baseline and every 4 weeks; in the other 3 trials, patients received placebo or golimumab 50 or 100 mg.The carotid ultrasound substudy showed inconsistent changes in common carotid artery intima-media thickness in the golimumab + MTX groups over time, and there was large variability in the measurements. Increases in interadventitial diameter were observed in the golimumab 100 mg + placebo group, but not in the golimumab + MTX groups. There were no significant differences in the distensibility coefficient and plaque count between the golimumab and placebo groups. Very few patients overall experienced a cardiovascular SAE, and the incidence of cardiovascular SAEs was not statistically different between the golimumab and placebo groups.The results of the carotid ultrasound substudy were inconclusive, and no increase or decrease in cardiovascular SAEs was observed following 2 years of treatment with golimumab with or without MTX.

  View details for DOI 10.1097/RHU.0000000000000053

  View details for PubMedID 24356481

• Effects of golimumab, an anti-tumour necrosis factor-alpha human monoclonal antibody, on lipids and markers of inflammation ANNALS OF THE RHEUMATIC DISEASES Kirkham, B. W., Wasko, M. C., Hsia, E. C., Fleischmann, R. M., Genovese, M. C., Matteson, E. L., Liu, H., Rahman, M. U. 2014; 73 (1): 161-169

  Abstract

  To assess the effect of golimumab, with or without methotrexate (MTX), on serum lipids and inflammatory markers of cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA) in two phase 3, randomised, placebo-controlled trials (GO-BEFORE and GO-FORWARD).Patients in GO-BEFORE (n=637, MTX-naïve) and GO-FORWARD (n=444, MTX-inadequate response) were randomised to placebo+MTX, golimumab 100 mg+placebo, golimumab 50 mg+MTX, or golimumab 100 mg+MTX. Subcutaneous injections (placebo and golimumab) were given every 4 weeks. Patients with an insufficient response entered early escape at week 16 (GO-FORWARD) or 28 (GO-BEFORE). All placebo+MTX patients in GO-FORWARD crossed over to golimumab 50 mg+MTX at week 24. Changes from baseline to weeks 14 (GO-FORWARD) or 24 (GO-BEFORE), and 52 in serum lipid levels and inflammatory markers were assessed.At week 14 in the GO-FORWARD trial, total cholesterol (TC), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) increased in golimumab+MTX patients versus MTX-only patients (16.00 vs 2.00 (p<0.001); 3.00 vs 0.00 (p<0.05); 8.00 vs 4.00 (p<0.001); respectively); favourable changes in LDL subfractions were only observed in golimumab-treated patients. At week 24 in GO-BEFORE, TC and LDL increased, and LDL subfractions improved in the MTX-only and golimumab+MTX groups. Inflammatory markers of CVD risk improved significantly with golimumab+MTX versus placebo+MTX in both studies and were generally maintained through week 52. Atherogenic indices were generally stable.While TC and LDL levels increased mildly in RA patients receiving golimumab+MTX, atherogenic indices generally remained stable, favourable changes in LDL subfractions were observed, and inflammatory markers improved.

  View details for DOI 10.1136/annrheumdis-2012-202089

  View details for Web of Science ID 000327835100029

  View details for PubMedID 23300117

  View details for PubMedCentralID PMC3888596

• A Phase 2b, 12-Week Study of VX-509, an Oral Selective Janus Kinase 3 Inhibitor, in Combination with Background Methotrexate in Rheumatoid Arthritis Genovese, M. C., van Vollenhoven, R., Bloom, B. J., Jiang, J. G., Kinnman, N. WILEY-BLACKWELL. 2013: 3320

  View details for Web of Science ID 000327692600044

• Results Of 64 Weeks Of Treatment With An Anti-IL-17 Antibody, Ixekizumab, In Patients With Rheumatoid Arthritis In a Phase 2 Study Genovese, M. C., Carlier, H., Erickson, J., Braun, D., Banerjee, S. WILEY-BLACKWELL. 2013: S188

  View details for Web of Science ID 000325359201433

• Sustained Improvement In Health-Related Quality Of Life, Work Productivity, Employability, and Reduced Healthcare Resource Utilization Of Patients With Rheumatoid Arthritis, Psoriatic Arthritis and Ankylosing Spondylitis Treated With Golimumab: 5-Year Results From 3 Phase III Studies Han, C., Kavanaugh, A., Genovese, M. C., Hsu, B., Deodhar, A. A., Hsia, E. C. WILEY-BLACKWELL. 2013: S137

  View details for Web of Science ID 000325359201319

• Clinical Response To Brodalumab, An Anti-Interleukin-17 Receptor Antibody, In Subjects With Psoriatic Arthritis Genovese, M. C., Mease, P. J., Greenwald, M. W., Ritchlin, C. T., Beaulieu, A., Deodhar, A., Newmark, R., Feng, J., Erondu, N., Nirula, A. WILEY-BLACKWELL. 2013: S347–S348

  View details for Web of Science ID 000325359202322

• Final 5-Year Safety and Efficacy Results Of a Phase 3, Randomized Placebo-Controlled Trial Of Golimumab In Patients With Active Rheumatoid Arthritis Despite Prior Treatment With Methotrexate Keystone, E., Genovese, M. C., Hall, S., Miranda, P., Bae, S., Han, C., Gathany, T. A., Zhou, Y., Xu, S., Hsia, E. C. WILEY-BLACKWELL. 2013: S597–S598

  View details for Web of Science ID 000325359203395

• Prediction Of TNF Inhibitor Response In Rheumatoid Arthritis Patients Using Single Cell Network Profiling Of Intracellular Immune Signaling Ptacek, J., Hawtin, R., Louie, B., Evensen, E., Cordeiro, J., Mittleman, B., Atallah, M., Cesano, A., Bingham, C. O., Cofield, S., Curtis, J. R., Danila, M. I., Furie, R. A., Genovese, M. C., Levesque, M. C., Moreland, L. W., Nigrovic, P. A., O'Dell, J. R., Robinson, W. H., Shadick, N. A., St Clair, E., Striebich, C. C., Thiele, G. M., Gregersen, P. K., Bridges, S. WILEY-BLACKWELL. 2013: S375

  View details for Web of Science ID 000325359202381

• Lack Of Early Clinical Response To Treatment With Baricitinib Predicts Low Probability Of Achieving Long Term DAS28-ESR Low Disease Activity Or Remission In Patients With Rheumatoid Arthritis. Keystone, E., Genovese, M. C., Taylor, P., Zhu, B., Beattie, S. D., de Bono, S., Rooney, T., Schlichting, D. E., Macias, W. WILEY-BLACKWELL. 2013: S607

  View details for Web of Science ID 000325359203414

• Effect Of Brodalumab (AMG 827) On Pain and Physical Functioning In Patients With Psoriatic Arthritis Genovese, M. C., Mease, P. J., Viswanathan, H., Chau, D., Feng, J., Erondu, N., Nirula, A. WILEY-BLACKWELL. 2013: S136

  View details for Web of Science ID 000325359201317

• Efficacy and Safety Of Subcutaneous Administration Of Tabalumab, An Anti-B Cell Activating Factor Monoclonal Antibody, In Rheumatoid Arthritis: Results From a Phase 3 Multicenter, Randomized, Double-Blind Study Genovese, M. C., Silverman, G. J., Emery, P., Gupta, R., Gill, A., Komocsar, W. J., Veenhuizen, M., Xie, L., Berclaz, P., Lee, C. WILEY-BLACKWELL. 2013: S733–S734

  View details for Web of Science ID 000325359204191

• Novel Biomarkers From Peripheral Blood Mononuclear Cells Indicate Disease Activity In Rheumatoid Arthritis Patients. Ptacek, J., Hawtin, R., Louie, B., Evensen, E., Cordeiro, J., Mittleman, B., Atallah, M., Cesano, A., Bingham, C. O., Cofield, S., Curtis, J. R., Danila, M. I., Furie, R. A., Genovese, M. C., Levesque, M. C., Moreland, L. W., Nigrovic, P. A., O'Dell, J. R., Robinson, W. H., Shadick, N. A., St Clair, E., Striebich, C. C., Thiele, G. M., Gregersen, P. K., Bridges, S. WILEY-BLACKWELL. 2013: S974–S975

  View details for Web of Science ID 000325359205235

• Oskira-3: A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Parallel-Group Study Of 2 Dosing Regimens Of Fostamatinib In Rheumatoid Arthritis Patients With An Inadequate Response To a Tumor Necrosis Factor-alpha Antagonist. Genovese, M., van der Heijde, D., Keystone, E., Spindler, A., Benhamou, C., Kavanaugh, A., Fudman, E., Lampl, K., O'Brien, C., Duffield, E., Poiley, J., Weinblatt, M. WILEY-BLACKWELL. 2013: S199–S200

  View details for Web of Science ID 000325359201455

• Disease Activity in Moderate and Severe Rheumatoid Arthritis At Discontinuation in 10-Year Open-Label Extension Studies With Etanercept Weinblatt, M. E., Bathon, J. M., Hooper, M., Bitman, B., Yang, Y., Collier, D. H., Chung, J., Genovese, M. C. WILEY-BLACKWELL. 2013: S986–S987

  View details for Web of Science ID 000325359205264

• Transaminase Levels and Hepatic Events Observed During Tocilizumab Treatment: Pooled Analysis Of Long-Term Clinical Trial Safety Data In Patients With Rheumatoid Arthritis. Genovese, M. C., Kremer, J. M., van Vollenhoven, R. F., Alten, R., Jose Scali, J., Kelman, A., Rowell, L., Pitts, L. WILEY-BLACKWELL. 2013: S201

  View details for Web of Science ID 000325359201458

• Oskira-2: A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Parallel-Group Study Of 2 Dosing Regimens Of Fostamatinib In Rheumatoid Arthritis Patients With An Inadequate Response To Disease-Modifying Antirheumatic Drugs. Dawes, P., Dimic, A., Genovese, M. C., van der Heijde, D., Jenkins, M., O'Brien, C., Oemar, B., Vencovsky, J., Weinblatt, M. WILEY-BLACKWELL. 2013: S198–S199

  View details for Web of Science ID 000325359201454

• A phase 2 dose-ranging study of subcutaneous tabalumab for the treatment of patients with active rheumatoid arthritis and an inadequate response to methotrexate ANNALS OF THE RHEUMATIC DISEASES Genovese, M. C., Lee, E., Satterwhite, J., Veenhuizen, M., Disch, D., Berclaz, P., Myers, S., Sides, G., Benichou, O. 2013; 72 (9): 1453-1460

  Abstract

  OBJECTIVES: To assess the dose-response relationship, efficacy and safety of tabalumab, a human monoclonal antibody that neutralises membrane-bound and soluble B-cell activating factor (BAFF), in patients with rheumatoid arthritis (RA) with inadequate response to methotrexate (MTX). METHODS: In this phase 2, 24-week, double-blind, placebo-controlled, dose-ranging study, patients with RA (N=158) on stable  MTX were randomised by Bayesian-adaptive method to receive 1, 3, 10, 30, 60, or 120 mg tabalumab or placebo subcutaneously every 4 weeks for 24 weeks. The primary objective was to test for a significant dose-response relationship using a statistical model of the proportion of patients having ≥50% improvement in American College of Rheumatology (ACR) criteria (ACR50) at week 24 (prespecified α=0.10). RESULTS: At week 24, a significant dose-response relationship was observed using ACR50 (p=0.059) and ACR20 (p=0.044) response rates. Using model-estimated data, only 120 mg had significantly higher ACR50 and ACR20 response rates versus placebo (p<0.05). Observed response rates were significantly higher for 120 mg versus placebo as measured by ACR50 at weeks 12 (p=0.039) and 20 (p=0.018), but not week 24, and by ACR20 at weeks 12 (p=0.011) and 24 (p=0.039). Mean DAS28 C-reactive protein  improved with 120 mg at week 24 (p=0.048). Frequency of TEAEs was similar across groups (range 50-69%, p=0.884). Ten (8.2%) tabalumab and 5 (13.9%) placebo patients reported a serious adverse event (SAE). Infections occurred more frequently in patients exposed to tabalumab (30.3% vs 19.4%). Serious infections were reported in 3 (2.5%) tabalumab-treated patients only. CONCLUSIONS: A dose-response relationship was detected with monthly subcutaneous tabalumab. A significant effect was detected with the 120 mg dose with no unexpected safety signals. CLINICAL TRIAL #: NCT00785928.

  View details for DOI 10.1136/annrheumdis-2012-202864

  View details for Web of Science ID 000323161100004

  View details for PubMedID 23599435

• Tabalumab, an anti-BAFF monoclonal antibody, in patients with active rheumatoid arthritis with an inadequate response to TNF inhibitors ANNALS OF THE RHEUMATIC DISEASES Genovese, M. C., Fleischmann, R. M., Greenwald, M., Satterwhite, J., Veenhuizen, M., Xie, L., Berclaz, P., Myers, S., Benichou, O. 2013; 72 (9): 1461-1468

  Abstract

  OBJECTIVE: To evaluate the efficacy and safety of tabalumab, a monoclonal antibody that neutralises membrane-bound and soluble B-cell activating factor (BAFF), in patients with active rheumatoid arthritis (RA) who showed inadequate response to tumour necrosis factor (TNF) inhibitors. METHODS: Patients on stable methotrexate and with inadequate response to one or more TNF inhibitors were randomised to placebo (n=35), 30 mg tabalumab (n=35) or 80 mg tabalumab (n=30) given intravenously at 0, 3 and 6 weeks. The primary outcome was the proportion of patients achieving an American College of Rheumatology 50% response (ACR50) at week 16 (all tabalumab-treated patients vs placebo). RESULTS: At week 16, no significant differences were observed in the combined tabalumab group versus placebo in ACR50 (12.7% vs 2.9%, p=0.101) or ACR20 response rates (27.0% vs 17.1%, p=0.198). However, significant differences between the combined tabalumab group and placebo were observed at earlier time points for ACR20, ACR50 and Disease Activity Score in 28 joints (DAS28)-C-reactive protein (CRP) reduction. Treatment-emergent adverse events (AEs) were similar with 30 mg tabalumab (65.7%), 80 mg tabalumab (76.7%) and placebo (71.4%), although certain events occurred more often with tabalumab than placebo (eg, infection, anaemia and gastrointestinal events). Serious AEs occurred in two (6.7%) patients receiving 80 mg tabalumab and three (8.6%) receiving placebo, with one serious infection in the placebo group. Initial increases in total and mature B cells were followed by progressive decreases, despite declines in serum tabalumab. CONCLUSIONS: At week 16, the primary end point was not achieved, but an indication of efficacy was observed at earlier time points. Safety findings for tabalumab were consistent with other biological RA therapies. CLINICAL TRIAL REGISTRATION NUMBER: NCT00689728.

  View details for DOI 10.1136/annrheumdis-2012-202775

  View details for Web of Science ID 000323161100005

  View details for PubMedID 23268367

• Tofacitinib in Combination With Nonbiologic Disease-Modifying Antirheumatic Drugs in Patients With Active Rheumatoid Arthritis A Randomized Trial ANNALS OF INTERNAL MEDICINE Kremer, J., Li, Z., Hall, S., Fleischmann, R., Genovese, M., Martin-Mola, E., Isaacs, J. D., Gruben, D., Wallenstein, G., Krishnaswami, S., Zwillich, S. H., Koncz, T., Riese, R., Bradley, J. 2013; 159 (4): 253-?

  Abstract

  Many patients with rheumatoid arthritis (RA) do not achieve adequate and safe responses with disease-modifying antirheumatic drugs (DMARDs). Tofacitinib is a novel, oral, Janus kinase inhibitor that treats RA.To evaluate the efficacy and safety of tofacitinib in combination with nonbiologic DMARDs.1-year, double-blind, randomized trial (ClinicalTrials.gov: NCT00856544).114 centers in 19 countries.792 patients with active RA despite nonbiologic DMARD therapy.Patients were randomly assigned 4:4:1:1 to oral tofacitinib, 5 mg or 10 mg twice daily, or placebo advanced to tofacitinib, 5 mg or 10 mg twice daily.Primary end points were 20% improvement in American College of Rheumatology (ACR20) criteria; Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6; DAS28-4(ESR)-defined remission, change in Health Assessment Questionnaire Disability Index (HAQ-DI) score, and safety assessments.Mean treatment differences for ACR20 response rates (month 6) for the 5-mg and 10-mg tofacitinib groups compared with the combined placebo groups were 21.2% (95% CI, 12.2% to 30.3%; P < 0.001) and 25.8% (CI, 16.8% to 34.8%; P < 0.001), respectively. The HAQ-DI scores (month 3) and DAS28-4(ESR) less than 2.6 response rates (month 6) were also superior in the tofacitinib groups versus placebo. The incidence rates of serious adverse events for patients receiving 5-mg tofacitinib, 10-mg tofacitinib, or placebo were 6.9, 7.3, or 10.9 events per 100 patient-years of exposure, respectively. In the tofacitinib groups, 2 cases of tuberculosis, 2 cases of other opportunistic infections, 3 cardiovascular events, and 4 deaths occurred. Neutrophil counts decreased, hemoglobin and low- and high-density lipoprotein cholesterol levels increased, and serum creatinine levels had small increases in the tofacitinib groups.Placebo groups were smaller and of shorter duration. Patients received primarily methotrexate. The ability to assess drug combinations other than tofacitinib plus methotrexate was limited.Tofacitinib improved disease control in patients with active RA despite treatment with nonbiologic DMARDs, primarily methotrexate.Pfizer.

  View details for Web of Science ID 000323421700015

  View details for PubMedID 24026258

• Novel small molecule therapeutics in rheumatoid arthritis RHEUMATOLOGY Kelly, V., Genovese, M. 2013; 52 (7): 1155-1162

  Abstract

  A new wave of emerging therapies for the treatment of autoimmune and inflammatory diseases is under development. These therapies interrupt intracellular signalling through kinase inhibition. By interrupting one or more kinases it is possible to modulate the function of cellular structures such as surface receptors, signalling proteins and transcription of nuclear proteins and thus influence the behaviour of the cell types targeted. With these advances comes the significant potential to develop highly effective orally bioavailable therapeutics. The targets generating the greatest enthusiasm at this time for the treatment of autoimmune and inflammatory diseases include Janus-associated kinase, spleen tyrosine kinase, phosphodiesterase-4, Bruton's tyrosine kinase and phosphatidylinositol-3 kinase. Ultimately human trials will help us understand the potential risks and benefits of these novel approaches across a number of diseases.

  View details for DOI 10.1093/rheumatology/kes367

  View details for Web of Science ID 000321061200003

  View details for PubMedID 23297340

• Golimumab in Patients with Active Rheumatoid Arthritis Despite Methotrexate Therapy: Results Through 2 Years of the GO-FORWARD Study Extension JOURNAL OF RHEUMATOLOGY Keystone, E. C., Genovese, M. C., Hall, S., Miranda, P. C., Bae, S., Palmer, W., Wu, Z., Xu, S., Hsia, E. C. 2013; 40 (7): 1097-1103

  Abstract

  OBJECTIVE: To assess the longterm efficacy and safety of golimumab in patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) therapy. METHODS: We randomized 444 RA patients with inadequate response to MTX (3:3:2:2) to placebo + MTX (Group 1), golimumab 100 mg + placebo (Group 2), golimumab 50 mg + MTX (Group 3), or golimumab 100 mg + MTX (Group 4). Subcutaneous golimumab/placebo was injected every 4 weeks. Patients could escape early (Group 1 added golimumab 50 mg, Group 2 added MTX, Group 3 increased golimumab to 100 mg, Group 4 continued 100 mg) based on Week 16 swollen and tender joint counts. From Week 24, Group 1 patients received golimumab 50 mg + MTX. After the Week 52 database lock, patients in the longterm extension received golimumab 50-100 mg ± MTX. Coprimary endpoints [Week 14 American College of Rheumatology (ACR)20, Week 24 Health Assessment Questionnaire Disability Index (HAQ-DI)] and Week 52 findings have been published; 2-year findings (observed data by randomized group, no imputation) are presented. RESULTS: Of 444 randomized patients, 392 continued from Week 52 (Group 1: n = 116, Group 2: n = 116, Group 3: n = 84, Group 4: n = 76). Clinical improvement was maintained through Week 104; ~75% and 72% of patients randomized to golimumab 50 mg + MTX and 100 mg + MTX achieved ACR20 response, respectively. The majority [88% (105/120)] of golimumab + MTX-treated patients with Week 24 HAQ-DI improvement ≥ 0.25 maintained improved physical function through Week 104. Group 1 patients with delayed golimumab treatment exhibited more Week 104 radiographic progression (mean change score = 1.15) than golimumab + MTX-randomized patients (0.52). Incidences of serious infections were 2.24, 4.77, 5.78/100 patient-years of followup for golimumab 50 mg + MTX, 100 mg + placebo, and 100 mg + MTX, respectively. CONCLUSION: Clinical improvement was maintained and no new safety signals were identified with 2 years of golimumab + MTX. Golimumab efficacy and safety, including serious infections, will continue to be monitored through 5 years (Clinical Trial No. NCT00264550).

  View details for DOI 10.3899/jrheum.120584

  View details for Web of Science ID 000321993800012

  View details for PubMedID 23678153

• Longterm Safety and Efficacy of Tocilizumab in Patients with Rheumatoid Arthritis: A Cumulative Analysis of Up to 4.6 Years of Exposure JOURNAL OF RHEUMATOLOGY Genovese, M. C., Rubbert-Roth, A., Smolen, J. S., Kremer, J., Khraishi, M., Gomez-Reino, J., Sebba, A., Pilson, R., Williams, S., van Vollenhoven, R. 2013; 40 (6): 768-780

  Abstract

  OBJECTIVE: To assess the longterm safety and efficacy of tocilizumab (TCZ) in patients with moderate to severe rheumatoid arthritis (RA). METHODS: Patient data were from 5 randomized controlled TCZ trials (n = 4211), their open-label extension phases (n = 3512), and a drug interaction study (n = 23). All randomly assigned patients, regardless of previous RA treatment, were analyzed. Measures of safety included number of adverse events (AE), serious AE (SAE), AE leading to treatment discontinuation, laboratory tests, and deaths. Efficacy measures included American College of Rheumatology (ACR) 20/50/70 responses, tender joint count (TJC), swollen joint count (SJC), ACR core set components, and low disease activity (LDA) or Disease Activity Score in 28 joints (DAS28) remission. ACR/European League Against Rheumatism (EULAR) disease remission was a posthoc exploratory analysis. RESULTS: Total duration of observation was 12,293 patient-years (PY). No new safety signals were identified; infections were the most common AE and SAE. The rate of serious infections was 4.5/100 PY. Improvements from baseline in clinical efficacy, measured as ACR20/50/70 responses, TJC, SJC, ACR core set components, and LDA and DAS28 remission, were generally sustained through at least 216 weeks of followup. ACR/EULAR disease remission was attained by 16.5% (Boolean) and 22.7% (index) of patients at Week 216. CONCLUSION: TCZ has to date been studied for up to 4.6 years (240 weeks) of treatment in patients with RA. Our analysis reveals a longer-term safety profile consistent with previous observations, no new safety signals, and durable efficacy of TCZ in a large clinical trial program.

  View details for DOI 10.3899/jrheum.120687

  View details for PubMedID 23457383

• Validation of Remission of Rheumatoid Arthritis by Traditional Disease Activity Score and Provisional Criteria by American College of Rheumatology and European League Against Rheumatism: Analysis Based on Patient Reported Outcomes Analyzed from 3 Phase III Golimumab Clinical Trials of Golimumab Keystone, E., Han, C., Fleischmann, R., Smolen, J., Emery, P., Genovese, M., Doyle, M., Hsia, E. J RHEUMATOL PUBL CO. 2013: 968–69

  View details for Web of Science ID 000320009600081

• Longterm Remission with Golimumab in Active Rheumatoid Arthritis Patients Despite Methotrexate Through 2 Years Keystone, E., Genovese, M., Klareskog, L., Xu, S., Han, C., Hsia, E. J RHEUMATOL PUBL CO. 2013: 968

  View details for Web of Science ID 000320009600080

• Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study. Annals of the rheumatic diseases Genovese, M. C., Durez, P., Richards, H. B., Supronik, J., Dokoupilova, E., Mazurov, V., Aelion, J. A., Lee, S., Codding, C. E., Kellner, H., Ikawa, T., Hugot, S., Mpofu, S. 2013; 72 (6): 863-869

  Abstract

  To assess the safety and efficacy of secukinumab, a fully human monoclonal anti-interleukin-17A antibody, in patients with rheumatoid arthritis (RA).Patients (n=237) with inadequate response to methotrexate were randomly assigned to receive monthly subcutaneous injections of secukinumab 25 mg, 75 mg, 150 mg, 300 mg or placebo. The primary endpoint was the American College of Rheumatology 20% response (ACR20) at week 16.Demographics and baseline characteristics were comparable across all treatment groups. The primary efficacy endpoint was not achieved: the proportion of ACR20 responders at week 16 with secukinumab 25-300 mg was 36.0-53.7% versus placebo (34%). Disease activity score in 28 joints (DAS28)-C-reactive protein (CRP) was a secondary endpoint and clinically relevant decreases with secukinumab 75-300 mg were reported versus placebo. Serum high sensitivity CRP levels at week 16 were significantly reduced with secukinumab 75 mg, 150 mg and 300 mg doses versus placebo. The safety profile of secukinumab was consistent with that seen with other biological agents. Most adverse events (AE) were mild to moderate in severity. Infections were slightly more frequent with secukinumab than placebo. Six serious AE were reported: secukinumab 75 mg (one), secukinumab 300 mg (four) and placebo (one).ACR20 response rates differed between secukinumab 75 mg, 150 mg and 300 mg doses and placebo; however, the primary efficacy endpoint was not achieved. Greater decreases in DAS28 were observed with secukinumab 75 mg, 150 mg and 300 mg than placebo. There were no unexpected safety signals and no specific organ-related toxicities. Further trials with secukinumab in the treatment of RA are warranted.

  View details for DOI 10.1136/annrheumdis-2012-201601

  View details for PubMedID 22730366

• Efficacy and Safety of Belimumab in Patients with Rheumatoid Arthritis: A Phase II, Randomized, Double-blind, Placebo-controlled, Dose-ranging Study JOURNAL OF RHEUMATOLOGY Stohl, W., Merrill, J. T., McKay, J. D., Lisse, J. R., Zhong, Z. J., Freimuth, W. W., Genovese, M. C. 2013; 40 (5): 579-589

  Abstract

  To evaluate the efficacy/safety of belimumab in patients with rheumatoid arthritis (RA).Patients fulfilling American College of Rheumatology (ACR) criteria for RA for ≥ 1 year who had at least moderate disease activity while receiving stable disease-modifying antirheumatic drug (DMARD) therapy and failed ≥ 1 DMARD were randomly assigned to placebo or belimumab 1, 4, or 10 mg/kg, administered intravenously on Days 1, 14, and 28, and then every 4 weeks for 24 weeks (n = 283). This was followed by an optional 24-week extension (n = 237) in which all patients received belimumab. Primary efficacy endpoint was the Week 24 ACR20 response.Week 24 ACR20 responses with placebo and belimumab 1, 4, and 10 mg/kg were 15.9%, 34.7% (p = 0.010), 25.4% (p = 0.168), and 28.2% (p = 0.080), respectively. Patients taking any belimumab dose who continued with belimumab in the open-label extension had an ACR20 response of 41% at 48 weeks. A similar ACR20 response (42%) at 48 weeks was seen in patients taking placebo who switched in the extension to belimumab 10 mg/kg. Greater response rates were observed in patients who at baseline were rheumatoid factor-positive, anticitrullinated protein antibody-positive, or tumor necrosis factor inhibitor-naive, or had elevated C-reactive protein levels, Disease Activity Score 28 > 5.1, or low B lymphocyte stimulator levels (< 0.858 ng/ml). Adverse event rates were similar across treatment groups.In this phase II trial, belimumab demonstrated efficacy and was generally well tolerated in patients with RA who had failed previous therapies. [ClinicalTrials.gov identifier NCT00071812].

  View details for DOI 10.3899/jrheum.120886

  View details for Web of Science ID 000319171900008

  View details for PubMedID 23547209

• Immunogenicity, Safety, and Efficacy of Abatacept Administered Subcutaneously With or Without Background Methotrexate in Patients With Rheumatoid Arthritis: Results From a Phase III, International, Multicenter, Parallel-Arm, Open-Label Study ARTHRITIS CARE & RESEARCH Nash, P., Nayiager, S., Genovese, M. C., Kivitz, A. J., Oelke, K., Ludivico, C., Palmer, W., Rodriguez, C., Delaet, I., Elegbe, A., Corbo, M. 2013; 65 (5): 718-728

  Abstract

  To evaluate the impact of concomitant methotrexate (MTX) on subcutaneous (SC) abatacept immunogenicity, and to assess safety and efficacy.This phase III, open-label study had a 4-month short-term (ST) period and an ongoing long-term extension (LTE) period. Rheumatoid arthritis patients were stratified to receive SC abatacept (125 mg/week) with (combination) or without MTX (monotherapy), with no intravenous loading dose; patients receiving monotherapy could add MTX in the LTE period. Immunogenicity (percentage of anti-abatacept antibody-positive patients) was assessed. ST and LTE period data are reported, including efficacy through LTE month 14 and safety through LTE month 20.Ninety-six of 100 enrolled patients completed the ST period; 3.9% (combination) and 4.1% of patients (monotherapy) developed transient immunogenicity, and no patients were antibody positive at month 4. Serious adverse events (SAEs) were reported in 3.9% (combination) and 6.1% of patients (monotherapy); 5.9% (combination) and 8.2% of patients (monotherapy) experienced SC injection reactions, and all were mild in intensity. Mean 28-joint Disease Activity Score (DAS28) changes were -1.67 (95% confidence interval [95% CI] -2.06, -1.28; combination) and -1.94 (95% CI -2.46, -1.42; monotherapy) at month 4. Ninety patients entered and were treated in the LTE period; 83.3% (75 of 90) remained ongoing at month 24. One LTE-treated patient (1.1%) developed immunogenicity, 14.4% of patients experienced SAEs, and no SC injection reactions were reported. For patients entering the LTE period, mean DAS28 changes from baseline were -1.84 (95% CI -2.23, -1.34; combination) and -2.86 (95% CI -3.46, -2.27; monotherapy) at month 18.SC abatacept did not elicit immunogenicity associated with loss of safety or efficacy, either with or without MTX.

  View details for DOI 10.1002/acr.21876

  View details for Web of Science ID 000318114700008

  View details for PubMedID 23097311

• Tabalumab in Rheumatoid Arthritis Patients With an Inadequate Response to Methotrexate and Naive to Biologic Therapy: A Phase II, Randomized, Placebo-Controlled Trial ARTHRITIS AND RHEUMATISM Genovese, M. C., Bojin, S., Biagini, I. M., Mociran, E., Cristei, D., Mirea, G., Georgescu, L., Sloan-Lancaster, J. 2013; 65 (4): 880-889

  Abstract

  Tabalumab, a fully human IgG4 monoclonal antibody, neutralizes soluble and membrane-bound BAFF. The aim of this study was to examine the tolerability and efficacy of tabalumab in patients with active rheumatoid arthritis receiving methotrexate.In this randomized, double-blind, placebo-controlled, parallel, multiple-dose study, patients who were naive to biologic therapy received infusions of tabalumab (30, 60, or 160 mg) or placebo at weeks 0, 3, and 6 in combination with methotrexate and were evaluated for 24 weeks. The primary efficacy end point was the percentage of patients meeting American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 16.At week 16, the percentages of patients achieving an ACR20 response in the 30-mg (57.6%), 60-mg (67.6%), and 160-mg (51.5%) groups were significantly greater than the percentage of patients achieving an ACR20 response in the placebo group (29.4%; P<0.05). There were initial transient increases from baseline in the frequency of CD20+ and IgD+/CD27- B cells, followed by reductions, although B cells were not completely depleted. Also, the frequency of IgD-/CD27+ B cells increased in all tabalumab groups compared with the placebo group and returned toward baseline levels by the end of the study. The incidence of adverse events was similar across all treatment groups; no deaths occurred. Serum IgM levels decreased significantly in all tabalumab groups combined compared with the placebo group. There were no significant decreases in serum IgG or IgA levels in the tabalumab groups compared with the placebo group.Tabalumab treatment significantly reduces the signs and symptoms of rheumatoid arthritis and has a safety profile similar to that seen with placebo treatment.

  View details for DOI 10.1002/art.37820

  View details for Web of Science ID 000316962000006

  View details for PubMedID 23359344

• VALIDATION OF REMISSION OF RHEUMATOID ARTHRITIS BY TRADITIONAL DISEASE ACTIVITY SCORE AND PROVISIONAL CRITERIA BY AMERICAN COLLEGE OF RHEUMATOLOGY AND EUROPEAN LEAGUE AGAINST RHEUMATISM: ANALYSIS BASED ON PATIENT-REPORTED OUTCOMES ANALYSED FROM THREE PHASE III GOLIMUMAB CLINICAL TRIALS Han, C., Keystone, E. C., Fleischmann, R., Smolen, J., Emery, P., Genovese, M., Doyle, M., Hsia, E. C. OXFORD UNIV PRESS. 2013: 83

  View details for Web of Science ID 000318569000236

• WEEKLY SUBCUTANEOUS ABATACEPT CONFERS COMPARABLE ONSET OF TREATMENT RESPONSE AND MAGNITUDE OF EFFICACY IMPROVEMENT OVER 6 MONTHS WHEN ADMINISTERED WITH OR WITHOUT AN INTRAVENOUS ABATACEPT LOADING DOSE Annual Meeting of the British-Society-for-Rheumatology and British-Health-Professionals-in-Rheumatology Schiff, M., Alten, R., Weinblatt, M. E., Nash, P., Fleischmann, R., Durez, P., Kaine, J., Delaet, I., Kelly, S., Maldonado, M., Patel, S., Genovese, M. OXFORD UNIV PRESS. 2013: 91–92

  View details for Web of Science ID 000318569000256

• LONG-TERM SAFETY OF TOCILIZUMAB IN RA PATIENTS TREATED FOR A MEAN DURATION OF 3.7 YEARS Genovese, M., Sebba, A., Rubbert-Roth, A., Scali, J. J., Alten, R., Kremer, J. M., Pitts, L., Vernon, E., van Vollenhoven, R. F. OXFORD UNIV PRESS. 2013: 93–94

  View details for Web of Science ID 000318569000261

• 24-WEEK RESULTS OF A BLINDED PHASE IIB DOSE-RANGING STUDY OF BARICITINIB, AN ORAL JAK1/JAK2 INHIBITOR, IN COMBINATION WITH TRADITIONAL DMARDS IN PATIENTS WITH RHEUMATOID ARTHRITIS Annual Meeting of the British-Society-for-Rheumatology and British-Health-Professionals-in-Rheumatology Taylor, P., Genovese, M., Keystone, E. C., Drescher, E., Berclaz, P., Lee, C., Fidelus-Gort, R., Schlichting, D., Beattie, S., Luchi, M., Macias, W. OXFORD UNIV PRESS. 2013: 44–45

  View details for Web of Science ID 000318569000138

• Effects of Fostamatinib (R788), an Oral Spleen Tyrosine Kinase Inhibitor, on Health-related Quality of Life in Patients with Active Rheumatoid Arthritis: Analyses of Patient-reported Outcomes from a Randomized, Double-blind, Placebo-controlled Trial JOURNAL OF RHEUMATOLOGY Weinblatt, M. E., Kavanaugh, A., Genovese, M. C., Jones, D. A., Musser, T. K., Grossbard, E. B., Magilavy, D. B. 2013; 40 (4): 369-378

  Abstract

  To assess the influence of fostamatinib on patient-reported outcomes (PRO) in patients with active rheumatoid arthritis and an inadequate response to methotrexate (MTX).Patients taking background MTX (N = 457) were enrolled in a phase II clinical trial (NCT00665925) and randomized equally to placebo, fostamatinib 100 mg twice daily (bid), or fostamatinib 150 mg once daily (qd) for 24 weeks. Self-administered PRO measures included pain, patient's global assessment (PtGA) of disease activity, physical function, health-related quality of life (HRQOL), and fatigue. Mean change from baseline and a responder analysis of the proportion of patients achieving a minimal clinically important difference were determined.At Week 24, there were statistically significant improvements in pain, PtGA, physical function, fatigue, and the physical component summary of the Medical Outcomes Study Short Form-36 (SF-36) for fostamatinib 100 mg bid compared with placebo. Mean (standard error) changes from baseline in the fostamatinib 100 mg bid group versus the placebo group were -31.3 (2.45) versus -17.8 (2.45), p < 0.001 for pain; -29.1 (2.26) versus -16.7 (2.42), p < 0.001 for PtGA; -0.647 (0.064) versus -0.343 (0.062), p < 0.001 for physical function; 7.40 (1.00) versus 4.50 (0.94), p < 0.05 for fatigue; 8.52 (0.77) versus 4.90 (0.78), p < 0.01 for SF-36 physical component score; and 3.99 (0.93) versus 3.71 (0.99), p = 0.83 for SF-36 mental component score. Patients receiving fostamatinib 150 mg qd showed improvements in some PRO, including physical function.Patients treated with fostamatinib 100 mg bid showed significant improvements in HRQOL outcomes.

  View details for DOI 10.3899/jrheum.120923

  View details for Web of Science ID 000317540600007

  View details for PubMedID 23378467

• Tocilizumab as Monotherapy or in Combination With Nonbiologic Disease-Modifying Antirheumatic Drugs: Twenty-Four-Week Results of an Open-Label, Clinical Practice Study ARTHRITIS CARE & RESEARCH Weinblatt, M. E., Kremer, J., Cush, J., Rigby, W., Teng, L. L., Devenport, J., Singh, N., Lepley, D., Genovese, M. C. 2013; 65 (3): 362-371

  Abstract

  To assess the safety and tolerability of tocilizumab (TCZ) as monotherapy or in combination with nonbiologic disease-modifying antirheumatic drugs (DMARDs) in patients with moderate to severe rheumatoid arthritis (RA) who had an inadequate response at study entry to their current treatment with biologic agents or DMARDs.This 24-week, multicenter, open-label, phase IIIb study conducted in the US enrolled 886 patients. Treatments were allocated to patients based on their current therapy at study entry. Patients receiving monotherapy with biologic agents were assigned to TCZ 8 mg/kg monotherapy. All other patients were randomized to either TCZ 4 mg/kg + DMARDs or TCZ 8 mg/kg + DMARDs. The primary end point was the number and percentage of patients with serious adverse events (SAEs) during 24 weeks of TCZ treatment. Efficacy assessments were evaluated as secondary outcomes. Data were analyzed descriptively.Overall, 69 patients (7.8%) reported ≥1 SAEs. The rate of SAEs per 100 person-years was 28.3 (95% confidence interval [95% CI] 23.1-34.4) overall and was similar across treatment groups: 29.1 (95% CI 21.0-39.2), 30.3 (95% CI 22.2-40.2), and 20.6 (95% CI 10.3-36.9) in the TCZ 4/8 mg/kg + DMARDs, TCZ 8 mg/kg + DMARDs, and TCZ 8 mg/kg monotherapy groups, respectively. The most common SAEs were infections (i.e., pneumonia [1.0%] and cellulitis [0.9%]). In addition, American College of Rheumatology response rates and reductions in mean Disease Activity Score based on a 28-joint count were generally similar among treatment groups.The safety findings in this study were consistent with the previously identified safety profile of TCZ. TCZ had an AE profile consistent with prior randomized blinded studies and was effective when administered as either monotherapy or in combination with DMARDs for the treatment of RA.

  View details for DOI 10.1002/acr.21847

  View details for Web of Science ID 000316907700004

  View details for PubMedID 22972745

• Effects of sclerostin antibody on healing of a non-critical size femoral bone defect JOURNAL OF ORTHOPAEDIC RESEARCH Jawad, M. U., Fritton, K. E., Ma, T., Ren, P., Goodman, S. B., Ke, H. Z., Babij, P., Genovese, M. C. 2013; 31 (1): 155-163

  Abstract

  Sclerostin is a glycoprotein secreted by osteocytes and inhibits osteoblastogenesis via inhibition of Wnt signaling. We hypothesized that sclerostin antibody (Scl-AbIII) would accelerate the healing of a murine femoral non-critical size bone defect model. A unilateral and unicortical 0.8 mm-sized drill hole was made in the proximal femoral shaft of adult female nude mice. One group of mice received subcutaneous injections of Scl-AbIII and a second group received vehicle only. Reporter MC3T3 osteoprogenitor cells were injected via the tail vein 3 days after surgery to monitor systemic trafficking of exogenous osteoprogenitors. Bioluminescence imaging (BLI), microcomputed tomography (microCT), micropositron emission tomography (microPET) and histological analysis were used to compare the bone healing responses to Scl-AbIII treatment. Bone mineral density (BMD) significantly increased at the defect site after week 1, and was significantly higher in the treatment compared with the control group at all time points. This finding was also confirmed on histological analysis by increased deposition of new woven bone. MicroPET scanning showed a trend for greater activity in the control group at day 21 compared with the Scl-AbIII group, indicating early bone maturation following treatment with Scl-AbIII. Whereas the BLI signals derived from the injected osteoprogenitor cells showed no differences between vehicle and Scl-AbIII treated groups, systemic migration of MC3T3 cells to the bone defect was clearly identified in both groups using immunohistochemistry. Systemic administration of Scl-AbIII resulted in earlier healing and maturation of a non-critical size bone defect. These findings underscore the potential use of Scl-AbIII for treatment of complicated fractures, non-unions, and other clinical scenarios.

  View details for DOI 10.1002/jor.22186

  View details for PubMedID 22887736

• Magnetic Resonance Imaging Substudy in a Phase 2b Dose-Ranging Study of Baricitinib, an Oral Janus Kinase 1/Janus Kinase 2 Inhibitor, in Combination with Traditional Disease-Modifying Antirheumatic Drugs in Patients with Rheumatoid Arthritis. Annual Scientific Meeting of the American-College-of-Rheumatology (ACR) and Association-of-Rheumatology-Health-Professionals (ARHP) Peterfy, C. G., Emery, P., Genovese, M. C., Keystone, E., Taylor, P., Berclaz, P., Dicarlo, J. C., Lee, C. H., Schlichting, D. E., Beattie, S. D., Luchi, M. E., Macias, W. WILEY-BLACKWELL. 2012: S1050–S1051

  View details for Web of Science ID 000309748305408

• Efficacy, safety and tolerability of HZT-501, including users of low-dose aspirin (LDA), a single-tablet combination of ibuprofen-famotidine: results of two phase 3 trials. Weinblatt, M., Genovese, M. C., Kivitz, A., Bello, A. E., Grahn, A., Sherman, J. W., Schiff, M. H., Magelli, M. WILEY-BLACKWELL. 2012: E203

  View details for Web of Science ID 000309452700090

• Long-Term Safety of Tocilizumab in Patients with Rheumatoid Arthritis and a Mean Treatment Duration of 3.7 Years. Genovese, M. C., Sebba, A., Rubbert-Roth, A., Jose Scali, J., Alten, R., Kremer, J. M., Pitts, L., Vernon, E., van Vollenhoven, R. F. WILEY-BLACKWELL. 2012: S700–S701

  View details for Web of Science ID 000309748303361

• Sarilumab, a Subcutaneously-Administered, Fully-Human Monoclonal Antibody Inhibitor of the IL-6 Receptor: Effects On Hemoglobin Levels in a Clinical Trial for the Treatment of Moderate-to-Severe Rheumatoid Arthritis Genovese, M. C., Fleischmann, R. M., Jasson, M., Radin, A. R., Hamilton, J., Huizinga, T. J. WILEY-BLACKWELL. 2012: S568

  View details for Web of Science ID 000309748303041

• Validation of Remission of Rheumatoid Arthritis by Traditional Disease Activity Score and Provisional Criteria by American College of Rheumatology and European League Against Rheumatism: Patient Reported Outcomes Analyzed From 3 Phase III Golimumab Trials. Han, C., Keystone, E., Fleischmann, R., Smolen, J. S., Emery, P., Genovese, M. C., Doyle, M. K., Hsia, E. C. WILEY-BLACKWELL. 2012: S35–S36

  View details for Web of Science ID 000309748300081

• 12-and 24-Week Patient-Reported Outcomes From a Phase 2b Dose-Ranging Study of Baricitinib, an Oral Janus Kinase 1/Janus Kinase 2 Inhibitor, in Combination with Traditional Disease-Modifying Antirheumatic Drugs in Patients with Rheumatoid Arthritis Annual Scientific Meeting of the American-College-of-Rheumatology (ACR) and Association-of-Rheumatology-Health-Professionals (ARHP) Smolen, J. S., Schlichting, D. E., Sterling, K. L., Keystone, E., Taylor, P., Genovese, M. C., Johnson, L., Rizo Rodriguez, J. C., Lee, C. H., Gaich, C. L. WILEY-BLACKWELL. 2012: S214–S214

  View details for Web of Science ID 000309748301029

• 24-Week Results of a Blinded Phase 2b Dose-Ranging Study of Baricitinib, an Oral Janus Kinase 1/Januse Kinase 2 Inhibitor, in Combination with Traditional Disease Modifying Antirheumatic Drugs in Patients with Rheumatoid Arthritis. Annual Scientific Meeting of the American-College-of-Rheumatology (ACR) and Association-of-Rheumatology-Health-Professionals (ARHP) Genovese, M. C., Keystone, E., Taylor, P., Drescher, E., Berclaz, P., Lee, C. H., Schlichting, D. E., Beattie, S. D., Fidelus-Gort, R. K., Luchi, M. E., Macias, W. WILEY-BLACKWELL. 2012: S1049–S1050

  View details for Web of Science ID 000309748305407

• Gene Expression Profiling and Pathway Changes Associated with Clinical Response to Tabalumab Blockade of Membrane Bound and Soluble B Cell Activating Factor in Rheumatoid Arthritis Komocsar, W. J., Genovese, M. C., Dow, E. R., Banerjee, P., Penny, M. A., Nantz, E. P., Stepaniants, S., Ho, A., Berclaz, P., Hoffman, R. W. WILEY-BLACKWELL. 2012: S565

  View details for Web of Science ID 000309748303036

• Prolonged Exposure to Subcutaneous and Intravenous Abatacept in Patients with Rheumatoid Arthritis Does Not Affect Rates of Infection, Malignancy and Autoimmune Events: Results From Pooled Clinical Trial Data. Annual Scientific Meeting of the American-College-of-Rheumatology (ACR) and Association-of-Rheumatology-Health-Professionals (ARHP) Genovese, M. C., Hochberg, M. C., Cohen, R. B., Weinblatt, M. E., Kaine, J., Keystone, E., Nash, P., Delaet, I., Alten, R. WILEY-BLACKWELL. 2012: S725–S725

  View details for Web of Science ID 000309748303416

• Subcutaneous Abatacept: Long-Term Data From the Acquire Trial Annual Scientific Meeting of the American-College-of-Rheumatology (ACR) and Association-of-Rheumatology-Health-Professionals (ARHP) Genovese, M. C., Pacheco-Tena, C., Covarrubias, A., LEON, G., Mysler, E., Keiserman, M., Valente, R., Nash, P., Simon-Campos, J. A., Box, J., Legerton, C., Nasonov, E., Durez, P., Delaet, I., Alten, R. WILEY-BLACKWELL. 2012: S201–S201

  View details for Web of Science ID 000309748301001

• Longterm Safety and Efficacy of Abatacept Through 5 Years of Treatment in Patients with Rheumatoid Arthritis and an Inadequate Response to Tumor Necrosis Factor Inhibitor Therapy JOURNAL OF RHEUMATOLOGY Genovese, M. C., Schiff, M., Luggen, M., Le Bars, M., Aranda, R., Elegbe, A., DougadoS, M. 2012; 39 (8): 1546-1554

  Abstract

  To evaluate abatacept safety and efficacy over 5 years in patients with rheumatoid arthritis (RA) who had inadequate response to anti-tumor necrosis factor (TNF) therapy in the ATTAIN trial.Patients completing the 6-month, double-blind (DB) placebo-controlled period were eligible to enter the longterm extension (LTE), where all patients received abatacept every 4 weeks (∼10 mg/kg, according to weight range). Safety, efficacy, physical function, and health-related quality of life were monitored throughout.In total, 317 patients (218 DB abatacept, 99 DB placebo) entered the LTE; 150 (47.3%) completed it. Overall incidences of serious adverse events, infections, serious infections, malignant neoplasms, and autoimmune events did not increase during the LTE versus the DB period. American College of Rheumatology responses with abatacept at Month 6 were maintained over 5 years. At Year 5, among patients who received abatacept for 5 years and had available data, 38/103 (36.9%) achieved low disease activity as defined by the 28-joint Disease Activity Score (DAS28)/C-reactive protein (CRP); 23/103 (22.3%) achieved DAS28/CRP-defined remission. Health Assessment Questionnaire response was achieved by 62.5% of patients remaining on treatment at Year 5; mean improvements from baseline in physical component summary and mental component summary scores were 7.34 and 6.42, respectively. High proportions of patients maintained efficacy and physical function benefits or improved their disease state at each timepoint throughout the LTE, if remaining on abatacept treatment.Safety remained consistent, and abatacept efficacy was maintained from 6 months to 5 years, demonstrating the benefits of switching to abatacept in this difficult-to-treat population of patients with RA previously failing anti-TNF therapy.

  View details for DOI 10.3899/jrheum.111531

  View details for Web of Science ID 000307795800010

  View details for PubMedID 22798265

• Effect of Golimumab on Patient-reported Outcomes in Rheumatoid Arthritis: Results from the GO-FORWARD Study JOURNAL OF RHEUMATOLOGY Genovese, M. C., Han, C., Keystone, E. C., Hsia, E. C., Buchanan, J., Gathany, T., Murphy, F. T., Wu, Z., Parasuraman, S., Rahman, M. U. 2012; 39 (6): 1185-1191

  Abstract

  To evaluate the effect of golimumab on physical function, general health, and fatigue in patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) therapy.In the multicenter, randomized, placebo-controlled GO-FORWARD study, 444 adults with active RA despite MTX received subcutaneous placebo + MTX (crossover to golimumab 50 mg at Week 24), golimumab 100 mg + placebo, golimumab 50 mg + MTX, or golimumab 100 mg + MTX every 4 weeks. Physical function and general health were assessed using the Health Assessment Questionnaire-Disability Index (HAQ-DI) and Physical and Mental Component Summary (PCS, MCS) scores of the Medical Outcomes Study Short Form-36 questionnaire (SF-36), respectively, through Week 52. Fatigue was measured through Week 24 using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) questionnaire.Mean improvements from baseline in HAQ-DI, SF-36 PCS, and FACIT-Fatigue scores (Weeks 14 and 24) were significantly greater for golimumab 50 mg + MTX and 100 mg + MTX versus placebo + MTX. Significantly greater proportions of patients treated with golimumab + MTX achieved clinically meaningful improvements from baseline to Weeks 14 and 24 in HAQ-DI, PCS, and FACIT-Fatigue scores. Mean improvements in SF-36 PCS (Week 14), MCS (Week 24), and FACIT-Fatigue (Weeks 14 and 24) scores were significantly greater for golimumab 100 mg + placebo versus placebo + MTX. Mean improvements from baseline in HAQ-DI, SF-36 PCS, and MCS scores through Week 24 were sustained through Week 52.Patients with active RA despite MTX had significant improvement in physical function, general health, and fatigue following golimumab + MTX therapy; improvements in physical function and general health were maintained through Week 52. (Clinical Trials Registration NCT00264550).

  View details for DOI 10.3899/jrheum.111195

  View details for Web of Science ID 000304893800015

  View details for PubMedID 22505702

• SAFETY PROFILE OF SUBCUTANEOUS ABATACEPT FOCUSING ON CLINICALLY RELEVANT EVENTS IN PATIENTS WITH RHEUMATOID ARTHRITIS AND UP TO 4.5 YEARS OF EXPOSURE Annual Meeting of the British-Society-for-Rheumatology Alten, R., Kaine, J. L., Keystone, E., Nash, P. T., Delaet, I., Qi, K., Genovese, M. C. OXFORD UNIV PRESS. 2012: 127–128

  View details for Web of Science ID 000302487900350

• SUBCUTANEOUS ABATACEPT VERSUS INTRAVENOUS ABATACEPT IN PATIENTS WITH RHEUMATOID ARTHRITIS: LONG-TERM DATA FROM THE ACQUIRE TRIAL Genovese, M. C., Covarrubias Cobos, A., Leon, G., Mysler, E. F., Keiserman, M. W., Valente, R. M., Nash, P. T., Simon Campos, J., Porawska, W., Box, J. H., Legerton, C. W., Nasonov, E. L., Durez, P., Pappu, R., Delaet, I., Teng, J., Alten, R. OXFORD UNIV PRESS. 2012: 128–29

  View details for Web of Science ID 000302487900352

• SECUKINUMAB TREATMENT PROVIDES SUSTAINED RESPONSE OVER ONE YEAR IN PATIENTS WITH RHEUMATOID ARTHRITIS Durez, P., Genovese, M. C., Richards, H. B., Supronik, J., Dokoupilova, E., Aelion, J. A., Lee, S., Codding, C. E., Kellner, H., Ikawa, T., Hugot, S., Ligozio, G., Mpofu, S. OXFORD UNIV PRESS. 2012: 29

  View details for Web of Science ID 000302487900096

• LONG-TERM SAFETY OF TOCILIZUMAB IN RHEUMATOID ARTHRITIS CLINICAL TRIALS Genovese, M. C., Sebba, A., Rubbert-Roth, A., Scali, J., Zilberstein, M., Thompson, L., Van Vollenhoven, R. OXFORD UNIV PRESS. 2012: 75–76

  View details for Web of Science ID 000302487900214

• Effect of golimumab combined with methotrexate on radiographic progression in rheumatoid arthritis: comment on the article by Emery et al Reply ARTHRITIS AND RHEUMATISM Emery, P., Conaghan, P. G., Fleischmann, R., van der Heijde, D., Keystone, E. C., Genovese, M. C., Hsia, E. C., Xu, W., Beutler, A., Baratelle, A., Rahman, M. U. 2012; 64 (4): 1298–99

  View details for DOI 10.1002/art.34367

  View details for Web of Science ID 000302475500049

• Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs ARTHRITIS AND RHEUMATISM Fleischmann, R., Cutolo, M., Genovese, M. C., Lee, E. B., Kanik, K. S., Sadis, S., Connell, C. A., Gruben, D., Krishnaswami, S., Wallenstein, G., Wilkinson, B. E., Zwillich, S. H. 2012; 64 (3): 617-629

  Abstract

  To compare the efficacy, safety, and tolerability of 5 doses of oral tofacitinib (CP-690,550) or adalimumab monotherapy with placebo for the treatment of active rheumatoid arthritis (RA) in patients with an inadequate response to disease-modifying antirheumatic drugs.In this 24-week, double-blind, phase IIb study, patients with RA (n = 384) were randomized to receive placebo, tofacitinib at 1, 3, 5, 10, or 15 mg administered orally twice a day, or adalimumab at 40 mg injected subcutaneously every 2 weeks (total of 6 injections) followed by oral tofacitinib at 5 mg twice a day for 12 weeks. The primary end point was the responder rate according to the American College of Rheumatology 20% improvement criteria (ACR20) at week 12.Treatment with tofacitinib at a dose of ≥3 mg twice a day resulted in a rapid response with significant efficacy when compared to placebo, as indicated by the primary end point (ACR20 response at week 12), achieved in 39.2% (3 mg; P ≤ 0.05), 59.2% (5 mg; P < 0.0001), 70.5% (10 mg; P < 0.0001), and 71.9% (15 mg; P < 0.0001) in the tofacitinib group and 35.9% of patients in the adalimumab group (P = 0.105), compared with 22.0% of patients receiving placebo. Improvements were sustained at week 24, according to the ACR20, ACR50, and ACR70 response rates as well as classifications of remission according to the 3-variable Disease Activity Score in 28 joints (DAS28) using C-reactive protein and the 4-variable DAS28 using the erythrocyte sedimentation rate. The most common treatment-emergent adverse events (AEs) in patients across all tofacitinib treatment arms (n = 272) were urinary tract infection (7.7%), diarrhea (4.8%), headache (4.8%), and bronchitis (4.8%).Tofacitinib monotherapy at ≥3 mg twice a day was efficacious in the treatment of patients with active RA over 24 weeks and demonstrated a manageable safety profile.

  View details for DOI 10.1002/art.33383

  View details for Web of Science ID 000300835900005

  View details for PubMedID 21952978

• Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to at least one tumor necrosis factor inhibitor: Results of a forty-eight-week randomized, double-blind, placebo-controlled, parallel-group phase III trial ARTHRITIS AND RHEUMATISM Tak, P. P., Mease, P. J., Genovese, M. C., Kremer, J., Haraoui, B., Tanaka, Y., Bingham, C. O., Ashrafzadeh, A., Travers, H., Safa-Leathers, S., Kumar, S., Dummer, W. 2012; 64 (2): 360-370

  Abstract

  To evaluate the safety and efficacy of ocrelizumab plus methotrexate (MTX) or leflunomide (LEF) in patients with active rheumatoid arthritis (RA) and an inadequate response to tumor necrosis factor α inhibitors.This was a multicenter randomized, double-blind, placebo-controlled, parallel-group study that continued over 48 weeks. Patients receiving stable doses of MTX or LEF were randomized to receive 2 infusions of placebo (n = 277), ocrelizumab 200 mg (n = 278), or ocrelizumab 500 mg (n = 285) on days 1 and 15 as well as at weeks 24 and 26. Coprimary end points were the proportion of patients with response according to the American College of Rheumatology 20% improvement criteria (ACR20) at weeks 24 and 48. Secondary end points included the change from baseline in the modified Sharp/van der Heijde score (SHS) and the ACR50/70 responses.ACR20 responses were 22.0% in the placebo group, 42.2% in the ocrelizumab 200 mg group, and 47.9% in the ocrelizumab 500 mg group at 24 weeks and 19.5%, 48.7%, and 50.7%, respectively, at 48 weeks (P < 0.0001 versus placebo for each comparison at each time point). At 48 weeks, patients receiving both doses of ocrelizumab showed significantly improved ACR50 and ACR70 responses of ~3-fold versus placebo. Only those in the ocrelizumab 500 mg group showed statistically significant (P = 0.0017) inhibition of joint damage progression (mean change in the SHS) relative to placebo (61% inhibition) at 48 weeks. Overall adverse events and infections during the 48 weeks of study were comparable in all treatment groups. Serious infections were observed more frequently in patients taking ocrelizumab (5.1% and 4.3%) than in those taking placebo (2.5%).Patients in both of the ocrelizumab groups met the clinical primary efficacy end points. Inhibition of change in the SHS was statistically significant at 48 weeks for those in the ocrelizumab 500 mg group. The rate of serious infections in this trial was higher for both ocrelizumab doses as compared with placebo.

  View details for DOI 10.1002/art.33353

  View details for Web of Science ID 000299625700006

  View details for PubMedID 22389919

• IL-17 receptor and its functional significance in psoriatic arthritis MOLECULAR AND CELLULAR BIOCHEMISTRY Raychaudhuri, S. P., Raychaudhuri, S. K., Genovese, M. C. 2012; 359 (1-2): 419–29

  Abstract

  To delineate the functional significance of IL-17 Receptor (IL-17RA) and characterize the IL-17 producing T cell (Th17) subpopulation in psoriatic arthritis (PsA). Mononuclear cells from blood and synovial fluid (SF) were obtained from PsA (n=20), rheumatoid arthritis (RA, n=20) and osteoarthritis (OA, n=20) patients. Synoviocytes (FLS) were isolated from the synovium of RA (n=5), PsA (n=5) and OA (n=5) patients. IL-17RA expression in FLS was identified by western blotting (WB) and flowcytometry. T lymphocytes derived from the SF of these patients were studied to identify and phenotype the Th17 cells. The functional significance of IL-17RA was determined by evaluating its regulatory role on the production of proinflammatory cytokines and endopeptidase. IL-17RA expression was found to be significantly higher in FLS of RA (15.7%±4.9) and PsA (4.5%±0.9) in comparison to OA (1.14%±0.9). Western blot analyses showed that the relative intensity (RI) of IL-17RA protein was higher in RA and PsA compared to OA (Fisher exact, P<0.01). A significant enrichment of IL-17-producing CD4+ T cells (7.9%±2.8) was observed in the SF of PsA patients compared to that of OA patients (P<.001). Compared to OA-FLS, recombinant IL-17 induced higher levels of IL-6, IL-8, and MMP-3 production in PsA-FLS. Blockage of IL-17RA with an anti-IL-17RA antibody inhibited the production of IL-6, IL-8, and MMP-3. This is the first report to demonstrate the functional significance of IL-17RA in PsA. Results of this study support the hypothesis that IL-17RA blocking antibodies have the potential to be a therapeutic option for psoriatic arthritis.

  View details for DOI 10.1007/s11010-011-1036-6

  View details for Web of Science ID 000297174700043

  View details for PubMedID 21894442

• Exploratory analyses of the association of MRI with clinical, laboratory and radiographic findings in patients with rheumatoid arthritis ANNALS OF THE RHEUMATIC DISEASES Emery, P., van der Heijde, D., Ostergaard, M., Conaghan, P. G., Genovese, M. C., Keystone, E. C., Fleischmann, R., Hsia, E. C., Xu, W., Xu, S., Rahman, M. U. 2011; 70 (12): 2126-2130

  Abstract

  Evaluate relationships between MRI and clinical/laboratory/radiographic findings in rheumatoid arthritis (RA).637 methotrexate-naive patients (GO-BEFORE) and 444 patients with active RA despite methotrexate (GO-FORWARD) were randomly assigned to subcutaneous placebo + methotrexate, golimumab 100mg + placebo, golimumab 50mg + methotrexate, or golimumab 100mg + methotrexate every-4-weeks. In GO-BEFORE(n=318) and GO-FORWARD(n=240) substudies, MRI of dominant wrist/metacarpophalangeal joints were scored for synovitis, bone oedema and bone erosion (RA MRI scoring (RAMRIS) system). Relationships between RAMRIS scores and serum C-reactive protein (CRP), 28-joint count disease activity score (DAS28-CRP) and van der Heijde modified Sharp (vdH-S) scores were assessed.Baseline and weeks 24/28 DAS28-CRP, CRP, and vdH-S generally correlated well with baseline and week 24 RAMRIS synovitis, oedema and erosion scores. Early (week 4) CRP changes correlated with later (week 12) RAMRIS synovitis/oedema change scores; earlier (week 12) changes in some RAMRIS scores correlated with later (weeks 24/28) changes in vdH-S. Significant correlations between RAMRIS change scores and clinical/radiographic change scores were weak.MRI and clinical/laboratory/radiographic measures generally correlated well. Associations between earlier changes in CRP and later changes in RAMRIS synovitis/osteitis were observed. Changes in MRI and clinical/radiographic measures did not correlate well, probably because MRI is more sensitive than radiographs and more objective than DAS28-CRP.

  View details for DOI 10.1136/ard.2011.154500

  View details for Web of Science ID 000297571900011

  View details for PubMedID 21926186

  View details for PubMedCentralID PMC3212698

• Sarilumab for the Treatment of Moderate-to-Severe Rheumatoid Arthritis: Results of a Phase 2, Randomized, Double-Blind, Placebo-Controlled, International Study Genovese, M. C., Kivitz, A. J., Simon Campos, J., Rell-Bakalarska, M., Fleischmann, R. M., Jasson, M., Radin, A. R., Huang, X., Huizinga, T. J. WILEY-BLACKWELL. 2011: 4041–42

  View details for Web of Science ID 000297458500060

• Assessment by MRI of inflammation and damage in rheumatoid arthritis patients with methotrexate inadequate response receiving golimumab: results of the GO-FORWARD trial ANNALS OF THE RHEUMATIC DISEASES Conaghan, P. G., Emery, P., Ostergaard, M., Keystone, E. C., Genovese, M. C., Hsia, E. C., Xu, W., Rahman, M. U. 2011; 70 (11): 1968-1974

  Abstract

  To evaluate golimumab's effect on MRI-detected inflammation and structural damage in patients with active rheumatoid arthritis (RA) despite methotrexate (MTX).Patients (n=444) were randomly assigned to placebo plus MTX, golimumab 100 mg plus placebo, golimumab 50 mg plus MTX, or golimumab 100 mg plus MTX (subcutaneous injections every 4 weeks). A subset of 240 patients participated in an MRI substudy. MRIs (1.5T+contrast enhancement) of the dominant wrist and metacarpophalangeal (MCP) joints were obtained at baseline and weeks 12 and 24. Images were scored by two independent, blinded readers for synovitis (0-9 wrist only (n=240), 0-21 wrist+MCP (n=223)), bone oedema (osteitis) (0-69) and bone erosions (0-230) using the OMERACT Rheumatoid Arthritis MRI Scoring system.Significant improvements in synovitis and bone oedema (osteitis) were observed in the combined golimumab plus MTX groups versus placebo plus MTX at week 12 (-1.77 vs -0.15, p<0.001 wrist+MCP and -2.00 vs 0.19, p=0.003, respectively) and week 24 (-1.91 vs -0.38, p<0.001 wrist+MCP and -1.74 vs 0.71, p=0.004, respectively). Fewer than 10% of patients had a substantial degree of erosive progression (most showed no progression) across all treatment groups (including the control group), precluding adequate evaluation of golimumab's effect on bone erosions.Golimumab plus MTX significantly improved MRI-detected synovitis and osteitis (prognosticators of future structural damage) versus placebo plus MTX at weeks 12 and 24. The effect of golimumab on bone erosions could not be determined by semi-quantitative scoring in these RA patients with minimal progression of bone erosions.

  View details for DOI 10.1136/ard.2010.146068

  View details for Web of Science ID 000295399700015

  View details for PubMedID 21784729

  View details for PubMedCentralID PMC3184239

• Subcutaneous Abatacept Versus Intravenous Abatacept A Phase IIIb Noninferiority Study in Patients With an Inadequate Response to Methotrexate ARTHRITIS AND RHEUMATISM Genovese, M. C., Covarrubias, A., LEON, G., Mysler, E., Keiserman, M., Valente, R., Nash, P., Simon-Campos, J. A., PORAWSKA, W., Box, J., Legerton, C., Nasonov, E., Durez, P., Aranda, R., Pappu, R., Delaet, I., Teng, J., Alten, R. 2011; 63 (10): 2854-2864

  Abstract

  To compare the efficacy and safety of subcutaneous (SC) and intravenous (IV) abatacept.In this phase IIIb double-blind, double-dummy, 6-month study, patients with rheumatoid arthritis (RA) and inadequate responses to methotrexate were randomized to receive 125 mg SC abatacept on days 1 and 8 and weekly thereafter (plus an IV loading dose [∼10 mg/kg] on day 1) or IV abatacept (∼10 mg/kg) on days 1, 15, and 29 and every 4 weeks thereafter. The primary end point for determining the noninferiority of SC abatacept to IV abatacept was the proportion of patients in each group meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at month 6. Other efficacy end points, immunogenicity, and safety were also assessed.Of 1,457 patients, 693 of 736 (94.2%) treated with SC abatacept and 676 of 721 (93.8%) treated with IV abatacept completed 6 months. At month 6, 76.0% (95% confidence interval 72.9, 79.2) of SC abatacept-treated patients versus 75.8% (95% confidence interval 72.6, 79.0) of IV abatacept-treated patients achieved an ACR20 response (estimated difference between groups 0.3% [95% confidence interval -4.2, 4.8]), confirming noninferiority of SC abatacept to IV abatacept. Onset and magnitude of ACR responses and disease activity and physical function improvements were comparable between the SC and IV abatacept-treated groups. The proportions of adverse events (AEs) and serious AEs over 6 months were 67.0% and 4.2%, respectively, in the SC abatacept-treated group and 65.2% and 4.9%, respectively, in the IV abatacept-treated group, with comparable frequencies of serious infections, malignancies, and autoimmune events between groups. SC injection site reactions (mostly mild) occurred in 19 SC abatacept (IV placebo)-treated patients (2.6%) and 18 IV abatacept (SC placebo)-treated patients (2.5%). Abatacept-induced antibodies occurred in 1.1% of SC abatacept-treated patients and 2.3% of IV abatacept-treated patients.SC abatacept provides efficacy and safety comparable with that of IV abatacept, with low immunogenicity and high retention rates, consistent with the established IV abatacept profile. Rates of injection site reactions were low. SC abatacept will provide additional treatment options, such as an alternative route of administration, for patients with RA.

  View details for DOI 10.1002/art.30463

  View details for Web of Science ID 000295293000004

  View details for PubMedID 21618201

  View details for PubMedCentralID PMC3229984

• American College of Rheumatology hybrid measure for assessing efficacy of treatment in patients with refractory rheumatoid arthritis: comment on the article by Genovese et al Reply ARTHRITIS AND RHEUMATISM Genovese, M. C. 2011; 63 (10): 3182

  View details for DOI 10.1002/art.30540

  View details for Web of Science ID 000295293000048

• Tocilizumab Monotherapy and Tocilizumab Plus Disease-Modifying Antirheumatic Drugs in a US Rheumatoid Arthritis Population with Inadequate Response to Anti-Tumor Necrosis Factor Agents. Weinblatt, M. E., Kremer, J. M., Cush, J. J., Rigby, W., Teng, L., Singh, N., Malamet, R. L., Genovese, M. C. WILEY-BLACKWELL. 2011: S162

  View details for Web of Science ID 000297621500427

• Effects of the Oral SYK Inhibitor, Fostamatinib (R788), on Health-Related Quality of Life in a Phase II Study of Active Rheumatoid Arthritis. Weinblatt, M. E., Kavanaugh, A., Genovese, M. C., Jones, D. A., Musser, T. K., Grossbard, E. B., Magilavy, D. B. WILEY-BLACKWELL. 2011: S158–S159

  View details for Web of Science ID 000297621500420

• Longer-Term Safety of Fostamatinib (R788) in Patients with Rheumatoid Arthritis-Analysis of Clinical Trial Data From up to 2 Years of Exposure. Kavanaugh, A., Weinblatt, M. E., Genovese, M. C., Musser, T. K., Grossbard, E. B., Magilavy, D. B., Hollis, S., van-Sway, E., Millson, D. WILEY-BLACKWELL. 2011: S1018–S1019

  View details for Web of Science ID 000297621503174

• One Year Efficacy and Safety Results of a Phase II Trial of Secukinumab in Patients with Rheumatoid Arthritis. Genovese, M. C., Durez, P., Richards, H. B., Supronik, J., Dokoupilova, E., Aelion, J. A., Lee, S., Codding, C. E., Kellner, H., Ikawa, T., Hugot, S., Ligozio, G., Mpofu, S. WILEY-BLACKWELL. 2011: S149–S150

  View details for Web of Science ID 000297621500401

• Long-Term Safety of Tocilizumab in Rheumatoid Arthritis Clinical Trials. Genovese, M. C., Sebba, A., Rubbert-Roth, A., Scali, J., Zilberstein, M., Thompson, L., van Vollenhoven, R. F. WILEY. 2011: S866

  View details for Web of Science ID 000297621502603

• Immunogenicity Is Low and Transient with Intravenous (IV) Abatacept Therapy: Results From a Large Pooled Analysis of 3985 Patients (pts) with Rheumatoid Arthritis (RA) and up to 8 Years' Exposure Weinblatt, M. E., Genovese, M. C., Schiff, M. H., Westhovens, R., Alten, R., Delaet, I., Nys, M., Manning, J., Kremer, J. M. WILEY-BLACKWELL. 2011: S854

  View details for Web of Science ID 000297621502577

• A Phase 2 Study of Multiple Subcutaneous Doses of LY2439821, An Anti-IL-17 Monoclonal Antibody, in Patients with Rheumatoid Arthritis in Two Populations: Naive to Biologic Therapy or Inadequate Responders to Tumor Necrosis Factor Alpha Inhibitors. 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals (ARHP) Genovese, M. C., Greenwald, M. W., Cho, C. S., Berman, A., Jin, L., Cameron, G., Xie, L., Braun, D., Banerjee, S., Warner, L. WILEY-BLACKWELL. 2011: S1017–S1017

  View details for Web of Science ID 000297621503171

• Safety Profile of Subcutaneous Abatacept Focusing on Clinically Relevant Events in Patients with Rheumatoid Arthritis (RA) and up to 4.5 Years of Exposure. 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals (ARHP) Alten, R., Kaine, J. L., Keystone, E., Nash, P. T., Delaet, I., Qi, K., Genovese, M. C. WILEY-BLACKWELL. 2011: S150–S151

  View details for Web of Science ID 000297621500403

• Subcutaneous (SC) Abatacept (ABA) Versus Intravenous (IV) ABA in Patients (pts) with Rheumatoid Arthritis: Long-Term Data From the ACQUIRE (Abatacept Comparison of Sub[QU]cutaneous versus Intravenous in Inadequate Responders to MethotrexatE) Trial. 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals (ARHP) Genovese, M. C., Covarrubias Cobos, A., Leon, G., Mysler, E. F., Keiserman, M. W., Valente, R. M., Nash, P. T., Simon Campos, J. A., Porawska, W., Box, J. H., Legerton, C. W., Nasonov, E. L., Durez, P., Pappu, R., Delaet, I., Teng, J., Alten, R. WILEY-BLACKWELL. 2011: S150–S150

  View details for Web of Science ID 000297621500402

• Tofacitinib (CP-690,550) in Combination with Traditional Disease-Modifying Anti-Rheumatic Drugs: Phase 3 Study Patient-Reported Outcomes in Patients with Active Rheumatoid Arthritis and An Inadequate Response to Disease-Modifying Anti-Rheumatic Drugs. 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals (ARHP) Strand, V., Kremer, J. M., Li, Z. G., Hall, S., Fleischmann, R. M., Genovese, M. C., Martin-Mola, E., Isaacs, J., Gruben, D., Wallenstein, G., Krishnaswami, S., Zwillich, S. H., Koncz, T., Riese, R., Bradley, J. D. WILEY-BLACKWELL. 2011: S1032–S1032

  View details for Web of Science ID 000297621503206

• Atacicept in Patients With Rheumatoid Arthritis and an Inadequate Response to Tumor Necrosis Factor Antagonist Therapy Results of a Phase II, Randomized, Placebo-Controlled, Dose-Finding Trial ARTHRITIS AND RHEUMATISM Genovese, M. C., Kinnman, N., de La Bourdonnaye, G., Rossi, C. P., Tak, P. P. 2011; 63 (7): 1793-1803

  Abstract

  To assess the efficacy, safety, and biologic activity of atacicept in patients with rheumatoid arthritis (RA) in whom the response to treatment with tumor necrosis factor antagonists was inadequate.The Atacicept for Reduction of Signs and Symptoms in Rheumatoid Arthritis Trial (AUGUST I) was a multicenter, phase II, double-blind, placebo-controlled dose-finding study involving 256 patients randomized 1:1:1:1 to receive atacicept (25 mg, 75 mg, or 150 mg) or placebo twice weekly for 4 weeks, then weekly for 21 weeks, with a 13-week treatment-free followup period (week 38). The primary end point was a response at week 26 according to the American College of Rheumatology criteria for 20% improvement in disease severity, using the C-reactive protein level.No statistically significant differences were observed in the efficacy end points at week 26 (P = 0.410 for overall treatment effect). However, atacicept significantly reduced immunoglobulin and rheumatoid factor (RF) levels, but not anti-citrullinated protein antibody levels, in a dose-dependent manner, with levels returning toward baseline values during followup. The effects of treatment on IgG-RF and IgA-RF were more pronounced than the effects on total IgG and IgA. Adverse events (AEs), including serious AEs, leading to withdrawal were more common among patients treated with atacicept compared with placebo. AEs were variable in nature, and no dose-dependent trends were observed. The frequency of infection-related AEs was similar across treatments. No notable effect of treatment on immunization status (protective versus nonprotective titer) was observed after initiation of treatment.This study did not meet the primary efficacy end point. However, clear biologic activity consistent with the proposed mechanism of action was observed. The results suggest that decreasing the expression of RF may not be sufficient to induce clinical improvement in RA. The safety of atacicept was considered acceptable in this patient population.

  View details for DOI 10.1002/art.30373

  View details for Web of Science ID 000292809700007

  View details for PubMedID 21452293

• A 24-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study of the Efficacy of Oral SCIO-469, a p38 Mitogen-activated Protein Kinase Inhibitor, in Patients with Active Rheumatoid Arthritis JOURNAL OF RHEUMATOLOGY Genovese, M. C., Cohen, S. B., Wofsy, D., Weinblatt, M. E., Firestein, G. S., Brahn, E., Strand, V., Baker, D. G., Tong, S. E. 2011; 38 (5): 846-854

  Abstract

  To evaluate the efficacy, safety, and tolerability of oral SCIO-469, a p38 MAPK inhibitor that blocks tumor necrosis factor-α, interleukin-1ß, and cyclooxygenase-2 synthesis in patients with active rheumatoid arthritis (RA).Patients were randomized to receive SCIO-469 at either 30 or 60 mg three times daily in an immediate-release (IR) formulation or at 100 mg once daily in an extended-release (ER) formulation, or placebo for 24 weeks. The primary endpoint was American College of Rheumatology (ACR)20 response at Week 12. Safety was monitored through Week 26.Overall, 302 patients were randomized: 76 to placebo, 75 to 30 mg IR, 73 to 60 mg IR, and 78 to 100 mg ER. There were no significant differences in ACR20 responses at Week 12 between SCIO-469 and placebo. Declines in C-reactive protein and erythrocyte sedimentation rate during early treatment did not persist to Week 12 and were not a consequence of decreased SCIO-469 plasma levels. The 60 mg IR regimen showed a dose-limiting toxicity manifested by elevations in alanine aminotransferase. Adverse events were common in all groups (79.7% and 86.7% through 13 and 26 weeks, respectively). Twenty-one patients reported 28 serious adverse events (SAE). SAE were more common with IR SCIO-469 than with placebo (7% vs 4%) but were not reported with ER SCIO-469.In all regimens tested, SCIO-469 showed no greater efficacy compared to placebo in patients with RA. The transient effect of SCIO-469 on acute-phase reactants suggests a complex role of p38 MAPK in inflammation.

  View details for DOI 10.3899/jrheum.100602

  View details for Web of Science ID 000290780700010

  View details for PubMedID 21285160

• The Effects of Golimumab on Radiographic Progression in Rheumatoid Arthritis Results of Randomized Controlled Studies of Golimumab Before Methotrexate Therapy and Golimumab After Methotrexate Therapy ARTHRITIS AND RHEUMATISM Emery, P., Fleischmann, R., van der Heijde, D., Keystone, E. C., Genovese, M. C., Conaghan, P. G., Hsia, E. C., Xu, W., Baratelle, A., Beutler, A., Rahman, M. U. 2011; 63 (5): 1200-1210

  Abstract

  To evaluate the effects of golimumab on radiographic progression in patients with rheumatoid arthritis (RA).Methotrexate (MTX)-naive patients (in the Golimumab Before Employing Methotrexate as theFirst-Line Option in the Treatment of Rheumatoid Arthritis of Early Onset [GO-BEFORE] study; n = 637)and patients with active RA despite MTX therapy (in the Golimumab in Active Rheumatoid Arthritis Despite Methotrexate Therapy [GO-FORWARD] study; n =444) were randomly assigned to receive placebo plus MTX (group 1), golimumab 100 mg plus placebo (group 2), golimumab 50 mg plus MTX (group 3), or golimumab 100 mg plus MTX (group 4). Golimumab orplacebo was administered subcutaneously every 4 weeks. Radiographs of the hands and feet were taken at baseline, week 28, and week 52 in the GO-BEFORE study and at baseline, week 24 (week 16 for patients who entered early escape), and week 52 in the GO-FORWARD study. Radiographs were scored by 2 independent readers in each study using the van der Heijde modification of the Sharp score.In the GO-BEFORE study, the mean ± SD changes in the modified Sharp score from base line to week 52 (control period) were 1.4 ± 4.6 in group 1, 1.3 ± 6.2 in group 2 (P = 0.266), 0.7 ± 5.2 in group 3 (P = 0.015), and 0.1 ± 1.8 in group 4 (P = 0.025). In the GO-FORWARD study, changes from baseline to week 24 (control period) were 0.6 ± 2.4 in group 1, 0.3 ± 1.6 in group 2 (P = 0.361), 0.6 ± 2.7 in group 3 (P = 0.953), and 0.2 ± 1.3 in group 4 (P = 0.293).Golimumab in combination with MTX inhibited radiographic progression significantly better than did MTX alone in the GO-BEFORE study. Radiographic progression in the GO-FORWARD study was minimal in all treatment arms, precluding an adequate assessment of the effect of golimumab on radiographic progression in this study.

  View details for DOI 10.1002/art.30263

  View details for Web of Science ID 000290609800007

  View details for PubMedID 21305524

• THE EFFICACY AND SAFETY OF SUBCUTANEOUS (SC) ABATACEPT (ABA) WITH OR WITHOUT MTX IN PATIENTS WITH ACTIVE RA Nash, P., Nayiager, S., Genovese, M., Rodriguez, C., Delaet, I., Elegbe, A., Corbo, M., Bamford, T. WILEY-BLACKWELL. 2011: 15–15

  View details for Web of Science ID 000290489900051

• THE EFFICACY AND SAFETY OF SUBCUTANEOUS (SC) ABATACEPT (ABA) IS CONSISTENT WITH THE ESTABLISHED INTRAVENOUS (IV) PROFILE IN A STUDY OF 1457 PATIENTS WITH RA AND AN INADEQUATE RESPONSE TO MTX (MTX-IR) Nash, P., Genovese, M., COVARRUBIAS, J., LEON, G., Mysler, E., Keiserman, M., Valante, R., Simon, J., PORAWSKA, W., Box, J., Leggerton, C., Nasonov, E., Durez, P., Aranda, R., Pappau, R., Delaet, I., Teng, J., Alten, R., Bamford, T. WILEY-BLACKWELL. 2011: 16–16

  View details for Web of Science ID 000290489900053

• Abatacept in the Treatment of Patients With Psoriatic Arthritis ARTHRITIS AND RHEUMATISM Mease, P., Genovese, M. C., Gladstein, G., Kivitz, A. J., Ritchlin, C., Tak, P. P., Wollenhaupt, J., Bahary, O., Becker, J., Kelly, S., Sigal, L., Teng, J., Gladman, D. 2011; 63 (4): 939-948

  Abstract

  To assess the safety and efficacy of abatacept, a selective T cell costimulation modulator, in patients with psoriatic arthritis (PsA).In this 6-month, multicenter, randomized, double-blind, placebo-controlled, phase II study, 170 PsA patients with a psoriasis target lesion (TL) ≥2 cm who had previously taken disease-modifying antirheumatic drugs (DMARDs), including anti-tumor necrosis factor (anti-TNF) agents, were randomized (1:1:1:1) to receive placebo or abatacept at doses of 3 mg/kg, 10 mg/kg, or 30/10 mg/kg (2 initial doses of 30 mg/kg, followed by 10 mg/kg) on days 1, 15, and 29 and then once every 28 days thereafter. The primary end point was the American College of Rheumatology 20% criteria for improvement (ACR20 response) on day 169. Other key end points were magnetic resonance imaging (MRI) scores for joint erosion, osteitis, and synovitis, scores on the Health Assessment Questionnaire (HAQ) and the Short Form-36 (SF-36) health survey, the investigator's global assessment of psoriasis, the TL score, and the Psoriasis Area and Severity Index (PASI) score.Proportions of patients achieving an ACR20 response were 19%, 33%, 48%, and 42% in the placebo, the abatacept 3 mg/kg, the abatacept 10 mg/kg, and the abatacept 30/10 mg/kg groups, respectively. Compared with placebo, improvements were significantly higher for the abatacept 10 mg/kg (P = 0.006) and 30/10 mg/kg (P = 0.022) groups, but not for 3 mg/kg group (P = 0.121). All abatacept regimens resulted in improved MRI, HAQ, and SF-36 scores, with 10 mg/kg showing the greatest improvements. Improvements in the TL and PASI scores were observed in all abatacept arms; a response according to the investigator's global assessment was seen only with 3 mg/kg of abatacept. The safety profiles were similar among the treatment arms.The results of this study suggest that 10 mg/kg of abatacept, the approved dosage for rheumatoid arthritis and juvenile idiopathic arthritis, may be an effective treatment option for PsA.

  View details for DOI 10.1002/art.30176

  View details for Web of Science ID 000289421100013

  View details for PubMedID 21128258

• LONG-TERM EXTENSION STUDIES OF TOCILIZUMAB IN RA: SAFETY AND TOLERABILITY Genovese, M. C., Sebba, A., Rubbert-Roth, A., Scali, J., Zilberstein, M., Vernon, E., Vollenhoven, R. OXFORD UNIV PRESS. 2011: 33

  View details for Web of Science ID 000289163800093

• SAFETY OF SUBSEQUENT BIOLOGIC THERAPY IN RA PATIENTS WHO DISCONTINUED RITUXIMAB Genovese, M. C., Breedveld, F. C., Emery, P., Cohen, S. B., Keystone, E., Matteson, E. L., Burke, L., Chai, A., Reiss, W., Sweetser, M., Shaw, T. OXFORD UNIV PRESS. 2011: 126

  View details for Web of Science ID 000289163800328

• SAFETY, EFFICACY AND HEALTH-RELATED QUALITY OF LIFE THROUGH 5 YEARS OF ABATACEPT TREATMENT IN PATIENTS WITH RHEUMATOID ARTHRITIS AND AN INADEQUATE RESPONSE TO ANTI-TUMOUR NECROSIS FACTOR THERAPY Annual Meeting of the British-Society-for-Rheumatology 2011 Genovese, M. C., Schiff, M., Luggen, M., Le Bars, M., Becker, J., Aranda, R., Li, T., Elegbe, A., DougadoS, M. OXFORD UNIV PRESS. 2011: 123–123

  View details for Web of Science ID 000289163800321

• Safety and Efficacy of Etanercept Beyond 10 Years of Therapy in North American Patients With Early and Longstanding Rheumatoid Arthritis ARTHRITIS CARE & RESEARCH Weinblatt, M. E., Bathon, J. M., Kremer, J. M., Fleischmann, R. M., Schiff, M. H., Martin, R. W., Baumgartner, S. W., Park, G. S., Mancini, E. L., Genovese, M. C. 2011; 63 (3): 373-382

  Abstract

  To evaluate the long-term safety and efficacy of etanercept therapy in rheumatoid arthritis (RA) patients.Adult patients with early RA or longstanding RA received etanercept in open-label extension studies following initial double-blind trials of etanercept.Of 558 early RA patients and 714 longstanding RA patients who received at least 1 dose of etanercept, a total of 194 early RA patients and 217 longstanding RA patients were treated with 25 mg of etanercept twice weekly through 10 years. Five opportunistic infections were reported: in early RA, 1 Candida septicemia; in longstanding RA, 1 herpes zoster, 1 atypical mycobacterium infection, 1 meningoencephalitis (unspecified), and 1 fungal sepsis (unspecified). Twenty-nine cases of sepsis occurred (10 early RA, 19 longstanding RA). Occurrence of all malignancies was similar to that expected in the general population, but the occurrence of lymphomas was higher than expected in the general population. Fourteen lymphomas (7 early RA, 7 longstanding RA) and 2 cases of demyelinating disease (1 early RA, 1 longstanding RA) were reported. Deaths occurred in 18 early RA patients and 43 longstanding RA patients. Both patient groups showed sustained improvement in American College of Rheumatology responses, swollen joint counts, Health Assessment Questionnaire disability index scores, and C-reactive protein levels.Etanercept maintained therapeutic benefits beyond 10 years of therapy in both early RA and longstanding RA patients, suggesting that etanercept is well tolerated and effective as a long-term, continuous therapy for the treatment of RA, with a favorable risk/benefit ratio.

  View details for DOI 10.1002/acr.20372

  View details for Web of Science ID 000288095800009

  View details for PubMedID 20957659

• An Oral Syk Kinase Inhibitor in the Treatment of Rheumatoid Arthritis A Three-Month Randomized, Placebo-Controlled, Phase II Study in Patients With Active Rheumatoid Arthritis That Did Not Respond to Biologic Agents ARTHRITIS AND RHEUMATISM Genovese, M. C., Kavanaugh, A., Weinblatt, M. E., Peterfy, C., DiCarlo, J., White, M. L., O'Brien, M., Grossbard, E. B., Magilavy, D. B. 2011; 63 (2): 337-345

  Abstract

  To assess the efficacy and safety of R788 (fostamatinib disodium), an inhibitor of spleen tyrosine kinase (Syk), in patients with active rheumatoid arthritis (RA) that did not respond to biologic therapies.A total of 219 patients with active RA in whom treatment with biologic agents had failed were enrolled in a 3-month multicenter, randomized, double-blind, placebo-controlled trial of R788. The primary end point was the percentage of patients who met the American College of Rheumatology 20% improvement criteria (achieved an ACR20 response) at month 3. Secondary end points included changes in inflammation and damage, as assessed by magnetic resonance imaging (MRI), and changes in the Disease Activity Score.The ACR20 response in the R788 100 mg twice daily group was 38%, versus 37% in the placebo group, at month 3. No significant differences were achieved in the ACR20, ACR50, or ACR70 response levels at 3 months. There were differences between the groups from baseline to month 3 in the secondary end points C-reactive protein (CRP) level and synovitis score on MRI. There were baseline differences in steroid use, prior biologic use, and synovitis score on MRI between the R788 group and the placebo group that may have affected the outcomes. A high placebo response rate was seen in this trial, and exploratory analysis suggested that this may in part have been driven by patients who entered the trial with an elevated erythrocyte sedimentation rate but normal CRP level.Our findings indicate that there were no differences in the primary end point between the R788 and placebo groups. Differences were observed between the R788 and placebo groups in secondary end points, particularly in those patients who entered the study with an elevated CRP level.

  View details for DOI 10.1002/art.30114

  View details for Web of Science ID 000287202600007

  View details for PubMedID 21279990

• An Oral Spleen Tyrosine Kinase (Syk) Inhibitor for Rheumatoid Arthritis. NEW ENGLAND JOURNAL OF MEDICINE Weinblatt, M. E., Kavanaugh, A., Genovese, M. C., Musser, T. K., Grossbard, E. B., Magilavy, D. B. 2010; 363 (14): 1303-1312

  Abstract

  Spleen tyrosine kinase (Syk) is an important modulator of immune signaling. The objective of this phase 2 study was to evaluate the efficacy and safety of R788, an oral inhibitor of Syk, in patients with active rheumatoid arthritis despite methotrexate therapy.We enrolled 457 patients who had active rheumatoid arthritis despite long-term methotrexate therapy in a 6-month, double-blind, placebo-controlled trial. The primary outcome was the American College of Rheumatology (ACR) 20 response (which indicates at least a 20% reduction in the number of both tender and swollen joints and improvement in at least three of five other criteria) at month 6.R788, at a dose of 100 mg twice daily and at a dose of 150 mg once daily, was significantly superior to placebo at month 6 (ACR 20 response rates of 67% and 57%, respectively, vs. 35%; P<0.001 for the comparison of both doses with placebo). It was also significantly superior with respect to ACR 50, which indicates at least a 50% improvement (43% and 32% vs. 19%; P<0.001 for the comparison of the 100-mg dose with placebo, P=0.007 for the comparison of the 150-mg dose with placebo) and ACR 70 (28% and 14% vs. 10%; P<0.001 for the comparison of the 100-mg dose with placebo, P=0.34 for the comparison of the 150-mg dose with placebo). A clinically significant effect was noted by the end of the first week of treatment. Adverse effects included diarrhea (in 19% of subjects taking the 100-mg dose of R788 vs. 3% of those taking placebo), upper respiratory infections (14% vs. 7%), and neutropenia (6% vs. 1%). R788 was associated with an increase in systolic blood pressure of approximately 3 mm Hg between baseline and month 1, as compared with a decrease of 2 mm Hg with placebo; 23% of the patients taking R788 vs. 7% of the patients receiving placebo required the initiation of or a change in antihypertensive therapy.In this phase 2 study, a Syk inhibitor reduced disease activity in patients with rheumatoid arthritis; adverse events included diarrhea, hypertension, and neutropenia. Additional studies will be needed to further assess the safety and efficacy of Syk-inhibition therapy in patients with rheumatoid arthritis. (Funded by Rigel; ClinicalTrials.gov number, NCT00665925.)

  View details for DOI 10.1056/NEJMoa1000500

  View details for Web of Science ID 000282271500004

  View details for PubMedID 20879879

• Edward D. Harris, Jr., MD, 1937-2010 IN MEMORIAM ARTHRITIS AND RHEUMATISM Genovese, M. C., Moynihan, E. M. 2010; 62 (9): 2623–24

  View details for DOI 10.1002/art.27612

  View details for Web of Science ID 000283059100009

• Continued inhibition of structural damage over 2 years in patients with rheumatoid arthritis treated with rituximab in combination with methotrexate ANNALS OF THE RHEUMATIC DISEASES Cohen, S. B., Keystone, E., Genovese, M. C., Emery, P., Peterfy, C., Tak, P. P., Cravets, M., Shaw, T., Hagerty, D. 2010; 69 (6): 1158-1161

  Abstract

  Rituximab inhibited structural damage at 1 year in patients with rheumatoid arthritis (RA) who had had a previous inadequate response to tumour necrosis factor (TNF) inhibitors.To assess structural damage progression through 2 years.Intention-to-treat patients with one post-baseline radiograph (rituximab n=281; placebo n=187) received background methotrexate (MTX) and were randomised to rituximab (2 x 1000 mg infusions, 2 weeks apart) or placebo; patients were eligible for rituximab re-treatment every 6 months. By week 104, 82% of the placebo population had received > or = 1 dose of rituximab. Radiographic end points included the change in total Sharp score (TSS), erosion and joint space narrowing scores at week 104.At week 104, significantly lower changes in TSS (1.14 vs 2.81; p<0.0001), erosion score (0.72 vs 1.80; p<0.0001) and joint space narrowing scores (0.42 vs 1.00; p<0.0009) were observed with rituximab plus MTX vs placebo plus MTX. Within the rituximab group, 87% who had no progression of joint damage at 1 year remained non-progressive at 2 years.Rituximab plus MTX demonstrated significant and sustained effects on joint damage progression in patients with RA and a previously inadequate response to TNF inhibitors.

  View details for DOI 10.1136/ard.2009.119222

  View details for Web of Science ID 000278017700039

  View details for PubMedID 20439295

  View details for PubMedCentralID PMC2935326

• Golimumab in patients with active rheumatoid arthritis despite methotrexate therapy: 52-week results of the GO-FORWARD study ANNALS OF THE RHEUMATIC DISEASES Keystone, E., Genovese, M. C., Klareskog, L., Hsia, E. C., Hall, S., Miranda, P. C., Pazdur, J., Bae, S., Palmer, W., Xu, S., Rahman, M. U. 2010; 69 (6): 1129-1135

  Abstract

  To evaluate the efficacy and safety of golimumab to 52 weeks in patients with active rheumatoid arthritis despite methotrexate.Patients were randomly assigned to receive placebo plus methotrexate (group 1), golimumab 100 mg plus placebo (group 2), golimumab 50 mg plus methotrexate (group 3) and golimumab 100 mg plus methotrexate (group 4). At week 16, patients in groups 1, 2 and 3 who had less than 20% improvement in tender and swollen joints entered early escape. At week 24, patients in group 1 who had not entered early escape crossed over to 50 mg golimumab plus methotrexate.At week 16, 31%, 27% and 17% of patients in groups 1, 2 and 3, respectively, entered early escape. At week 52, 44%, 45%, 64% and 58% of patients in groups 1, 2, 3 and 4, respectively, achieved 20% improvement in the American College of Rheumatology criteria; and 34%, 31%, 42% and 53%, respectively, achieved low disease activity (< or = 3.2) according to the 28-joint disease activity score. Patients in group 4 appeared to have an increased risk of serious adverse events and serious infections.The results of various outcome measures showed that the response rates achieved by patients receiving golimumab to 24 weeks were sustained to 52 weeks. The safety profile appeared to be consistent with the known safety profile of tumour necrosis factor inhibitors.

  View details for DOI 10.1136/ard.2009.116319

  View details for Web of Science ID 000278017700032

  View details for PubMedID 20444749

• LY2439821, a Humanized Anti-Interleukin-17 Monoclonal Antibody, in the Treatment of Patients With Rheumatoid Arthritis A Phase I Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Study ARTHRITIS AND RHEUMATISM Genovese, M. C., Van den Bosch, F., ROBERSON, S. A., Bojin, S., Biagini, I. M., Ryan, P., Sloan-Lancaster, J. 2010; 62 (4): 929-939

  Abstract

  We undertook this study to evaluate safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy of LY2439821, a humanized anti-interleukin-17 (anti-IL-17) monoclonal antibody, in a first in-human trial in rheumatoid arthritis (RA) patients taking oral disease-modifying antirheumatic drugs (DMARDs).This randomized, double-blind, placebo-controlled study consisted of 2 parts. In part A, 20 patients received 1 intravenous (IV) dose of LY2439821 (0.06, 0.2, 0.6, or 2.0 mg/kg, escalating) or placebo followed by 8 weeks of evaluation. End points included safety, tolerability, and pharmacokinetics. In part B, 77 patients received 1 IV dose of LY2439821 (0.2, 0.6, or 2.0 mg/kg) or placebo every 2 weeks for a total of 5 doses, with a total evaluation period of 16 weeks. End points included safety, tolerability, pharmacokinetics/pharmacodynamics, and efficacy (Disease Activity Score in 28 joints [DAS28] and percentages of patients meeting American College of Rheumatology 20%, 50%, or 70% improvement criteria [achieving an ACR20, ACR50, or ACR70 response]). The primary efficacy end point was the DAS28 at week 10.Baseline characteristics were similar across all groups. Changes in the DAS28 were significantly greater in the 0.2 mg/kg, 2.0 mg/kg, and all-LY2439821-combined groups (-2.3, -2.4, and -2.3, respectively) than in the placebo group (-1.7) at week 10 (P < or = 0.05), and these differences were significant as early as week 1. Percentages of ACR20, ACR50, and ACR70 responses as well as improvements in the ACR core set of measures were greater in LY2439821-treated patients than in placebo-treated patients at multiple time points. There was no apparent dose-response relationship in treatment-emergent adverse events.LY2439821 added to oral DMARDs improved signs and symptoms of RA, with no strong adverse safety signal noted. This first evaluation of LY2439821 supports neutralization of IL-17 as a potential novel goal for the treatment of RA.

  View details for DOI 10.1002/art.27334

  View details for Web of Science ID 000279432300003

  View details for PubMedID 20131262

• AN ASSESSMENT OF THE SERIOUS INFECTION RATE IN RITUXIMAB-TREATED RHEUMATOID ARTHRITIS (RA) PATIENTS WHO SUBSEQUENTLY RECEIVED OTHER BIOLOGIC THERAPIES: A FOLLOW-UP FROM RITUXIMAB CLINICAL TRIALS Genovese, M. C., Breedveld, F. C., Emery, P., Cohen, S. B., Keystone, E. C., Matteson, E. L., Burke, L. S., Chai, A., Reiss, W. G., Sweetser, M. T., Shaw, T. M. OXFORD UNIV PRESS. 2010: I4

  View details for Web of Science ID 000276047500008

• IMPACT OF GOLIMUMAB ON PHYSICAL FUNCTION, HEALTH-RELATED QOL, PRODUCTIVITY AND EMPLOYMENT IN RA PATIENTS: WEEK 52 RESULTS FROM GO-FORWARD Genovese, M. C., Rubbert, A., Keystone, E. C., Hsia, E. C., Buchanan, J., Klareskog, L., Murphy, F. T., Wu, Z., Parasuraman, S., Rahman, M. U., GO-FORWARD Investigators OXFORD UNIV PRESS. 2010: I109–I110

  View details for Web of Science ID 000276047500277

• EFFICACY OF GOLIMUMAB, A HUMAN ANTI-TNF alpha ANTIBODY, BY BASELINE CRP LEVEL IN PATIENTS WITH RHEUMATOID ARTHRITIS: RESULTS FROM THREE PHASE 3, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED STUDIES Emery, P., Genovese, M. C., Fleischmann, R. M., Matteson, E. L., Hsia, E. C., Xu, S., Doyle, M. K., Rahman, M. U., GO-BEFORE GO-FORWARD, GO-AFTER Investigators OXFORD UNIV PRESS. 2010: I101

  View details for Web of Science ID 000276047500258

• Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study ANNALS OF THE RHEUMATIC DISEASES Jones, G., Sebba, A., Gu, J., Lowenstein, M. B., CALVO, A., Gomez-Reino, J. J., Siri, D. A., Tomsic, M., Alecock, E., Woodworth, T., Genovese, M. C. 2010; 69 (1): 88-96

  Abstract

  The anti-interleukin (IL) 6 receptor antibody tocilizumab inhibits signalling of IL6, a key cytokine in rheumatoid arthritis (RA) pathogenesis.To evaluate through the AMBITION study the efficacy and safety of tocilizumab monotherapy versus methotrexate in patients with active RA for whom previous treatment with methotrexate/biological agents had not failed.This 24-week, double-blind, double-dummy, parallel-group study, randomised 673 patients to either tocilizumab 8 mg/kg every 4 weeks, or methotrexate, starting at 7.5 mg/week and titrated to 20 mg/week within 8 weeks, or placebo for 8 weeks followed by tocilizumab 8 mg/kg. The primary end point was the proportion of patients achieving American College of Rheumatology (ACR) 20 response at week 24.The intention-to-treat analysis demonstrated that tocilizumab was better than methotrexate treatment with a higher ACR20 response (69.9 vs 52.5%; p<0.001), and 28-joint Disease Activity Score (DAS28) <2.6 rate (33.6 vs 12.1%) at week 24. Mean high-sensitivity C-reactive protein was within the normal range from week 12 with tocilizumab, whereas levels remained elevated with methotrexate. The incidence of serious adverse events with tocilizumab was 3.8% versus 2.8% with methotrexate (p = 0.50), and of serious infections, 1.4% versus 0.7%, respectively. There was a higher incidence of reversible grade 3 neutropenia (3.1% vs 0.4%) and increased total cholesterol > or =240 mg/dl (13.2% vs 0.4%), and a lower incidence of alanine aminotransferase elevations >3x-<5x upper limit of normal (1.0% vs 2.5%), respectively.Tocilizumab monotherapy is better than methotrexate monotherapy, with rapid improvement in RA signs and symptoms, and a favourable benefit-risk, in patients for whom treatment with methotrexate or biological agents has not previously failed.

  View details for DOI 10.1136/ard.2008.105197

  View details for Web of Science ID 000272594100017

  View details for PubMedID 19297346

• Association of serum markers with improvement in clinical response measures after treatment with golimumab in patients with active rheumatoid arthritis despite receiving methotrexate: results from the GO-FORWARD study ARTHRITIS RESEARCH & THERAPY Visvanathan, S., Rahman, M. U., Keystone, E., Genovese, M., Klareskog, L., Hsia, E., Mack, M., Buchanan, J., Elashoff, M., Wagner, C. 2010; 12 (6)

  Abstract

  The goal of this study was to identify serum markers that are modulated by treatment with golimumab with or without methotrexate (MTX) and are associated with clinical response.Sera were collected at weeks 0 and 4 from a total of 336 patients (training dataset, n = 100; test dataset, n = 236) from the GO-FORWARD study of patients with active rheumatoid arthritis despite MTX. Patients were randomly assigned to receive placebo plus MTX; golimumab, 100 mg plus placebo; golimumab, 50 mg plus MTX; or golimumab, 100 mg plus MTX. Subcutaneous injections were administered every 4 weeks. Samples were tested for select inflammatory, bone, and cartilage markers and for protein profiling using multianalyte profiles.Treatment with golimumab with or without MTX resulted in significant decreases in a variety of serum proteins at week 4 as compared with placebo plus MTX. The American College of Rheumatology (ACR) 20, ACR 50, and Disease Activity Score (DAS) 28 responders showed a distinct biomarker profile compared with nonresponding patients.ACR 20 and ACR 50 responders among the golimumab/golimumab + MTX-treated patients had a distinct change from baseline to week 4 in serum protein profile as compared with nonresponders. Some of these changed markers were also associated with multiple clinical response measures and improvement in outcome measures in golimumab/golimumab + MTX-treated patients. Although the positive and negative predictive values of the panel of markers were modest, they were stronger than C-reactive protein alone in predicting clinical response to golimumab.http://ClinicalTrials.gov identification number: NCT00264550.

  View details for DOI 10.1186/ar3188

  View details for Web of Science ID 000287517000021

  View details for PubMedID 21083889

  View details for PubMedCentralID PMC3046519

• Safety of biological therapies following rituximab treatment in rheumatoid arthritis patients ANNALS OF THE RHEUMATIC DISEASES Genovese, M. C., Breedveld, F. C., Emery, P., Cohen, S., Keystone, E., Matteson, E. L., Baptiste, Y., Chai, A., Burke, L., Reiss, W., Sweetser, M., Shaw, T. M. 2009; 68 (12): 1894-1897

  Abstract

  To assess the safety of biological disease-modifying antirheumatic drugs (DMARD) in rheumatoid arthritis (RA) patients following rituximab.RA patients who participated in an international rituximab clinical trial programme were included. Patients who had received one or more rituximab courses and entered safety follow-up (SFU) were permitted additional biological DMARD. Serious infection events (SIE) were collected.Of 185 of 2578 patients who entered SFU and received another biological DMARD, 88.6% had peripheral B-cell depletion at the time of initiation of another biological agent. Thirteen SIE (6.99 events/100 patient-years) occurred following rituximab but before another biological DMARD and 10 SIE (5.49 events/100 patient-years) occurred following another biological DMARD. SIE were of typical type and severity for RA patients. 153 had received one or more tumour necrosis factor inhibitor(s). No fatal or opportunistic infections occurred.In this analysis, treatment with biological DMARD after rituximab was not associated with an increased serious infection rate. Sample size with limited follow-up restricts definitive conclusions.

  View details for DOI 10.1136/ard.2008.101675

  View details for Web of Science ID 000271730700017

  View details for PubMedID 19155233

• Epitope-Specific Immunotherapy of Rheumatoid Arthritis Clinical Responsiveness Occurs With Immune Deviation and Relies on the Expression of a Cluster of Molecules Associated With T Cell Tolerance in a Double-Blind, Placebo-Controlled, Pilot Phase II Trial ARTHRITIS AND RHEUMATISM Koffeman, E. C., Genovese, M., Amox, D., Keogh, E., Santana, E., Matteson, E. L., Kavanaugh, A., Molitor, J. A., Schiff, M. H., Posever, J. O., Bathon, J. M., Kivitz, A. J., Samodal, R., Belardi, F., Dennehey, C., Van den Broek, T., van Wijk, F., Zhang, X., Zieseniss, P., Le, T., Prakken, B. A., Cutter, G. C., Albani, S. 2009; 60 (11): 3207-3216

  Abstract

  Induction of immune tolerance to maintain clinical control with a minimal drug regimen is a current research focus in rheumatoid arthritis (RA). Accordingly, we are developing a tolerization approach to dnaJP1, a peptide part of a pathogenic mechanism that contributes to autoimmune inflammation in RA. We undertook this study to test 2 hypotheses: 1) that mucosal induction of immune tolerance to dnaJP1 would lead to a qualitative change from a proinflammatory phenotype to a more tolerogenic functional phenotype, and 2) that immune deviation of responses to an inflammatory epitope might translate into clinical improvement.One hundred sixty patients with active RA and with immunologic reactivity to dnaJP1 were enrolled in a pilot phase II trial. They received oral doses of 25 mg of dnaJP1 or placebo daily for 6 months.The dnaJP1 peptide was safe and well-tolerated. In response to treatment with dnaJP1, there was a significant reduction in the percentage of T cells producing tumor necrosis factor alpha and a corresponding trend toward an increased percentage of T cells producing interleukin-10. Coexpression of a cluster of molecules (programmed death 1 and its ligands) associated with T cell regulation was also found to be a prerequisite for successful tolerization in clinical responders. Analysis of the primary efficacy end point (meeting the American College of Rheumatology 20% improvement criteria at least once on day 112, 140, or 168) showed a difference between treatment groups that became significant in post hoc analysis using generalized estimating equations. Differences in clinical responses were also found between treatment groups on day 140 and at followup. Post hoc analysis showed that the combination of dnaJP1 and hydroxychloroquine (HCQ) was superior to the combination of HCQ and placebo.Tolerization to dnaJP1 leads to immune deviation and a trend toward clinical efficacy. Susceptibility to treatment relies on the coexpression of molecules that can down-regulate adaptive immunity.

  View details for DOI 10.1002/art.24916

  View details for Web of Science ID 000271781400008

  View details for PubMedID 19877047

• The AMBITION Study: Superiority Of Tocilizumab vs Methotrexate Monotherapy in Patients with Rheumatoid Arthritis Khraishi, M., Jones, G., Genovese, M. J RHEUMATOL PUBL CO. 2009: 2574–75

  View details for Web of Science ID 000271593700082

• Safety of Other Biologic Therapies Following Rituximab Treatment in RA Patients Khraishi, M., Genovese, M. C., Breedveld, F. J RHEUMATOL PUBL CO. 2009: 2598–99

  View details for Web of Science ID 000271593700159

• The 6-month safety and efficacy of abatacept in patients with rheumatoid arthritis who underwent a washout after anti-tumour necrosis factor therapy or were directly switched to abatacept: the ARRIVE trial ANNALS OF THE RHEUMATIC DISEASES Schiff, M., Pritchard, C., Huffstutter, J. E., Rodriguez-Valverde, V., Durez, P., Zhou, X., Li, T., Bahrt, K., Kelly, S., Le Bars, M., Genovese, M. C. 2009; 68 (11): 1708-1714

  Abstract

  To assess the safety, tolerability and efficacy of abatacept in patients with rheumatoid arthritis (RA) who had failed anti-tumour necrosis factor (TNF) therapy and were switched to abatacept directly or after completing washout.In this international, 6-month, open-label trial, patients had active RA, an inadequate response to anti-TNF therapy for 3 months or longer and a disease activity score in 28 joints (DAS28 (C-reactive protein; CRP) of 5.1 or greater. "Washout" patients discontinued anti-TNF therapy 2 months or longer pre-screening; "direct-switch" patients began abatacept ( approximately 10 mg/kg) at their next scheduled anti-TNF therapy dose.1046 patients were treated (449 washout, 597 direct-switch; baseline characteristics were similar between groups). At 6 months, adverse events (AE; 78.0% vs 79.2%), serious AE (11.1% vs 9.9%) and discontinuations due to AE (3.8% vs 4.0%) and serious AE (2.0% vs 1.3%) were comparable in washout versus direct-switch patients. There were no opportunistic infections. At 6 months, in washout versus direct-switch patients, similar clinically meaningful improvements were seen in DAS28 (CRP) (> or =1.2 unit improvement, 59.5% vs 53.6%, respectively; low disease activity state, 22.5% vs 22.3%; DAS28-defined remission, 12.0% vs 13.7%), physical function (health assessment questionnaire disability index > or =0.22 improvement; 46.3% vs 47.1%) and health-related quality of life (mean change in short-form 36 scores: physical component summary, 5.5 vs 6.1; mental component summary, 4.8 vs 5.4).Abatacept demonstrated acceptable safety and tolerability and clinically meaningful efficacy over 6 months in patients with inadequate response to anti-TNF therapy. Results were comparable with or without a washout, supporting direct switching from anti-TNF therapy to abatacept as an option in clinical practice. Trial registration number: NCT00124982.

  View details for DOI 10.1136/ard.2008.099218

  View details for Web of Science ID 000270700900010

  View details for PubMedID 19074911

• Independent Predictors for the Development of Upper Gastrointestinal Ulcers: Results from Two 24-Week Double-Blind Trials of a Single-Tablet Combination of Ibuprofen-Famotidine vs. Ibuprofen Alone Laine, L., Schiff, M., Genovese, M., Kivitz, A., Bello, A., Grahn, A., Walbert, T., Weinblatt, M. NATURE PUBLISHING GROUP. 2009: S535–S536

  View details for Web of Science ID 000270853601412

• First Report of Idiopathic Granulomatous Mastitis Treated with Methotrexate Monotherapy JOURNAL OF RHEUMATOLOGY Schmajuk, G., Genovese, M. C. 2009; 36 (7): 1559-1560

  View details for DOI 10.3899/jrheum.090091

  View details for Web of Science ID 000267847700039

  View details for PubMedID 19567642

• Less Radiographic Progression with Adalimumab Plus Methotrexate Versus Methotrexate Monotherapy Across the Spectrum of Clinical Response in Early Rheumatoid Arthritis JOURNAL OF RHEUMATOLOGY Emery, P., Genovese, M. C., van Vollenhoven, R., Sharp, J. T., Patra, K., Sasso, E. H. 2009; 36 (7): 1429-1441

  Abstract

  To determine the relationship between radiographic progression and clinical response for adalimumab plus methotrexate (MTX) versus either monotherapy in patients with early rheumatoid arthritis (RA) in the PREMIER study.Patients with early RA who received adalimumab plus MTX (n = 240), adalimumab (n = 222), or MTX (n = 216) were grouped by American College of Rheumatology (ACR) response, 28-joint Disease Activity Score (DAS28), or remission-like state [tender joint count (TJC) = 0; DAS28 < 2.6; swollen joint count = 0; ACR100] at 26 and 104 weeks. Radiographic progression was assessed by cumulative probability plots, mean changes in total Sharp score (DeltaTSS), and percentages of progressors (DeltaTSS > 0.5).Across the spectrum of clinical outcomes, including ACR20 nonresponses and remission-like responses, therapy with adalimumab plus MTX permitted less radiographic progression at Weeks 26 and 104 than MTX monotherapy. Adalimumab monotherapy was generally intermediate. A strong, proportional relationship was observed between clinical response and radiographic efficacy only for MTX monotherapy. The monotherapies approximated the radiographic efficacy of adalimumab plus MTX only among remission-like responders, although progression was significantly greater with MTX monotherapy versus adalimumab plus MTX for patients with TJC = 0. Concurrent clinical (DAS28 < 2.6) and radiographic (DeltaTSS

  View details for DOI 10.3899/jrheum.081018

  View details for Web of Science ID 000267847700014

  View details for PubMedID 19369462

• Golimumab, a human antibody to tumour necrosis factor alpha given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study ANNALS OF THE RHEUMATIC DISEASES Keystone, E. C., Genovese, M. C., Klareskog, L., Hsia, E. C., Hall, S. T., Miranda, P. C., Pazdur, J., Bae, S., Palmer, W., ZRUBEK, J., Wiekowski, M., Visvanathan, S., Wu, Z., Rahman, M. U. 2009; 68 (6): 789-796

  Abstract

  The phase III GO-FORWARD study examined the efficacy and safety of golimumab in patients with active rheumatoid arthritis (RA) despite methotrexate therapy.Patients were randomly assigned in a 3 : 3 : 2 : 2 ratio to receive placebo injections plus methotrexate capsules (group 1, n = 133), golimumab 100 mg injections plus placebo capsules (group 2, n = 133), golimumab 50 mg injections plus methotrexate capsules (group 3, n = 89), or golimumab 100 mg injections plus methotrexate capsules (group 4, n = 89). Injections were administered subcutaneously every 4 weeks. The co-primary endpoints were the proportion of patients with 20% or greater improvement in the American College of Rheumatology criteria (ACR20) at week 14 and the change from baseline in the health assessment questionnaire-disability index (HAQ-DI) score at week 24.The proportion of patients who achieved an ACR20 response at week 14 was 33.1% in the placebo plus methotrexate group, 44.4% (p = 0.059) in the golimumab 100 mg plus placebo group, 55.1% (p = 0.001) in the golimumab 50 mg plus methotrexate group and 56.2% (p<0.001) in the golimumab 100 mg plus methotrexate group. At week 24, median improvements from baseline in HAQ-DI scores were 0.13, 0.13 (p = 0.240), 0.38 (p<0.001) and 0.50 (p<0.001), respectively. During the placebo-controlled portion of the study (to week 16), serious adverse events occurred in 2.3%, 3.8%, 5.6% and 9.0% of patients and serious infections occurred in 0.8%, 0.8%, 2.2% and 5.6%, respectively.The addition of golimumab to methotrexate in patients with active RA despite methotrexate therapy significantly reduced the signs and symptoms of RA and improved physical function.

  View details for DOI 10.1136/ard.2008.099010

  View details for Web of Science ID 000266917100006

  View details for PubMedID 19066176

  View details for PubMedCentralID PMC2674549

• Efficacy of a p38 mitogen activated protein kinase inhibitor in mitigating an established inflammatory reaction to polyethylene particles in vivo. Journal of biomedical materials research. Part A Ma, T., Ren, P., Larsen, D. M., Suenaga, E., Zilber, S., Genovese, M., Smith, R. L., Goodman, S. B. 2009; 89 (1): 117-123

  Abstract

  The inhibitor of p38 mitogen-activated protein kinase (MAPK) is of interest in the nonoperative treatment of periprosthetic osteolysis due to wear particles. Previous studies demonstrated that an oral p38 MAPK inhibitor did not suppress bone formation when given during the initial phase of tissue differentiation. However, the oral p38 MAPK inhibitor also did not curtail the foreign body and chronic inflammatory response to particles when given simultaneously. The purpose of the current study was to examine the efficacy of a p38 MAPK inhibitor, SCIO-323, on mitigating an established inflammatory reaction that parallels the clinical situation more closely. The Bone Harvest Chamber was implanted in rabbits and submicron polyethylene particles were placed in the chamber for 6 weeks. The contents of the chambers were harvested every 6 weeks. Oral treatment with the SCIO-323 included delivery for 3 weeks and stopping for 3 weeks, delivery for 3 weeks after an initial 3-week delay, and delivery for 6 weeks continuously. Administration of the SCIO-323 continuously for 6 weeks with/without the presence of particles, or for the initial 3 of 6 weeks had minor effects on bone ingrowth. After establishing a particle-induced chronic inflammatory reaction for 3 weeks, administration of SCIO-323 for a subsequent 3 weeks suppressed net bone formation. The activity of osteoclast-like cells remained low among all treatments when compared with the first control. Using the present model, the oral p38 MAPK inhibitor was ineffective in improving bone ingrowth in the presence of polyethylene particles.

  View details for DOI 10.1002/jbm.a.31957

  View details for PubMedID 18431764

• CONTINUED INHIBITION OF STRUCTURAL DAMAGE IN RHEUMATOID ARTHRITIS PATIENTS TREATED WITH RITUXIMAB AT 2 YEARS: REFLEX STUDY Cohen, S. B., Keystone, E. C., Genovese, M., Emery, P., Peterfy, C., Tak, P., Cravets, M. W., Shaw, T., Hagerty, D. OXFORD UNIV PRESS. 2009: I88

  View details for Web of Science ID 000266198600287

• GOLIMUMAB ADMINISTERED SUBCUTANEOUSLY EVERY 4 WEEKS IN ACTIVE RHEUMATOID ARTHRITIS DESPITE METHOTREXATE: WEEK 24 RESULTS OF GO-FORWARD STUDY Rubbert, A., Keystone, E., Genovese, M., Klareskog, L., Hsia, E. C., Zrubek, J., Wu, Z., Rahman, M. U., GO-FORWARD Study Investigators OXFORD UNIV PRESS. 2009: I92

  View details for Web of Science ID 000266198600301

• IN PATIENTS WITH EARLY RA WHO HAD ACHIEVED A NORMAL CRP, ADALIMUMAB INHIBITED RADIOGRAPHIC PROGRESSION MORE EFFECTIVELY THAN METHOTREXATE Annual Meeting of the British-Society-of-Rheumatology Emery, P., Genovese, M., Van Vollenhoven, R. F., Sasso, E. H. OXFORD UNIV PRESS. 2009: I85–I85

  View details for Web of Science ID 000266198600279

• Efficacy of a p38 mitogen activated protein kinase inhibitor in mitigating an established inflammatory reaction to polyethylene particles in vivo JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A Ma, T., Ren, P., Larsen, D. M., Suenaga, E., Zilber, S., Genovese, M., Smith, R. L., Goodman, S. B. 2009; 89A (1): 117-123

  Abstract

  The inhibitor of p38 mitogen-activated protein kinase (MAPK) is of interest in the nonoperative treatment of periprosthetic osteolysis due to wear particles. Previous studies demonstrated that an oral p38 MAPK inhibitor did not suppress bone formation when given during the initial phase of tissue differentiation. However, the oral p38 MAPK inhibitor also did not curtail the foreign body and chronic inflammatory response to particles when given simultaneously. The purpose of the current study was to examine the efficacy of a p38 MAPK inhibitor, SCIO-323, on mitigating an established inflammatory reaction that parallels the clinical situation more closely. The Bone Harvest Chamber was implanted in rabbits and submicron polyethylene particles were placed in the chamber for 6 weeks. The contents of the chambers were harvested every 6 weeks. Oral treatment with the SCIO-323 included delivery for 3 weeks and stopping for 3 weeks, delivery for 3 weeks after an initial 3-week delay, and delivery for 6 weeks continuously. Administration of the SCIO-323 continuously for 6 weeks with/without the presence of particles, or for the initial 3 of 6 weeks had minor effects on bone ingrowth. After establishing a particle-induced chronic inflammatory reaction for 3 weeks, administration of SCIO-323 for a subsequent 3 weeks suppressed net bone formation. The activity of osteoclast-like cells remained low among all treatments when compared with the first control. Using the present model, the oral p38 MAPK inhibitor was ineffective in improving bone ingrowth in the presence of polyethylene particles.

  View details for DOI 10.1002/jbm.a.31957

  View details for Web of Science ID 000263981300011

• SAFETY OF OTHER BIOLOGIC THERAPIES FOLLOWING RITUXIMAB TREATMENT IN RA PATIENTS Genovese, M. C., Breedveld, F. C., Emery, P., Cohen, S. B., Keystone, E., Matteson, E., Baptiste, Y., Burke, L., Reiss, W., Sweetser, M., Shaw, T. OXFORD UNIV PRESS. 2009: I90–I91

  View details for Web of Science ID 000266198600296

• GOLIMUMAB SIGNIFICANTLY IMPROVES SELF-REPORTED PRODUCTIVITY IN PATIENTS WITH RHEUMATOID ARTHRITIS Wordsworth, P., Buchanan, J., Fleischmann, R., Genovese, M., Kay, J., Hsia, E., Doyle, M., Rahman, M., Han, C., Parasuraman, S. OXFORD UNIV PRESS. 2009: I83

  View details for Web of Science ID 000266198600274

• EVALUATION OF JOINT DAMAGE IN RA PATIENTS TREATED WITH RITUXIMAB: COMPARISON OF GENANT- AND VAN DER HEIJDE-MODIFIED SHARP RADIOGRAPHIC SCORING Genovese, M., Peterfy, C., Emery, P., Keystone, E., Tak, P., Cohen, S. B., DiCarlo, J., Hagerty, D., Cravets, M., Shaw, T. OXFORD UNIV PRESS. 2009: I65

  View details for Web of Science ID 000266198600213

• GOLIMUMAB SIGNIFICANTLY IMPROVES PHYSICAL FUNCTION, HEALTH-RELATED QUALITY OF LIFE, AND FATIGUE IN RA (GO-FORWARD STUDY) Rubbert, A., Genovese, M. C., Keystone, E., Hsia, E. C., Buchanan, J., Klareskog, L., Murphy, F., Wu, Z., Parasuraman, S., Rahman, M. U. OXFORD UNIV PRESS. 2009: I84

  View details for Web of Science ID 000266198600276

• RAPID AND SIGNIFICANT REDUCTION IN DISEASE ACTIVITY WITH TOCILIZUMAB IN COMBINATION WITH SIX DIFFERENT DMARDS IN RHEUMATOID ARTHRITIS PATIENTS WITH AN INADEQUATE RESPONSE TO DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS: THE TOWARD STUDY Annual Meeting of the British-Society-of-Rheumatology Gomez-Reino, J. J., Nasonov, E. L., McKay, J. D., Mysler, E. F., da Silva, N., Alecock, E., Woodworth, T., Genovese, M. C. OXFORD UNIV PRESS. 2009: I89–I89

  View details for Web of Science ID 000266198600292

• RAPID AND SIGNIFICANT REDUCTION OF DAS28 FOLLOWING TOCILIZUMAB TREATMENT IN PATIENTS WITH RHEUMATOID ARTHRITIS INADEQUATELY RESPONDING TO DISEASE-MODIFYING ANTI-RHEUMATIC DRUGS Annual Meeting of the British-Society-of-Rheumatology Smolen, J. S., Mysler, E. F., Rubbert-Roth, A., Gomez-Reino, J., Alten, R., Law, A., Woodworth, T., Genovese, M. OXFORD UNIV PRESS. 2009: I91–I91

  View details for Web of Science ID 000266198600297

• Efficacy and safety of up to 10 years of etanercept therapy in North American patients with early and long-standing rheumatoid arthritis Weinblatt, M., Bathon, J., Kremer, J., Genovese, M. MOSBY-ELSEVIER. 2009: AB56

  View details for Web of Science ID 000263934100222

• Inhibition of p38: Has the Fat Lady Sung ARTHRITIS AND RHEUMATISM Genovese, M. C. 2009; 60 (2): 317-320

  View details for DOI 10.1002/art.24264

  View details for Web of Science ID 000263276400002

  View details for PubMedID 19180514

• Rituximab inhibits structural joint damage in patients with rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitor therapies ANNALS OF THE RHEUMATIC DISEASES Keystone, E., Emery, P., Peterfy, C. G., Tak, P. P., Cohen, S., Genovese, M. C., Dougados, M., Burmester, G. R., Greenwald, M., Kvien, T. K., Williams, S., Hagerty, D., Cravets, M. W., Shaw, T. 2009; 68 (2): 216-221

  Abstract

  To determine if treatment with a B cell-targeted therapy can inhibit the progression of structural joint damage in patients with rheumatoid arthritis (RA), exhibiting an inadequate response to tumour necrosis factor (TNF) inhibitors.In this phase III study, patients with an inadequate response to a TNF inhibitor and receiving methotrexate were randomised to rituximab or placebo. Radiographs were obtained at baseline, week 24 and week 56 after randomisation. Patients with an inadequate response to their randomised therapy could receive rescue medication from week 16. From week 24, eligible patients from both treatment arms could receive open-label rituximab. Patients were analysed according to their original treatment group. Radiographs were scored using the Genant-modified Sharp method. The primary radiographic endpoint was change in total Genant-modified Sharp score at week 56.Rituximab treatment caused significant reduction in joint damage progression compared with placebo. The mean change from baseline in the total Genant-modified Sharp score at week 56 was significantly lower for patients treated with rituximab than for patients treated with placebo (1.00 vs 2.31; p = 0.005), and was supported by changes in erosion score (0.59 and 1.32 for rituximab plus methotrexate vs placebo plus methotrexate, respectively; p = 0.011) and joint space narrowing score (0.41 and 0.99, respectively; p<0.001).This study provides the first evidence that a B cell-targeted therapy-rituximab-can significantly inhibit the progression of structural joint damage in patients with RA with long-standing, active and treatment-resistant disease.

  View details for DOI 10.1136/ard.2007.085787

  View details for Web of Science ID 000262394000011

  View details for PubMedID 18388156

• Blood autoantibody and cytokine profiles predict response to anti-tumor necrosis factor therapy in rheumatoid arthritis ARTHRITIS RESEARCH & THERAPY Hueber, W., Tomooka, B. H., Batliwalla, F., Li, W., Monach, P. A., Tibshirani, R. J., Van Vollenhoven, R. F., Lampa, J., Saito, K., Tanaka, Y., Genovese, M. C., Klareskog, L., Gregersen, P. K., Robinson, W. H. 2009; 11 (3)

  Abstract

  Anti-TNF therapies have revolutionized the treatment of rheumatoid arthritis (RA), a common systemic autoimmune disease involving destruction of the synovial joints. However, in the practice of rheumatology approximately one-third of patients demonstrate no clinical improvement in response to treatment with anti-TNF therapies, while another third demonstrate a partial response, and one-third an excellent and sustained response. Since no clinical or laboratory tests are available to predict response to anti-TNF therapies, great need exists for predictive biomarkers.Here we present a multi-step proteomics approach using arthritis antigen arrays, a multiplex cytokine assay, and conventional ELISA, with the objective to identify a biomarker signature in three ethnically diverse cohorts of RA patients treated with the anti-TNF therapy etanercept.We identified a 24-biomarker signature that enabled prediction of a positive clinical response to etanercept in all three cohorts (positive predictive values 58 to 72%; negative predictive values 63 to 78%).We identified a multi-parameter protein biomarker that enables pretreatment classification and prediction of etanercept responders, and tested this biomarker using three independent cohorts of RA patients. Although further validation in prospective and larger cohorts is needed, our observations demonstrate that multiplex characterization of autoantibodies and cytokines provides clinical utility for predicting response to the anti-TNF therapy etanercept in RA patients.

  View details for DOI 10.1186/ar2706

  View details for PubMedID 19460157

• Interleukin-6 Receptor Inhibition With Tocilizumab Reduces Disease Activity in Rheumatoid Arthritis With Inadequate Response to Disease-Modifying Antirheumatic Drugs The Tocilizumab in Combination With Traditional Disease-Modifying Antirheumatic Drug Therapy Study ARTHRITIS AND RHEUMATISM Genovese, M. C., McKay, J. D., Nasonov, E. L., Mysler, E. F., da Silva, N. A., Alecock, E., Woodworth, T., Gomez-Rein, J. J. 2008; 58 (10): 2968-2980

  Abstract

  To examine the efficacy and safety of the humanized anti-interleukin-6 receptor antibody tocilizumab combined with conventional disease-modifying antirheumatic drugs (DMARDs) in patients with active rheumatoid arthritis (RA).A total of 1,220 patients were randomized (2:1 ratio) in the phase III, double-blind, placebo-controlled, multicenter TOWARD (Tocilizumab in Combination With Traditional DMARD Therapy) study. Patients remained on stable doses of DMARDs and received tocilizumab 8 mg/kg or placebo (control group) every 4 weeks for 24 weeks.At week 24, the proportion of patients achieving a response according to the American College of Rheumatology criteria for 20% improvement (ACR20) was significantly greater in the tocilizumab plus DMARD group than in the control group (61% versus 25%; P<0.0001). Secondary end points including 50% or 70% improvement (ACR50/70), the Disease Activity Score in 28 joints (DAS28), DAS28 remission responses (DAS28<2.6), European League Against Rheumatism responses, and systemic markers such as the C-reactive protein and hemoglobin levels showed superiority of tocilizumab plus DMARDs over DMARDs alone. Seventy-three percent of patients in the tocilizumab group had >or=1 adverse event (AE), compared with 61% of patients in the control group. AEs leading to withdrawal from the study were infrequent (4% of patients in the tocilizumab group and 2% of those in the control group). Serious AEs occurred in 6.7% and 4.3% of patients in the tocilizumab and control groups, respectively, and serious infections occurred in 2.7% and 1.9%, respectively. Elevations in the alanine aminotransferase level, from normal at baseline to >3-fold the upper limit of normal, occurred in 4% of patients in the tocilizumab group and 1% of those in the control group, and elevated total cholesterol levels were observed in 23% and 6% of patients, respectively. Sixteen patients started lipid-lowering therapy during the study. Grade 3 neutropenia occurred in 3.7% of patients receiving tocilizumab and none of the patients in the control group, and no grade 4 neutropenia was reported.Tocilizumab combined with any of the DMARDs evaluated was safe and effective in reducing articular and systemic symptoms in patients with an inadequate response to these agents.

  View details for DOI 10.1002/art.23940

  View details for Web of Science ID 000260024400007

  View details for PubMedID 18821691

• Golimumab administered subcutaneously every 4 wks in patients with active rheumatoid arthritis despite methotrexate: Wk 24 results of the randomized, double-blind, placebo-controlled, GO-FORWARD study 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals Keystone, E., Genovese, M. C., Klareskog, L., Hsia, E. C., Livingston, J., Wiekowski, M., Hall, S. T., Miranda, P., Pazdur, J., Bae, S. C., Palmer, W., Wu, Z., Rahman, M. U. WILEY-BLACKWELL. 2008: S618–S619

  View details for Web of Science ID 000259244201466

• Low immunogenic potential of tocilizumab in patients with rheumatoid arthritis: Analysis of four phase 3 clinical trials Ramos-Remus, C., Genovese, M. C., Harre, R. A., Woodworth, T., Alecock, E. WILEY-LISS. 2008: S534

  View details for Web of Science ID 000259244201253

• Concomitant use of statins in tocilizumab-treated patients with rheumatoid arthritis with elevated low density lipoprotein cholesterol: Analysis of five phase 3 clinical trials Genovese, M. C., Smolen, J. S., Emery, P., Jones, G., Lee, J. S., Alecock, E., Kremer, J. M. WILEY-LISS. 2008: S785–S786

  View details for Web of Science ID 000259244202166

• Tocilizmab treatment results in rapid improvements in the signs and symptoms of moderate-to-severe rheumatoid arthritis in four patient Populations with different prior therapy exposure Smolen, J. S., Churchill, M., Rizzo, W., Ridley, D., Law, A., Bahrt, K., Genovese, M. C. WILEY-LISS. 2008: S532–S533

  View details for Web of Science ID 000259244201249

• Adalimumab inhibited radiographic progression more effectively than methotrexate in early RA patients who had achieved a normal c-reactive protein concentration Emery, P., Genovese, M., van Vollenhoven, R., Ozol-Godfrey, A., Sasso, E. H. WILEY-LISS. 2008: S536

  View details for Web of Science ID 000259244201257

• Phenotypic and functional features of th-17 cells in psoriasis and psoriatic arthritis Raychaudhuri, S. P., Raychaudhuti, S. K., Genovese, M. C. WILEY-LISS. 2008: S352

  View details for Web of Science ID 000259244200524

• Lipid and inflammatory biomarker profiles in patients receiving tocilizumab for rheumatoid arthritis: Analysis of five phase 3 clinical trials Genovese, M. C., Smolen, J. S., Emery, P., Jones, G., Lee, J. S., Alecock, E., Kremer, J. M. WILEY-LISS. 2008: S531–S532

  View details for Web of Science ID 000259244201247

• Ocrelizumab, a humanized anti-CD20 monoclonal antibody, in the treatment of patients with rheumatoid arthritis - A phase I/II randomized, blinded, placebo-controlled, dose-ranging study ARTHRITIS AND RHEUMATISM Genovese, M. C., Kaine, J. L., Lowenstein, M. B., Del Giudice, J., Baldassare, A., Schechtman, J., Fudman, E., Kohen, M., Gujrathi, S., Trapp, R. G., Sweiss, N. J., Spaniolo, G., Dummer, W. 2008; 58 (9): 2652-2661

  Abstract

  Ocrelizumab, a humanized anti-CD20 monoclonal antibody, was studied in a first-in-human trial in rheumatoid arthritis (RA) patients receiving concomitant methotrexate (MTX).The ACTION trial was a combined phase I/II study of placebo plus MTX versus ocrelizumab plus MTX in 237 RA patients (intent-to-treat population). During phase I, 45 patients were treated with 1 of 5 escalating doses of study drug (infusions on days 1 and 15, 10-1,000 mg per each infusion). An additional 192 patients were randomized during phase II. Eligible patients had active disease, an inadequate response to treatment with at least MTX, rheumatoid factor positivity, and elevated levels of acute-phase reactants. The total study duration was 72 weeks. B cell pharmacodynamics over time was investigated.Baseline demographics were similar among the treatment groups. Based on the entire 72-week data set, the incidence of serious adverse events in the ocrelizumab-treated patients was 17.9%, as compared with 14.6% in placebo-treated patients. The incidence of serious infections was 2.0% in all ocrelizumab-treated patients and 4.9% in placebo-treated patients. Infusion-associated adverse events were mostly grade 1 or grade 2 and were more frequent around the time of the first infusion. No serious infusion-associated adverse events were reported in the ocrelizumab group. Evidence of clinical activity was observed at all doses evaluated. Peripheral B cell depletion after infusion was rapid at all doses, with earlier repletion of B cells at doses of 10 mg and 50 mg. Human anti-human antibodies were detected in 19% and 10%, respectively, of those receiving 10 mg and 50 mg of ocrelizumab, compared with 0-5% of those receiving 200, 500, and 1,000 mg.Ocrelizumab therapy in combination with MTX was well tolerated. Doses of 200 mg (2 infusions) and higher showed better clinical responses, better reduction of C-reactive protein levels, and very low immunogenicity.

  View details for DOI 10.1002/art.23732

  View details for Web of Science ID 000259244000009

  View details for PubMedID 18759293

• IL-6 receptor inhibition with tocilizumab reduces disease activity in patients with rheumatoid arthritis with inadequate response to a range of DMARDs: The TOWARD study 16th Winter Workshop of the Canadian-Rheumatology-Association Genovese, M., Brown, J. P., McKay, J., Nasonov, E., Mysler, E., da Silva, N., Alecock, E., Gomez-Reino, J. J RHEUMATOL PUBL CO. 2008: 1187–87

  View details for Web of Science ID 000256503900091

• Targeted inhibition of IL-6 signaling with tocilizumab improves quality of life and function in patients with rheumatoid arthritis with inadequate response to a range of DMARDs 16th Winter Workshop of the Canadian-Rheumatology-Association Gomez-Reino, J. J., Nair, B., FAIRFAX, M. J., Pavelka, K., Alecock, E., Woodworth, T., Genovese, M. J RHEUMATOL PUBL CO. 2008: 1216–16

  View details for Web of Science ID 000256503900182

• Inhibition of radiographic progression with rituximab is not dependent on clinical efficacy: Results from a study in rheumatoid arthritis patients with an inadequate response to one or more TNF inhibitors (reflex) Annual Meeting of the British-Society-Rheumatology/Spring Meeting of British Health Professional in Rheumatology Emery, P., Keystone, E., Peterfy, C. G., Tak, P., Cohen, S. B., Genovese, M. C., Williams, S., Hagerty, D., Cravets, M. W., Shaw, T. M. OXFORD UNIV PRESS. 2008: II50–II50

  View details for Web of Science ID 000254680900168

• Improved remission rates with the IL-6R inhibitor tocilizumab (TCZ) in patients with active rheumatoid arthritis despite DMARD therapy: The toward study Genovese, M. C., Mckay, J. D., Nasonov, E. L., Mysler, E. F., da Silva, N. A., Alecock, E., Woodworth, T., Laughton, J., Eves, D., Gomez-Reino, J. J. OXFORD UNIV PRESS. 2008: II50

  View details for Web of Science ID 000254680900169

• Repeat treatment with rituximab in active RA patients: Long-term efficacy in patients with one versus two or more prior TNF inhibitors Emery, P., Kremer, J. M., Tony, H. P., Genovese, M. C., Tak, P., Luggen, M., Bombardieri, S., Hessey, E., Safa-Leathers, S. OXFORD UNIV PRESS. 2008: II38

  View details for Web of Science ID 000254680900130

• Safety of tnf inhibitors and non-biologic DMARDs in rheumatoid arthritis patients previously treated with rituximab Emery, P., Genovese, M. C., Breedveld, F., Moreland, L., Keystone, E., Matteson, E. L., Baptiste, Y., Reiss, W., Sweetser, M., Shaw, T. OXFORD UNIV PRESS. 2008: II48–II49

  View details for Web of Science ID 000254680900163

• Radiographic progression and clinical status are differentially related for adalimumab plus methotrexate (MTX) vs. monotherapy with adalimumab or MTX: Subanalysis of premier Annual Meeting of the British-Society-Rheumatology/Spring Meeting of British Health Professional in Rheumatology Emery, P., Genovese, M., van Vollenhoven, R., Patra, K., Sasso, E. OXFORD UNIV PRESS. 2008: II115–II116

  View details for Web of Science ID 000254680900399

• Quality of life and functional improvements with the IL-6 receptor inhibitor tocilizumab in patients with active rheumatoid arthritis despite DMARD therapy: The toward study Annual Meeting of the British-Society-Rheumatology/Spring Meeting of British Health Professional in Rheumatology Gomez-Reino, J. J., FAIRFAX, M. J., Pavelka, K., Alecock, E., Woodworth, T., Laughton, J., Eves, D., Genovese, M. C. OXFORD UNIV PRESS. 2008: II49–II49

  View details for Web of Science ID 000254680900164

• Efficacy and safety of the selective co-stimulation modulator abatacept following 2 years of treatment in patients with rheumatoid arthritis and an inadequate response to anti-tumour necrosis factor therapy ANNALS OF THE RHEUMATIC DISEASES Genovese, M. C., Schiff, M., Luggen, M., Becker, J., Aranda, R., Teng, J., Li, T., Schmidely, N., Le Bars, M., Dougados, M. 2008; 67 (4): 547-554

  Abstract

  To evaluate the safety and efficacy of abatacept during 2 years of the ATTAIN (Abatacept Trial in Treatment of Anti-TNF INadequate responders) trial in patients with rheumatoid arthritis.Patients completing the 6-month, double-blind period were eligible to enter the long-term extension; patients received abatacept approximately 10 mg/kg, plus disease-modifying antirheumatic drugs. Safety and efficacy (American College of Rheumatology (ACR) criteria responses, DAS28 (C-reactive protein), HAQ-DI, SF-36, Medical Outcomes Study Sleep Problems Index, fatigue VAS) were assessed through 2 years.317 patients (218 from the abatacept and 99 from the placebo group) entered and 222 (70%) completed 18 months of long-term extension treatment. The incidence and type of adverse events were consistent between the double-blind and cumulative (double-blind plus long-term extension) periods. Rates of serious adverse events were 25.6 and 23.4 per 100 patient-years in the double-blind versus cumulative period. At 6 months and 2 years, using non-responder analyses, ACR responses in abatacept-treated patients were: ACR 20, 59.4% and 56.2%; ACR 50, 23.5% and 33.2%; ACR 70, 11.5% and 16.1%; HAQ-DI responses were 54.4% and 47.9%. At 6 months and 2 years, using post-hoc as-observed analyses, the percentage of patients (95% confidence interval) achieving DAS28 (C-reactive protein) low disease activity score (< or = 3.2) and DAS28 (C-reactive protein)-defined remission (< 2.6) increased from 18.3% (13.0, 23.5) to 32.0% (24.6, 39.4) and 11.1% (6.8, 15.3) to 20.3% (13.9, 26.6). Clinically meaningful improvements in SF-36, pain, fatigue and sleep problems were also maintained throughout the 2 years of abatacept treatment.No unique safety observations were reported during open-label exposure. Improvements in the signs and symptoms of rheumatoid arthritis, physical function and health-related quality of life observed after 6 months, were maintained throughout the 2 years in this population with difficult-to-treat disease.NCT00124982.

  View details for DOI 10.1136/ard.2007.074773

  View details for Web of Science ID 000254121100022

  View details for PubMedID 17921185

• Efficacy and safety of up to 10 years of etanercept therapy in North American patients with early and long-standing rheumatoid arthritis Weinblatt, M., Genovese, M., Moreland, L., Bathon, J. MOSBY-ELSEVIER. 2008: AB47

  View details for Web of Science ID 000252700800186

• Safety of TNF inhibitors (TNF-is) and non-biologic DMARDs in rheumatoid arthritis (RA) patients (pts) previously treated with Rituximab (RTX) Genovese, M., van Vollenhoven, R., Breedveld, F., Emery, P., Moreland, L., Keystone, E., Matteson, E., Baptiste, Y., Burke, L., Reiss, W., Sweetser, M., Shaw, T. INFORMA HEALTHCARE. 2008: 44–44

  View details for Web of Science ID 000253952900120

• Longitudinal Evaluation of the Occurrence of MRI-Detectable Bone Marrow Edema in Osteoarthritis of the Knee ACTA RADIOLOGICA Brem, M. H., Schlechtweg, P. M., Bhagwat, J., Genovese, M., Dillingham, M. F., Yoshioka, H., Lang, P. 2008; 49 (9): 1031-1037

  Abstract

  Bone marrow edema (BME) is a condition detectable with magnetic resonance imaging (MRI) and is present in different stages of osteoarthritis (OA). Its pathogenesis is still not completely known.To evaluate the longitudinal occurrence and persistence of BME in early OA of the knee.Twenty-three patients (eight females, 15 males; mean age 55.5+/-10.3 years) were scanned with a 1.5T MR imaging unit (sagittal fat-suppressed intermediate-weighted fast spin echo; 4-mm section thickness, 1-mm intersection gap, 256 x 192 matrix, 120-mm field of view). Images were obtained in all 23 patients at two time points (TPs) and in 12 patients at three TPs. Images were evaluated by two readers independently; discrepancies in image grading were reviewed and evaluated in consensus. A four-point image-grading scale was used (absence of BME to severe BME). Four main anatomical regions were evaluated (medial femur, lateral femur, medial tibia, lateral tibia), which were subcategorized into anterior, central, and posterior regions.One hundred five areas of BME in the 23 patients were found at all three TPs. In 16 areas, the BME was consistent at the same location over time, in seven locations the BME became larger, in six areas the BME became smaller, and in 16 locations it could not be detected in follow-up MRIs. In one case, the BME was smaller at TP2 but increased at TP3. In eight cases, only at the last time point could a BME be detected.BME is not a static phenomenon but changes over time. Correlation to physical activity and local inflammatory reaction should be evaluated.

  View details for DOI 10.1080/02841850802339413

  View details for Web of Science ID 000260053900011

  View details for PubMedID 18720084

• Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus: results of a multicenter, phase Ib, double-blind, placebo-controlled, dose-escalating trial. Arthritis and rheumatism Dall'Era, M., Chakravarty, E., Wallace, D., Genovese, M., Weisman, M., Kavanaugh, A., Kalunian, K., Dhar, P., Vincent, E., Pena-Rossi, C., Wofsy, D. 2007; 56 (12): 4142-4150

  Abstract

  To assess the safety and tolerability of atacicept in patients with systemic lupus erythematosus (SLE) and the biologic effect of atacicept on B lymphocyte and immunoglobulin levels. Atacicept is a TACI-Ig fusion protein that inhibits B cell stimulation by binding to B lymphocyte stimulator and a proliferation-inducing ligand.This phase Ib, double-blind, placebo-controlled, dose-escalating trial comprised 6 cohorts of patients treated with atacicept or placebo in a 3:1 ratio of active drug to placebo (n = 8 per group; n = 7 in cohort 5). Cohorts 1-4 received a single subcutaneous dose of placebo or either 0.3 mg/kg, 1 mg/kg, 3 mg/kg, or 9 mg/kg of atacicept. Cohorts 5 and 6 received weekly doses of placebo or either 1 mg/kg or 3 mg/kg of atacicept for 4 weeks. Patients were followed up for 6 weeks (cohorts 1-4) or 9 weeks (cohorts 5 and 6). Patients with mild-to-moderate SLE were enrolled.Biologic activity of atacicept was demonstrated by dose-dependent reductions in immunoglobulin levels and in mature and total B cell numbers. This effect was most pronounced in the repeated-dose cohorts and was sustained throughout the followup period. There were no changes in the numbers of T cells, natural killer cells, or monocytes. Mild injection-site reactions occurred more frequently among the atacicept group than the placebo group. There were no differences in the frequency or type of adverse events and no severe or serious adverse events in patients treated with atacicept.Atacicept administered subcutaneously was well tolerated and demonstrated biologic activity consistent with the proposed mechanism of action.

  View details for PubMedID 18050206

• Reduced B lymphocyte and immunoglobulin levels after atacicept treatment in patients with systemic lupus erythematosus ARTHRITIS AND RHEUMATISM Dall'Era, M., Chakravarty, E., Wallace, D., Genovese, M., Weisman, M., Kavanaugh, A., Kalunian, K., Dhar, P., Vincent, E., Pena-Rossi, C., Wofsy, D., Serono, M. 2007; 56 (12): 4142-4150

  Abstract

  To assess the safety and tolerability of atacicept in patients with systemic lupus erythematosus (SLE) and the biologic effect of atacicept on B lymphocyte and immunoglobulin levels. Atacicept is a TACI-Ig fusion protein that inhibits B cell stimulation by binding to B lymphocyte stimulator and a proliferation-inducing ligand.This phase Ib, double-blind, placebo-controlled, dose-escalating trial comprised 6 cohorts of patients treated with atacicept or placebo in a 3:1 ratio of active drug to placebo (n = 8 per group; n = 7 in cohort 5). Cohorts 1-4 received a single subcutaneous dose of placebo or either 0.3 mg/kg, 1 mg/kg, 3 mg/kg, or 9 mg/kg of atacicept. Cohorts 5 and 6 received weekly doses of placebo or either 1 mg/kg or 3 mg/kg of atacicept for 4 weeks. Patients were followed up for 6 weeks (cohorts 1-4) or 9 weeks (cohorts 5 and 6). Patients with mild-to-moderate SLE were enrolled.Biologic activity of atacicept was demonstrated by dose-dependent reductions in immunoglobulin levels and in mature and total B cell numbers. This effect was most pronounced in the repeated-dose cohorts and was sustained throughout the followup period. There were no changes in the numbers of T cells, natural killer cells, or monocytes. Mild injection-site reactions occurred more frequently among the atacicept group than the placebo group. There were no differences in the frequency or type of adverse events and no severe or serious adverse events in patients treated with atacicept.Atacicept administered subcutaneously was well tolerated and demonstrated biologic activity consistent with the proposed mechanism of action.

  View details for DOI 10.1002/art.23047

  View details for Web of Science ID 000251781200031

• IL-6 receptor inhibition with tocilizumab reduces disease activity in patients with rheumatoid arthritis with inadequate response to a range of DMARDs: The TOWARD study 71st Annual Scientific Meeting of the American-College-of-Rheumatology/42nd Association-of-Rheumatology-Health-Professionals Genovese, M., McKay, J., Nasonov, E., Myster, E., da Silva, N., Alecock, E., Woodworth, T., Gomez-Reino, J. WILEY-LISS. 2007: 4309–10

  View details for Web of Science ID 000251781200185

• Targeted inhibition of IL-6 signalling withtocilizumab improves quality of life and function in patients with rheumatoid arthritis with inadequate response to a range of DMARDs 71st Annual Scientific Meeting of the American-College-of-Rheumatology/42nd Association-of-Rheumatology-Health-Professionals Gomez-Reino, J. J., FAIRFAX, M. J., Pavelka, K., Alecock, E., Woodworth, T., Genovese, M. WILEY-LISS. 2007: 4234–34

  View details for Web of Science ID 000251781200051

• Efficacy results from pivotal clinical trials with abatacept CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Rozelle, A. L., Genovese, M. C. 2007; 25 (5): S30-S34

  Abstract

  Rheumatoid arthritis (RA) is a prevalent systemic disease that causes significant joint dysfunction and disability. Dramatic improvements in the management of RA have been achieved with the use of biologic therapies aimed at cytokines, and B and T lymphocytes. Abatacept, a soluble receptor-IgG fusion protein that interferes with T-cell co-stimulation, has now been shown to improve symptoms, signs and function in RA, while also slowing radiographic progression. The degree of improvement in these measures is comparable to that seen with other biologic agents.Abatacept is effective in a range of RA patients that are encountered in clinical practice, namely methotrexate-inadequate responders, as well patients with inadequate responses to tumor necrosis factor inhibitors and patients with co-morbidities common in an aging population. When used for up to 2 years, abatacept appears to be safe and remains efficacious, although there is a trend toward increased infection rates when used in combination with other biologic therapies, as well as a trend toward more adverse events when used in a background of chronic obstructive pulmonary disease. Backed by these data, ongoing extensions of these trials, and additional new studies, abatacept represents the first co-stimulation modulator approved for RA, and is a welcome addition to the biologic therapies available for the management of this disease.

  View details for Web of Science ID 000251248100005

  View details for PubMedID 17977486

• Impact of a positive youth development program in urban after-school settings on the prevention of adolescent substance use JOURNAL OF ADOLESCENT HEALTH Tebes, J. K., Feinn, R., Vanderploeg, J. J., Chinman, M. J., Shepard, J., Brabham, T., Genovese, M., Connell, C. 2007; 41 (3): 239-247

  Abstract

  Positive youth development (PYD) emphasizes a strengths-based approach to the promotion of positive outcomes for adolescents. After-school programs provide a unique opportunity to implement PYD approaches and to address adolescent risk factors for negative outcomes, such as unsupervised out-of-school time. This study examines the effectiveness of an after-school program delivered in urban settings on the prevention of adolescent substance use.A total of 304 adolescents participated in the study: 149 in the intervention group and 155 in a control group. A comprehensive PYD intervention that included delivery of an 18-session curriculum previously found to be effective in preventing substance use in school settings was adapted for use in urban after-school settings. The intervention emphasizes adolescents' use of effective decision-making skills to prevent drug use. Assessments of substance use attitudes and behaviors were conducted at program entry, program completion, and at the 1-year follow-up to program entry. Propensity scores were computed and entered in the analyses to control for any pretest differences between intervention and control groups. Hierarchical linear modeling (HLM) analyses were conducted to assess program effectiveness.The results demonstrate that adolescents receiving the intervention were significantly more likely to view drugs as harmful at program exit, and exhibited significantly lower increases in alcohol, marijuana, other drug use, and any drug use 1 year after beginning the program.A PYD intervention developed for use in an urban after-school setting is effective in preventing adolescent substance use.

  View details for DOI 10.1016/j.jadohealth.2007.02.016

  View details for Web of Science ID 000249054500005

  View details for PubMedID 17707293

• Safety of TNF inhibitors in rheumatoid arthritis patients previously treated with rituximab 15th Winter Meeting of the Canadian-Rheumatology-Association Breedveld, F. C., Khraishi, M. M., Genovese, M., Emery, P., Moreland, L. W., Keystone, E., Matteson, E. L., Burke, L., Agarwal, S., Kim, D., Cooper, S. J RHEUMATOL PUBL CO. 2007: 1602–

  View details for Web of Science ID 000248017700052

• A pilot trial of rituximab in the treatment of patients with dermatomyositis ARCHIVES OF DERMATOLOGY Chung, L., Genovese, M. C., Fiorentino, D. F. 2007; 143 (6): 763-767

  Abstract

  Dermatomyositis is an autoimmune disease that is associated with muscle and skin inflammation. Using quantitative scales, we sought to evaluate the effects of rituximab therapy on muscle strength and skin disease in patients with dermatomyositis.An open-label trial of rituximab therapy was conducted in 8 adult patients with dermatomyositis. Patients received 2 infusions of rituximab (1 g each) 2 weeks apart without peri-infusional steroids. The primary outcome was partial remission at week 24 (prespecified reduction in elevated creatine phosphokinase levels, muscle strength deficit (Manual Muscle Test), or skin disease (Dermatomyositis Skin Severity Index). After the first infusion of rituximab, all patients achieved sustained depletion of peripheral B cells. One patient withdrew at week 16 owing to a lack of treatment efficacy. Three patients (38%) achieved partial remission at week 24, in each case by improvement in muscle strength. Muscle enzyme levels and skin scores at week 24 were not significantly changed from those at baseline. Rituximab infusions were well tolerated, with no serious infectious complications. One patient died of metastatic cancer 9 months after his last infusion.Depletion of peripheral B cells had modest effects on muscle disease and limited effects on skin disease in our cohort of patients with dermatomyositis.

  View details for Web of Science ID 000247207400012

  View details for PubMedID 17576943

• Proteomic analysis of secreted proteins in early rheumatoid arthritis: anti-citrulline autoreactivity is associated with up regulation of proinflammatory cytokines ANNALS OF THE RHEUMATIC DISEASES Hueber, W., Tomooka, B. H., Zhao, X., Kidd, B. A., Drijfhout, J. W., Fries, J. F., van Venrooij, W. J., Metzger, A. L., Genovese, M. C., Robinson, W. H. 2007; 66 (6): 712-719

  Abstract

  To identify peripheral blood autoantibody and cytokine profiles that characterise clinically relevant subgroups of patients with early rheumatoid arthritis using arthritis antigen microarrays and a multiplex cytokine assay.Serum samples from 56 patients with a diagnosis of rheumatoid arthritis of <6 months' duration were tested. Cytokine profiles were also determined in samples from patients with psoriatic arthritis (PsA) and ankylosing spondylitis (n = 21), and from healthy individuals (n = 19). Data were analysed using Kruskal-Wallis test with Dunn's adjustment for multiple comparisons, linear correlation tests, significance analysis of microarrays (SAM) and hierarchical clustering software.Distinct antibody profiles were associated with subgroups of patients who exhibited high serum levels of tumour necrosis factor (TNF)alpha, interleukin (IL)1beta, IL6, IL13, IL15 and granulocyte macrophage colony-stimulating factor. Significantly increased autoantibody reactivity against citrullinated epitopes was observed in patients within the cytokine "high" subgroup. Increased levels of TNFalpha, IL1alpha, IL12p40 and IL13, and the chemokines eotaxin/CCL11, monocyte chemoattractant protein-1 and interferon-inducible protein 10, were present in early rheumatoid arthritis as compared with controls (p<0.001). Chemokines showed some of the most impressive differences. Only IL8/CXCL8 concentrations were higher in patients with PsA/ankylosing spondylitis (p = 0.02).Increased blood levels of proinflammatory cytokines are associated with autoantibody targeting of citrullinated antigens and surrogate markers of disease activity in patients with early rheumatoid arthritis. Proteomic analysis of serum autoantibodies, cytokines and chemokines enables stratification of patients with early rheumatoid arthritis into molecular subgroups.

  View details for DOI 10.1136/ard.2006.054924

  View details for PubMedID 16901957

• A pilot study of tumor necrosis factor inhibition in erosive/inflammatory osteoarthritis of the hands JOURNAL OF RHEUMATOLOGY Magnano, M. D., Chakravarty, E. F., Broudy, C., Chung, L., Kelman, A., Hillygus, J., Genovese, M. C. 2007; 34 (6): 1323-1327

  Abstract

  To determine if anti-tumor necrosis factor (TNF) therapy (adalimumab) can safely improve symptoms of erosive/inflammatory osteoarthritis (EOA).This was an open-label pilot trial in 12 patients with EOA. Patients > 45 years old with EOA of the hands defined by > or = 2 tender and > or = 2 swollen joints (distal interphalangeal, proximal interphalangeal, first carpometacarpal) despite nonsteroidal antiinflammatory drug therapy were eligible. Patients were excluded for autoimmune arthritis, recent disease modifying antirheumatic drug use, prior use of anti-TNF therapy, infection, malignancy, or poorly controlled medical conditions. All patients received adalimumab 40 mg every other week for 12 weeks. Safety was assessed 4 weeks after the final dose. Primary endpoints included safety and American College of Rheumatology (ACR) response.Patients were predominantly female with a mean age of 60 years and 12 years of arthritis. All patients completed the study and safety followup. Adverse events were mild without necessitating discontinuation of study drug. After 12 weeks, there was a statistically significant improvement in the number of swollen joints compared to baseline (p < 0.01). One patient achieved an ACR20 response and 42% achieved an OMERACT-OARSI response. Although we detected no statistically significant improvement in the number of tender joints, grip strength, disability, pain, or global disease assessments, trends suggested modest improvement in all efficacy measures.This small open-label study of patients with EOA demonstrated that adalimumab was well tolerated. Treatment with adalimumab for 3 months did not significantly improve the signs and symptoms of EOA and most patients did not achieve an ACR20. Trends suggested improvement and individual patients had some benefit. Factors limiting interpretation of this study include the lack of a control group, outcomes chosen, number of patients treated, and the duration of treatment.

  View details for Web of Science ID 000247116600019

  View details for PubMedID 17516620

• Safety and efficacy of adalimumab in treatment of patients with psoriatic arthritis who had failed disease modifying antirheumatic drug therapy JOURNAL OF RHEUMATOLOGY Genovese, M. C., Mease, P. J., Thomson, G. T., Kivitz, A. J., Perdok, R. J., Weinberg, M. A., Medich, J., Sasso, E. H. 2007; 34 (5): 1040-1050

  Abstract

  To demonstrate the safety and efficacy of adalimumab for the treatment of active psoriatic arthritis (PsA) in patients with an inadequate response to disease modifying antirheumatic drugs (DMARD).In a placebo controlled, double-blind, randomized, multicenter study, patients were treated for 12 weeks with subcutaneous injections of adalimumab 40 mg every other week (eow) or placebo, followed by a period of open-label treatment with adalimumab 40 mg eow. The primary efficacy endpoint was the percentage of patients who met the American College of Rheumatology (ACR20) core criteria at Week 12. Secondary efficacy measures included the modified Psoriatic Arthritis Response Criteria (PsARC) and assessments of disability, psoriatic lesions, and quality of life. For missing data, nonresponder imputation was used for ACR and PsARC scores and last observation carried forward for other measures.A total of 100 patients received study drug (51 adalimumab, 49 placebo). At Week 12, an ACR20 response was achieved by 39% of adalimumab patients versus 16% of placebo patients (p = 0.012), and a PsARC response was achieved by 51% with adalimumab versus 24% with placebo (p = 0.007). At Week 12, measures of skin lesions and disability were statistically significantly improved with adalimumab. After Week 12, open-label adalimumab provided continued improvement for adalimumab patients and initiated rapid improvement for placebo patients, with ACR20 response rates of 65% and 57%, respectively, observed at Week 24. Serious adverse events had similar frequencies during therapy with placebo (4.1%), blinded adalimumab (2.0%), and open-label adalimumab (3.1%). No serious infections occurred during adalimumab therapy.In this study of patients who had active PsA and a previous, inadequate response to DMARD therapy, adalimumab was well tolerated and significantly reduced the signs, symptoms, and disability of PsA during 12 weeks of blinded and 12 weeks of open-label therapy. Adalimumab also improved psoriasis in these patients.

  View details for Web of Science ID 000246230700024

  View details for PubMedID 17444593

• Sustained efficacy along with improvements in disease activity score 28 (DAS 28) and patient (Pt)-reported outcomes (PROs) with abatacept (Aba) in rheumatoid arthritis (RA) pts with an inadequate response to anti-tumor necrosis factor (TNF) therapy: The long-term extension (LTE) of the attain trial Annual Meeting of the British-Society-of-Rheumatology Dougados, M., Schiff, M., Luggen, M., Becker, J. C., Aranda, R., Li, T., McCann, T., Schmidely, N., LeBars, M., Sibilia, J., Genovese, M. C. OXFORD UNIV PRESS. 2007: I99–I99

  View details for Web of Science ID 000250724200309

• Signal transduction blockade with imatinib mesylate prevents and treats autoimmune arthritis Paniagua, R., Sharpe, O., Ho, P., Chan, S., Chang, A., Tomooka, B., Lee, D., Genovese, M., Utz, P., Steinman, L., Robinson, W. AMER ASSOC IMMUNOLOGISTS. 2007

  View details for Web of Science ID 000209758200096

• Safety and efficacy of up to 9 years of etanercept therapy in North American patients with rheumatoid arthritis Weinblatt, M., Genovese, M., Moreland, L., Bathon, J. MOSBY-ELSEVIER. 2007: AB183

  View details for Web of Science ID 000243972801272

• Trial of atacicept in patients with systemic lupus erythematosus (SLE). Dall'Era, M., Chakravarty, E., Genovese, M., Wallace, D., Kavanaugh, A., Kalunian, K., Dhar, P., Pena-Rossi, C., Wofsy, D., Serono Zymogenetics Atacicept S WILEY-LISS. 2006: 4042–43

  View details for Web of Science ID 000242780700070

• Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis JOURNAL OF CLINICAL INVESTIGATION Paniagua, R. T., Sharpe, O., Ho, P. P., Chan, S. M., Chang, A., Higgins, J. P., Tomooka, B. H., Thomas, F. M., Song, J. J., Goodman, S. B., Lee, D. M., Genovese, M. C., Utz, P. J., Steinman, L., Robinson, W. H. 2006; 116 (10): 2633-2642

  Abstract

  Tyrosine kinases play a central role in the activation of signal transduction pathways and cellular responses that mediate the pathogenesis of rheumatoid arthritis. Imatinib mesylate (imatinib) is a tyrosine kinase inhibitor developed to treat Bcr/Abl-expressing leukemias and subsequently found to treat c-Kit-expressing gastrointestinal stromal tumors. We demonstrate that imatinib potently prevents and treats murine collagen-induced arthritis (CIA). We further show that micromolar concentrations of imatinib abrogate multiple signal transduction pathways implicated in RA pathogenesis, including mast cell c-Kit signaling and TNF-alpha release, macrophage c-Fms activation and cytokine production, and fibroblast PDGFR signaling and proliferation. In our studies, imatinib attenuated PDGFR signaling in fibroblast-like synoviocytes (FLSs) and TNF-alpha production in synovial fluid mononuclear cells (SFMCs) derived from human RA patients. Imatinib-mediated inhibition of a spectrum of signal transduction pathways and the downstream pathogenic cellular responses may provide a powerful approach to treat RA and other inflammatory diseases.

  View details for DOI 10.1172/JCI28546

  View details for PubMedID 16981009

• Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis. 70th Annual Scientific Meeting of the American-College-of-Rheumatology/41st Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals Robinson, W. H., Paniagua, R. T., Ho, P. P., Chan, S. M., Sharpe, O., Utz, P. J., Genovese, M. C. WILEY-BLACKWELL. 2006: S356–S357

  View details for Web of Science ID 000240877201370

• Inhibition of joint structural damage with rituximab is not dependant on clinical response in rheumatoid arthritis patients with an inadequate response to one or more TNF inhibitors (REFLEX study). Keystone, E., Emery, P., Peterfy, C. G., Tak, P. P., Cohen, S. B., Genovese, M. C., Williams, S., Totoritis, M. C., Cravets, M. W., Shaw, T. WILEY-LISS. 2006: S542–S543

  View details for Web of Science ID 000240877203026

• Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy - Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks ARTHRITIS AND RHEUMATISM Cohen, S. B., Emery, P., Greenwald, M. W., DougadoS, M., Furie, R. A., Genovese, M. C., Keystone, E. C., Loveless, J. E., Burmester, G., Cravets, M. W., Hessey, E. W., Shaw, T., Totoritis, M. C. 2006; 54 (9): 2793-2806

  Abstract

  To determine the efficacy and safety of treatment with rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to anti-tumor necrosis factor (anti-TNF) therapies and to explore the pharmacokinetics and pharmacodynamics of rituximab in this population.We evaluated primary efficacy and safety at 24 weeks in patients enrolled in the Randomized Evaluation of Long-Term Efficacy of Rituximab in RA (REFLEX) Trial, a 2-year, multicenter, randomized, double-blind, placebo-controlled, phase III study of rituximab therapy. Patients with active RA and an inadequate response to 1 or more anti-TNF agents were randomized to receive intravenous rituximab (1 course, consisting of 2 infusions of 1,000 mg each) or placebo, both with background MTX. The primary efficacy end point was a response on the American College of Rheumatology 20% improvement criteria (ACR20) at 24 weeks. Secondary end points were responses on the ACR50 and ACR70 improvement criteria, the Disease Activity Score in 28 joints, and the European League against Rheumatism (EULAR) response criteria at 24 weeks. Additional end points included scores on the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Health Assessment Questionnaire (HAQ) Disability Index (DI), and Short Form 36 (SF-36) instruments, as well as Genant-modified Sharp radiographic scores at 24 weeks.Patients assigned to placebo (n = 209) and rituximab (n = 311) had active, longstanding RA. At week 24, significantly more (P < 0.0001) rituximab-treated patients than placebo-treated patients demonstrated ACR20 (51% versus 18%), ACR50 (27% versus 5%), and ACR70 (12% versus 1%) responses and moderate-to-good EULAR responses (65% versus 22%). All ACR response parameters were significantly improved in rituximab-treated patients, who also had clinically meaningful improvements in fatigue, disability, and health-related quality of life (demonstrated by FACIT-F, HAQ DI, and SF-36 scores, respectively) and showed a trend toward less progression in radiographic end points. Rituximab depleted peripheral CD20+ B cells, but the mean immunoglobulin levels (IgG, IgM, and IgA) remained within normal ranges. Most adverse events occurred with the first rituximab infusion and were of mild-to-moderate severity. The rate of serious infections was 5.2 per 100 patient-years in the rituximab group and 3.7 per 100 patient-years in the placebo group.At 24 weeks, a single course of rituximab with concomitant MTX therapy provided significant and clinically meaningful improvements in disease activity in patients with active, longstanding RA who had an inadequate response to 1 or more anti-TNF therapies.

  View details for DOI 10.1002/art.22025

  View details for Web of Science ID 000240872900010

  View details for PubMedID 16947627

• Sustained efficacy and safety through 2 years in patients with rheumatoid arthritis (RA) in the long-term extension of the ATTAIN trial. 70th Annual Scientific Meeting of the American-College-of-Rheumatology/41st Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals Genovese, M. C., Schiff, M., Luggen, M., Becker, J., Aranda, R., McCann, T., Schmidely, N., Le Bars, M., Dougados, M. WILEY-BLACKWELL. 2006: S244–S244

  View details for Web of Science ID 000240877201068

• A pilot study of TNF inhibition in Erosive/Inflammatory osteoarthritis of the hands. 70th Annual Scientific Meeting of the American-College-of-Rheumatology/41st Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals Magnano, M. D., Chakravarty, E. F., Broudy, C., Chung, L., Kelman, A., Hillygus, J. J., Genovese, M. C. WILEY-BLACKWELL. 2006: S674–S674

  View details for Web of Science ID 000240877203402

• Safety of TNF inhibitors in rheumatoid arthritis patients previously treated with rituximab Breedveld, F. C., Van Vollenhoven, R. F., Genovese, M., Emery, P., Moreland, L. W., Keystone, E., Matteson, E. L., Burke, L., Agarwal, S., Kim, D., Cooper, S. TAYLOR & FRANCIS AS. 2006: 11–11

  View details for Web of Science ID 000240407400008

• Safety of TNF inhibitors in rheumatoid arthritis patients previously treated with rituximab Annual European Congress of Rheumatology (EULAR 2006) Breedveld, F. C., Genovese, M., Emery, P., Moreland, L. W., Keystone, E., Matteson, E. L., Burke, L., Agarwal, S., Kim, D., Cooper, S. BMJ PUBLISHING GROUP. 2006: 178–179

  View details for Web of Science ID 000249372500551

• Effect of etanercept on fatigue in patients with recent or established rheumatoid arthritis ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH Moreland, L. W., Genovese, M. C., Sato, R., Singh, A. 2006; 55 (2): 287-293

  Abstract

  To assess the long-term impact of etanercept on fatigue in patients with recent-onset (mean duration 11 months) or established (mean duration 12 years) rheumatoid arthritis (RA).Patients participating in either of 2 multicenter, randomized, double-blind clinical trials were included. In one trial, patients with recent-onset RA received either etanercept 25 mg twice weekly or methotrexate in a double-blind fashion for 12 months, then open label for 12 months. All patients then received open-label etanercept. In the second trial, patients with established RA received etanercept 25 mg or placebo twice weekly for 6 months in a double-blinded fashion, then open-label etanercept. Up to 46 months of followup data were included. Fatigue was measured regularly using the Health Assessment Questionnaire vitality domain.Patients with recent-onset RA who received etanercept had a significantly faster improvement in fatigue than those receiving methotrexate in the first 2 months. Subsequently, patients receiving etanercept and methotrexate had 23-29% and 17-24% reductions in fatigue scores, respectively. In the group with established RA, patients who received etanercept had significantly greater reductions in fatigue than those receiving placebo during the blinded period. Patients initially receiving etanercept sustained a mean fatigue reduction of 25-36% for the entire followup. Patients achieving clinically meaningful improvement in fatigue were more likely to meet the American College of Rheumatology improvement criteria.Etanercept therapy reduces fatigue in patients with recent-onset or established RA. Improvement in fatigue was sustained for up to 46 months, and correlated with other RA-relevant outcomes.

  View details for DOI 10.1002/art.21838

  View details for Web of Science ID 000236830400018

  View details for PubMedID 16583424

• Long-term experience with etanercept in the treatment of rheumatoid arthritis in elderly and younger patients - Patient-reported outcomes from multiple controlled and open-label extension studies DRUGS & AGING Schiff, M. H., Yu, E. B., Weinblatt, M. E., Moreland, L. W., Genovese, M. C., White, B., Singh, A., Chon, Y., Woolley, J. M. 2006; 23 (2): 167-178

  Abstract

  The impact of long-term therapy for rheumatoid arthritis (RA) in elderly (> or = 65 years of age) and younger (< 65 years of age) patients, especially on patient-reported outcomes, has not been well studied. We evaluated patient-reported outcomes in elderly patients treated with etanercept, in contrast to outcomes in younger patients, using data from multiple controlled and open-label extension studies of patients with early RA (ERA; < or = 3 years) and late RA (LRA; disease-modifying antirheumatic drug [DMARD]-refractory RA).This post hoc analysis included adult patients with RA enrolled in controlled, double-blind studies (up to 2 years) and subsequent open-label extension studies (up to 4 years). Patients were evaluated according to age at baseline of the original study. Patients may have received etanercept, placebo or methotrexate during the blinded treatment phases, but all patients had been receiving etanercept 25 mg twice weekly for at least 4 years. Both ERA and LRA extension studies are ongoing. Patient-reported outcome assessments included improvement in Health Assessment Questionnaire-Disability Index (HAQ-DI), proportions of patients achieving an improvement in HAQ-DI > or = 0.22 points, patients exhibiting worsening of HAQ-DI and patients achieving an HAQ-DI score of 0.Elderly patients, with either ERA or LRA, had significantly worse baseline mean HAQ-DI scores than younger patients (p < 0.05, Student's t-test) in most studies, indicating greater disability. Improvement in HAQ-DI was greatest during the first 3 months after starting etanercept treatment in the controlled phase and appeared to be sustained over 3-6 months in patients with early or DMARD-refractory RA. Across the various controlled trials, mean improvements from baseline in HAQ-DI ranged from 0.39 to 0.92 points in elderly patients and from 0.57 to 1.00 points in younger patients. Patients with ERA and LRA, regardless of age group, maintained their improvement in HAQ-DI throughout the open-label extension trials for up to a total of 6 years of etanercept therapy. Change from baseline in HAQ-DI was moderately correlated with 28-joint Disease Activity Score within each age group across the multiple trials.Both elderly and younger patients with RA treated with etanercept exhibited similar and rapid improvements in functional status during controlled studies, and these improvements were sustained during open-label extension trials.

  View details for Web of Science ID 000237272800006

  View details for PubMedID 16536638

• A randomized, blinded, parallel group, placebo controlled pilot study evaluating the effect of PVAC treatment in patients with diffuse systemic sclerosis JOURNAL OF RHEUMATOLOGY Genovese, M. C., Chakravarty, E. F., Boyle, D. L., Tutuncu, Z., Thorburn, C. M., Halilhodzic, M., KROLL, S., Baughman, J., Stewart, S., Kavanaugh, A. 2005; 32 (12): 2345-2350

  Abstract

  Systemic sclerosis (SSc) is a disorder characterized by progressive thickening of the skin; there is no effective therapy. PVAC, a potential therapeutic agent derived from delipidated, deglycolipidated Mycobacterium vaccae, has shown effects on cutaneous disease in animal models of SSc. We evaluated the safety and possible biologic effect of intradermal injections of PVAC in patients with diffuse SSc.Eighteen patients enrolled in this double blind, placebo controlled, randomized, 24 week pilot study. All patients met criteria for diffuse SSc without evidence of significant renal dysfunction, pulmonary fibrosis, pulmonary hypertension, or congestive heart failure. Patients received 8 intradermal injections of 15 microg PVAC, 50 microg PVAC, or placebo at 3 week intervals. The primary efficacy endpoint was the change in Modified Rodnan Skin Score (MRSS) at Week 24. Each of the active drug arms was compared to placebo.Baseline demographic and disease characteristics were similar across the 3 treatment groups. The median age was 48 years and 14 of 18 (78%) patients were female. The regimens were well tolerated with no reported serious adverse events; however, grade 1 or 2 injection site reactions occurred in the majority of patients receiving PVAC. The MRSS improved by 20.6% in the 15 microg PVAC arm, while it worsened by 29.8% in the placebo arm and by 16.7% in the 50 microg arm. Change in physician and patient global assessments followed similar trends.In this pilot study, use of PVAC in patients with SSc appeared safe and was associated with a trend toward improved skin scores in the 15 microg treatment group. Additional evaluation of this therapeutic approach is warranted.

  View details for Web of Science ID 000233857500014

  View details for PubMedID 16331761

• Rituximab in the treatment of patients with dermatomyositis: 12 week interim analysis of a pilot trial. Chung, L., Genovese, M. C., Fiorentino, D. WILEY-LISS. 2005: 4088

  View details for Web of Science ID 000234131500136

• Computer-assisted pattern recognition of autoantibody results CLINICAL AND DIAGNOSTIC LABORATORY IMMUNOLOGY Binder, S. R., Genovese, M. C., Merrill, J. T., Morris, R. I., Metzger, A. L. 2005; 12 (12): 1353-1357

  Abstract

  Immunoassay-based anti-nuclear antibody (ANA) screens are increasingly used in the initial evaluation of autoimmune disorders, but these tests offer no "pattern information" comparable to the information from indirect fluorescence assay-based screens. Thus, there is no indication of "next steps" when a positive result is obtained. To improve the utility of immunoassay-based ANA screening, we evaluated a new method that combines a multiplex immunoassay with a k nearest neighbor (kNN) algorithm for computer-assisted pattern recognition. We assembled a training set, consisting of 1,152 sera from patients with various rheumatic diseases and non-diseased patients. The clinical sensitivity and specificity of the multiplex method and algorithm were evaluated with a test set that consisted of 173 sera collected at a rheumatology clinic from patients diagnosed by using standard criteria, as well as 152 age- and sex-matched sera from presumably healthy individuals (sera collected at a blood bank). The test set was also evaluated with a HEp-2 cell-based enzyme-linked immunosorbent assay (ELISA). Both the ELISA and multiplex immunoassay results were positive for 94% of the systemic lupus erythematosus (SLE) patients. The kNN algorithm correctly proposed an SLE pattern for 84% of the antibody-positive SLE patients. For patients with no connective tissue disease, the multiplex method found fewer positive results than the ELISA screen, and no disease was proposed by the kNN algorithm for most of these patients. In conclusion, the automated algorithm could identify SLE patterns and may be useful in the identification of patients who would benefit from early referral to a specialist, as well as patients who do not require further evaluation.

  View details for DOI 10.1128/CDLI.12.12.1353-1357.2005

  View details for Web of Science ID 000234061400001

  View details for PubMedID 16339056

  View details for PubMedCentralID PMC1317078

• Management of co-morbidities and general medical conditions in patients with rheumatoid arthritis. Current rheumatology reports Magnano, M. D., Genovese, M. C. 2005; 7 (5): 407-415

  Abstract

  Rheumatologists, in addition to providing subspecialty care, are frequently called to treat general medical conditions in their patients with rheumatoid arthritis (RA). Co-morbid medical problems are common in the RA population and may require a different approach from standard practice recommendations. In this paper, we review the evaluation and treatment of cardiovascular disease, chronic kidney disease, gastrointestinal disease, depression, and metabolic bone disease in patients with RA. Appreciation of the unique interaction between arthritis and common medical co-morbidities may have a significant impact on management and outcomes of RA.

  View details for PubMedID 16174493

• Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition NEW ENGLAND JOURNAL OF MEDICINE Genovese, M. C., Becker, J., Schiff, M., Luggen, M., Sherrer, Y., Kremer, J., Birbara, C., Box, J., Natarajan, K., Nuamah, I., Li, T., Aranda, R., Hagerty, D. T., Dougados, M. 2005; 353 (11): 1114-1123

  Abstract

  A substantial number of patients with rheumatoid arthritis have an inadequate or unsustained response to tumor necrosis factor alpha (TNF-alpha) inhibitors. We conducted a randomized, double-blind, phase 3 trial to evaluate the efficacy and safety of abatacept, a selective costimulation modulator, in patients with active rheumatoid arthritis and an inadequate response to at least three months of anti-TNF-alpha therapy.Patients with active rheumatoid arthritis and an inadequate response to anti-TNF-alpha therapy were randomly assigned in a 2:1 ratio to receive abatacept or placebo on days 1, 15, and 29 and every 28 days thereafter for 6 months, in addition to at least one disease-modifying antirheumatic drug. Patients discontinued anti-TNF-alpha therapy before randomization. The rates of American College of Rheumatology (ACR) 20 responses (indicating a clinical improvement of 20 percent or greater) and improvement in functional disability, as reflected by scores for the Health Assessment Questionnaire (HAQ) disability index, were assessed.After six months, the rates of ACR 20 responses were 50.4 percent in the abatacept group and 19.5 percent in the placebo group (P<0.001); the respective rates of ACR 50 and ACR 70 responses were also significantly higher in the abatacept group than in the placebo group (20.3 percent vs. 3.8 percent, P<0.001; and 10.2 percent vs. 1.5 percent, P=0.003). At six months, significantly more patients in the abatacept group than in the placebo group had a clinically meaningful improvement in physical function, as reflected by an improvement from baseline of at least 0.3 in the HAQ disability index (47.3 percent vs. 23.3 percent, P<0.001). The incidence of adverse events and peri-infusional adverse events was 79.5 percent and 5.0 percent, respectively, in the abatacept group and 71.4 percent and 3.0 percent, respectively, in the placebo group. The incidence of serious infections was 2.3 percent in each group.Abatacept produced significant clinical and functional benefits in patients who had had an inadequate response to anti-TNF-alpha therapy.

  View details for Web of Science ID 000231841900006

  View details for PubMedID 16162882

• Antigen microarray profiling of autoantibodies in rheumatoid arthritis ARTHRITIS AND RHEUMATISM Hueber, W., Kidd, B. A., Tomooka, B. H., Lee, B. J., Bruce, B., Fries, J. F., Sonderstrup, G., Monach, P., Drijfhout, J. W., van Venrooij, W. J., Utz, P. J., Genovese, M. C., Robinson, W. H. 2005; 52 (9): 2645-2655

  Abstract

  Because rheumatoid arthritis (RA) is a heterogeneous autoimmune disease in terms of disease manifestations, clinical outcomes, and therapeutic responses, we developed and applied a novel antigen microarray technology to identify distinct serum antibody profiles in patients with RA.Synovial proteome microarrays, containing 225 peptides and proteins that represent candidate and control antigens, were developed. These arrays were used to profile autoantibodies in randomly selected sera from 2 different cohorts of patients: the Stanford Arthritis Center inception cohort, comprising 18 patients with established RA and 38 controls, and the Arthritis, Rheumatism, and Aging Medical Information System cohort, comprising 58 patients with a clinical diagnosis of RA of <6 months duration. Data were analyzed using the significance analysis of microarrays algorithm, the prediction analysis of microarrays algorithm, and Cluster software.Antigen microarrays demonstrated that autoreactive B cell responses targeting citrullinated epitopes were present in a subset of patients with early RA with features predictive of the development of severe RA. In contrast, autoimmune targeting of the native epitopes contained on synovial arrays, including several human cartilage gp39 peptides and type II collagen, were associated with features predictive of less severe RA.Proteomic analysis of autoantibody reactivities provides diagnostic information and allows stratification of patients with early RA into clinically relevant disease subsets.

  View details for DOI 10.1002/art.21269

  View details for PubMedID 16142722

• Integrated serum proteome analysis of autoantibodies and cytokines delineates distinct biosignatures in subsets of patients with early RA. Hueber, W., Tomooka, B., Bruce, B., Monach, P., Fries, J. F., van Venrooij, W., Zatarain, E., Genovese, M. C., Robinson, W. H. WILEY-BLACKWELL. 2005: S276–S277

  View details for Web of Science ID 000232207801206

• The relationship of radiographic progression to clinical response in patients with early RA treated with adalimumab (HUMIRA (R)) plus MTX or MTX alone. Genovese, M. C., Kavanaugh, A. F., Cohen, S. B., Emery, P., Sasso, E. H., Spencer-Green, G. T. WILEY-BLACKWELL. 2005: S451

  View details for Web of Science ID 000232207802207

• Efficacy and safety of over 8 years of etanercept (Enbrel (R)) therapy in North American patients with early and long-standing rheumatoid arthritis. Weinblatt, M. E., Genovese, M. C., Moreland, L. W., Bathon, J. M., Kremer, J. M., Fleischmann, R. M., Schiff, M. H., Xia, H. A., Peloso, P., White, B. WILEY-BLACKWELL. 2005: S541

  View details for Web of Science ID 000232207802464

• Differential responsiveness to belimumab (BmAb) in combination with standard of care therapy in RF plus , TNF alpha-inhibitor and methotrexate partial responder subgroups of subjects with moderate-severe rheumatoid arthritis Genovese, M., Filipowicz-Sosnowska, A., Merrill, J., Wasko, M., Dilorio, E., Stevenson, J., Lisse, J., Zhong, J., Hall, L., Bieber, F., Zilberstein, M., LBRA01 Study Grp WILEY-BLACKWELL. 2005: S738

  View details for Web of Science ID 000232207803534

• Fibrinogen-induced arthritis in mice as a novel model for rheumatoid arthritis. Robinson, W. H., Tomooka, B., Genovese, M. C., Ho, P. P. WILEY-BLACKWELL. 2005: S157

  View details for Web of Science ID 000232207800353

• Selective co-stimulation modulation with abatacept leads to improvements in ACR responses in patients with an inadequate response to etanercept, infliximab or both: The ATTAIN trial. 69th Annual Scientific Meeting of the American-College-of-Rheumatology/40th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals Dougados, M., Kavanagh, A., Espinoza, L., Sibilia, J., Aranda, R., Becker, J. C., White, A., Genovese, M., Schiff, M., Luggen, M. WILEY-BLACKWELL. 2005: S137–S138

  View details for Web of Science ID 000232207800297

• The impact of disease duration on improvements in ACR responses and remission following abatacept treatment in patients with an inadequate response 2 to anti-TNF therapy in the ATTAIN trial. 69th Annual Scientific Meeting of the American-College-of-Rheumatology/40th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals Genovese, M., Luggen, M., Kremer, J., Sany, J., Aranda, R., Becker, J. C., White, A., Schiff, M., Dougados, M. WILEY-BLACKWELL. 2005: S137–S137

  View details for Web of Science ID 000232207800296

• Efficacy of abatacept following wash-out of anti-TNF therapy in rheumatoid arthritis patients in the ATTAIN (Abatacept Trial in Treatment of Anti-TNF INadequate Responders) trial: Current versus prior discontinuation. 69th Annual Scientific Meeting of the American-College-of-Rheumatology/40th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals Genovese, M., Schiff, M., Luggen, M., Aranda, R., Becker, J. C., White, A., Dougados, M. WILEY-BLACKWELL. 2005: S560–S561

  View details for Web of Science ID 000232207803035

• Longterm safety, efficacy, and radiographic outcome with etanercept treatment in patients with early rheumatoid arthritis JOURNAL OF RHEUMATOLOGY Genovese, M. C., Bathon, J. M., Fleischmann, R. M., Moreland, L. W., Martin, R. W., Whitmore, J. B., Tsuji, W. H., Leff, J. A. 2005; 32 (7): 1232-1242

  Abstract

  To evaluate safety, efficacy, and radiographic progression in patients with early rheumatoid arthritis (RA) undergoing longterm treatment with etanercept.Patients with early RA (disease duration of 3 years or less) who had completed a 2-year efficacy study comparing etanercept and methotrexate (MTX) were followed in an extension where they received 25 mg etanercept twice weekly. Safety was summarized descriptively and compared with data from the efficacy study. Efficacy and radiographic progression were assessed using American College of Rheumatology response criteria, disease activity scores, and Total Sharp Score (TSS).Rates of serious adverse events and serious infections did not increase with longterm exposure to etanercept, and were similar to rates reported for the blinded portion of the efficacy study. Efficacy was sustained in patients who completed 5 years of etanercept treatment at the time of this report (N = 201), even in those who decreased or discontinued use of MTX or corticosteroids. No radiographic progression (change in TSS < or = 0) was seen in 55% of patients with 5-year radiographs; negative change (TSS < 0) was seen in 11%.Etanercept treatment in patients with early RA was generally well tolerated for up to 5 years. The results indicate sustained efficacy and decreased rate of radiographic progression. The rate of radiographic progression was low compared with other studies, emphasizing the benefit gained in patients with early aggressive RA who undergo longterm treatment with etanercept.

  View details for PubMedID 15996057

• Abatacept leads to significant improvements in all American college of rheumatology core components in patients with an inadequate response to anti-TNF therapy in the attain trial Annual European Congress of Rheumatology Schiff, M., Dougados, M., Luggen, M., Espinoza, L., Nuamah, I., Aranda, R., Becker, J., Genovese, M. BMJ PUBLISHING GROUP. 2005: 435–436

  View details for Web of Science ID 000229909102105

• Beneficial effects of the selective CO-stimulation modulator abatacept on biomarkers of rheumatoid arthritis immunopathology in patients with an inadequate response to methotrexate or TNF-inhibitor treatment Annual European Congress of Rheumatology Emery, R., Westhovens, R., LEON, G., Nuamah, I., Ge, Z., Aranda, R., Becker, J., Genovese, M., Dougados, M. BMJ PUBLISHING GROUP. 2005: 432–433

  View details for Web of Science ID 000229909102097

• Factors that predict prematurity and preeclampsia in pregnancies that are complicated by systemic lupus erythematosus 71st Annual Meeting of the Central-Association-of-Obstetricians-and-Gynecologists Chakravarty, E. F., Colon, I., Langen, E. S., Nix, D. A., El-Sayed, Y. Y., Genovese, M. C., Druzin, M. L. MOSBY-ELSEVIER. 2005: 1897–1904

  Abstract

  The purpose of this study was to describe the outcomes of a 10-year cohort of pregnancies in patients with systemic lupus erythematosus and to evaluate clinical and laboratory markers for adverse outcomes.We reviewed all pregnancies in patients with systemic lupus erythematosus who were seen at Stanford University from 1991 to 2001. Univariate analyses were performed to identify potential risk factors for adverse outcomes.Sixty-three pregnancies in 48 women were identified. Approximately 35% of the pregnancies occurred in women with previous renal disease and 10% in women with previous central nervous system disease. Flares occurred in 68% of the pregnancies, the majority of which were mild to moderate. Preeclampsia complicated 12 pregnancies. Factors that were associated with premature delivery included prednisone use at conception (relative risk, 1.8), the use of antihypertensive medications (relative risk, 1.8), and a severe flare during pregnancy (relative risk, 2.0). Thrombocytopenia was associated with an increased risk of preeclampsia (relative risk, 3.2).Flares, most of which were mild to moderate, occurred most of the pregnancies in our cohort of patients with systemic lupus erythematosus. Thrombocytopenia, hypertension, and prednisone use may be predictive factors for particular adverse outcomes.

  View details for DOI 10.1016/j.ajog.2005.02.063

  View details for Web of Science ID 000230037600034

  View details for PubMedID 15970846

• Biologic therapies in clinical development for the treatment of rheumatoid arthritis JCR-JOURNAL OF CLINICAL RHEUMATOLOGY Genovese, M. C. 2005; 11 (3): S45-S54

  Abstract

  The therapeutic objective in patients with rheumatoid arthritis (RA) is reduction of disease activity with an ultimate goal of disease remission. Limitations of currently available disease-modifying antirheumatic drugs and biologic therapies suggest that there remains an unmet need for agents that advance these goals in a greater proportion of patients. Progress in our understanding of the regulatory molecules and pathways that mediate the immune and inflammatory responses necessary for the initiation and perpetuation of RA has led to the identification of new targets for therapy. It is expected that the therapeutic modulation of these targets, which include proinflammatory cytokines, T and B cells, adhesion molecules, chemokines, and intra- and extracellular signaling pathways, can provide new treatment strategies in patients with RA and other autoimmune disorders. Toward this end, a series of novel agents with diverse mechanisms of action are in development. Although many of these agents are still beyond the clinical horizon, several of them have shown promise in recent trials. This article reviews a few of the many treatment strategies currently being evaluated, which are hoped to lead to greater benefits and better disease management in the clinical setting.

  View details for DOI 10.1097/01.rhu.0000166625.65114.5f

  View details for Web of Science ID 000230136100003

  View details for PubMedID 16357750

• Temporal effects of a COX-2-selective NSAID on bone ingrowth. Journal of biomedical materials research. Part A Goodman, S. B., Ma, T., Mitsunaga, L., Miyanishi, K., Genovese, M. C., Smith, R. L. 2005; 72 (3): 279-287

  Abstract

  The effects of a short course of a COX-2 inhibitor on bone healing when the drug is discontinued are unknown. We examined the effects of rofecoxib on bone ingrowth over a 6-week period using a well-defined animal model. The Bone Harvest Chamber was implanted bilaterally in mature rabbits. After osseointegration of the chamber, the following treatments were given for 6 weeks each, followed by a harvest in each case: control-no drug; oral rofecoxib (12.5 mg/day) for the first 2 of 6 weeks; washout period-no drug; oral rofecoxib for the last 2 of 6 weeks; washout period-no drug; rofecoxib given continuously for all 6 weeks. Harvested specimens were snap-frozen, cut into serial 6-microm sections, and stained with hematoxylin and eosin and alkaline phosphatase (osteoblast marker), and processed using immunohistochemistry to identify the vitronectin receptor (osteoclast-like cells). Rofecoxib given continuously for 6 weeks yielded statistically less bone ingrowth compared to the control treatment. Rofecoxib given during the initial or final 2 weeks of a 6-week treatment did not appear to interfere with bone ingrowth. This suggests that the effects of COX-2 inhibitors on bone are less profound when the drug is administered for a short period of time.

  View details for PubMedID 15666361

• Temporal effects of a COX-2-selective NSAID on bone ingrowth JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A Goodman, S. B., Ma, T., Mitsunaga, L., Miyanishi, K., Genovese, M. C., Smith, R. L. 2005; 72A (3): 279-287

  Abstract

  The effects of a short course of a COX-2 inhibitor on bone healing when the drug is discontinued are unknown. We examined the effects of rofecoxib on bone ingrowth over a 6-week period using a well-defined animal model. The Bone Harvest Chamber was implanted bilaterally in mature rabbits. After osseointegration of the chamber, the following treatments were given for 6 weeks each, followed by a harvest in each case: control-no drug; oral rofecoxib (12.5 mg/day) for the first 2 of 6 weeks; washout period-no drug; oral rofecoxib for the last 2 of 6 weeks; washout period-no drug; rofecoxib given continuously for all 6 weeks. Harvested specimens were snap-frozen, cut into serial 6-microm sections, and stained with hematoxylin and eosin and alkaline phosphatase (osteoblast marker), and processed using immunohistochemistry to identify the vitronectin receptor (osteoclast-like cells). Rofecoxib given continuously for 6 weeks yielded statistically less bone ingrowth compared to the control treatment. Rofecoxib given during the initial or final 2 weeks of a 6-week treatment did not appear to interfere with bone ingrowth. This suggests that the effects of COX-2 inhibitors on bone are less profound when the drug is administered for a short period of time.

  View details for DOI 10.1002/jbm.a.30231

  View details for Web of Science ID 000227223200005

• Fibrinogen-induced arthritis in mice as a novel model for rheumatoid arthritis. 5th Annual Meeting of the Federation-of-Clinical-Immunology-Societies Ho, P. P., Tomooka, B. H., Higgins, J. P., Lee, L. Y., Genovese, M., Robinson, W. H. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2005: S32–S32

  View details for Web of Science ID 000229104400085

• A multicentre, randomised, double blind, placebo controlled phase II study of subcutaneous interferon beta-1a in the treatment of patients with active rheumatoid arthritis ANNALS OF THE RHEUMATIC DISEASES van Holten, J., Pavelka, K., Vencovsky, J., Stahl, H., Rozman, B., Genovese, M., Kivitz, A. J., Alvaro, J., Nuki, G., Furst, D. E., Herrero-Beaumont, G., McInnes, I. B., Musikic, P., Tak, P. P. 2005; 64 (1): 64-69

  Abstract

  To assess the efficacy of interferon beta (IFN beta) in combination with methotrexate in treatment of patients with rheumatoid arthritis.209 patients with active rheumatoid arthritis, who had been on methotrexate for at least six months and at a stable dose for four weeks before study entry, were randomised in double blind fashion to receive placebo (0.05 ml or 0.5 ml), IFN beta 2.2 microg (0.05 ml), or IFN beta 44 microg (0.5 ml), given subcutaneously three times weekly for 24 weeks. The primary efficacy measure was a change in radiological scores at week 24. The secondary endpoint was the proportion of patients who met the ACR 20% improvement criteria at the end of the study. Synovial biopsy specimens were obtained before and after treatment from a subset of patients. Immunohistochemistry was used to detect the presence of inflammatory cells and the results were measured by digital image analysis. Collagen crosslinks were measured in urine at different times throughout the study.Analysis of radiological scores and clinical variable showed no changes in any of the groups, and there were no differences between the groups. On microscopic analysis of synovial tissue there was no significant change in the scores for infiltration by inflammatory cells after IFN beta treatment. Urinary levels of collagen crosslinks were unchanged between the treatment groups.At the doses tested, treatment with IFN beta three times weekly in combination with methotrexate did not have a clinical or radiological effect in patients with rheumatoid arthritis.

  View details for DOI 10.1136/ard.2003.020347

  View details for Web of Science ID 000225800100014

  View details for PubMedID 15242865

• Pharmacologic modulation of periprosthetic osteolysis CLINICAL ORTHOPAEDICS AND RELATED RESEARCH Goodman, S. B., Trindade, M., Ma, T., Genovese, M., Smith, R. L. 2005: 39-45

  Abstract

  Wear and periprosthetic osteolysis of total joint replacements continue to be the most important problems in arthroplasty surgery. Despite the introduction of improved technologies including alternative bearing surfaces for TJRs, wear is inevitable because of relative movement at different interfaces and processes such as electrolysis and material degradation. Worn, clinically failing implants need to be followed closely and revised when appropriate. However, early wear and minor osteolysis do not result necessarily in progressive failure of the prosthesis. Indeed such cases may be followed up clinically and radiographically to establish the functional and biologic sequelae of wear and the timeline of these events. This scenario provides an opportunity to modulate the adverse biologic reaction associated with wear particles that includes chronic inflammation, the foreign body response, and periprosthetic bone destruction. Currently, immunological events associated with wear particles are becoming understood more clearly. Strategies to mitigate adverse processes associated with wear debris include local or systemic administration of immune modulators, signaling molecules, anti-inflammatory agents and growth factors, and altering osteoclast function. Ultimately, prevention of accelerated wear and periprosthetic osteolysis will be achieved with improved bearing surfaces and prosthetic designs.

  View details for DOI 10.1097/01/blo.0000149998.88218.05

  View details for PubMedID 15662302

• Efficacy and safety of abatacept (CTLA41g), a selective co-stimulation modulator, in rheumatoid arthritis patients not responding adequately to anti-TNF-alpha therapy: Results of the phase III ATTAIN (Abatacept trial in treatment of Anti-TNF INadequate responders) 68th Annual Scientific Meeting of the American-College-of-Rheumatology/39th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals Genovese, M., Luggen, M., Schiff, M., Sherrer, Y., Nuamah, I., Aranda, R., Becker, J. C., Dougados, M. WILEY-BLACKWELL. 2004: 4103–

  View details for Web of Science ID 000225750200114

• A randomized, controlled trial of interferon-beta-1a (Avonex(R)) in patients with rheumatoid arthritis: a pilot study [ISRCTN03626626]. Arthritis research & therapy Genovese, M. C., Chakravarty, E. F., Krishnan, E., Moreland, L. W. 2004; 6 (1): R73-R77

  Abstract

  The objective of this study was to evaluate the safety and possible efficacy of IFN-beta-1a for the treatment of patients with rheumatoid arthritis (RA). Twenty-two patients with active RA were enrolled in a phase II randomized, double-blind, placebo-controlled trial of 30 microg IFN-beta-1a by weekly self-injection for 24 weeks. The primary outcome of the study was safety. Secondary outcomes included the proportion of patients achieving an American College of Rheumatology (ACR) 20 response at 24 weeks. There were no significant differences in adverse events reported in the two groups. Fewer than 20% of patients in each arm of the study achieved an ACR 20 response at 24 weeks (P = 0.71). Sixty-nine percent of patients receiving IFN-beta and 67% receiving placebo terminated the study early, most of them secondary to a perceived lack of efficacy. Overall, IFN-beta-1a had a safety profile similar to that of placebo. There were no significant differences in the proportion of patients achieving an ACR 20 response between the two groups.

  View details for DOI 10.1186/ar1026

  View details for PubMedID 14979940

  View details for PubMedCentralID PMC400417

• Magnetic resonance imaging of articular cartilage of the knee: Comparison between fat-suppressed three-dimensional SPGR imaging, fat-suppressed FSE imaging, and fat-suppressed three-dimensional DEFT imaging, and correlation with arthroscopy JOURNAL OF MAGNETIC RESONANCE IMAGING Yoshioka, H., Stevens, K., Hargreaves, B. A., Steines, D., Genovese, M., Dillingham, M. F., Winalski, C. S., Lang, P. 2004; 20 (5): 857-864

  Abstract

  To compare signal-to-noise ratios (S/N) and contrast-to-noise ratios (C/N) in various MR sequences, including fat-suppressed three-dimensional spoiled gradient-echo (SPGR) imaging, fat-suppressed fast spin echo (FSE) imaging, and fat-suppressed three-dimensional driven equilibrium Fourier transform (DEFT) imaging, and to determine the diagnostic accuracy of these imaging sequences for detecting cartilage lesions in osteoarthritic knees, as compared with arthroscopy.Two sagittal fat-suppressed FSE images (repetition time [TR] / echo time [TE], 4000/13 [FSE short TE] and 4000/39 [FSE long TE]), sagittal fat-suppressed three-dimensional SPGR images (60/5, 40 degrees flip angle), and sagittal fat-suppressed echo-planar three-dimensional DEFT images (400/21.2) were acquired in 35 knees from 28 patients with osteoarthritis of the knee. The S/N efficiencies (S/Neffs) of cartilage, synovial fluid, muscle, meniscus, bone marrow, and fat tissue, and the C/N efficiencies (C/Neffs) of these structures were calculated. Kappa values, exact agreement, sensitivity, specificity, positive predictive value, and negative predictive value were determined by comparison of MR grading with arthroscopic results.The synovial fluid S/Neff on fat-suppressed FSE short TE images, fat-suppressed FSE long TE images, and fat-suppressed three-dimensional DEFT images showed similar values. Fat-suppressed three-dimensional DEFT images showed the highest fluid-cartilage C/Neff of all sequences. All images showed fair to good agreement with arthroscopy (kappa, 0.615 in FSE short TE, 0.601 in FSE long TE, 0.583 in three-dimensional SPGR, and 0.561 in three-dimensional DEFT). Although the sensitivity of all sequences was high (100% in FSE short TE, FSE long TE, and DEFT; 96.7% in SPGR), specificity was relatively low (67.6% in FSE short TE and FSE long TE; 85.3% in SPGR; 58.3% in DEFT). The peripheral area of bone marrow edema or whole area of bone marrow edema on fat-suppressed FSE images was demonstrated as low or iso-signal intensity on fat-suppressed three-dimensional DEFT images.Fat-suppressed three-dimensional SPGR imaging and fat-suppressed FSE imaging showed high sensitivity and high negative predictive values, but relatively low specificity. The Kappa value and exact agreement was the highest on fat-suppressed FSE short TE images. Fat-suppressed three-dimensional DEFT images showed results similar to the conventional sequences.

  View details for DOI 10.1002/jmri.20193

  View details for Web of Science ID 000224762700017

  View details for PubMedID 15503323

• Effects of prasterone on disease activity and symptoms in women with active systemic lupus erythematosus - Results of a multicenter randomized, double-blind, placebo-controlled trial Annual Meeting of the British-Society-for-Rheumatology Petri, M. A., Mease, P. J., Merrill, J. T., Lahita, R. G., Iannini, M. J., Yocum, D. E., GINZLER, E. M., Katz, R. S., Gluck, O. S., Genovese, M. C., van Vollenhoven, R., Kalunian, K. C., Manzi, S., Greenwald, M. W., Buyon, J. P., Olsen, N. J., Schiff, M. H., Kavanaugh, A. F., Caldwell, J. R., Ramsey-Goldman, R., St Clair, E. W., Goldman, A. L., Egan, R. M., Polisson, R. P., Moder, K. G., Rothfield, N. F., Spencer, R. T., Hobbs, K., Fessler, B. J., Calabrese, L. H., Moreland, L. W., Cohen, S. B., Quarles, B. J., Strand, V., GURWITH, M., Schwartz, K. E. WILEY-LISS. 2004: 2858–68

  Abstract

  To determine whether prasterone administration results in improvement or stabilization of systemic lupus erythematosus (SLE) disease activity and its symptoms.Women with active SLE were treated with prasterone 200 mg/day plus standard SLE treatments or with placebo plus standard SLE treatments for up to 12 months in this randomized, double-blind investigation conducted at 27 centers. Standard SLE treatments included prednisone (/=6 weeks prior to enrollment and remain unchanged during protocol treatment. Responders were patients who experienced no clinical deterioration and had improvement or stabilization over the duration of the study in 2 disease activity measures (the SLE Disease Activity Index [SLEDAI] and the Systemic Lupus Activity Measure) and 2 quality of life measures (patient's global assessment and the Krupp Fatigue Severity Scale).A total of 381 women with SLE were enrolled. Among patients with clinically active disease at baseline (SLEDAI score >2), 86 of 147 in the prasterone group (58.5%) demonstrated improvement or stabilization without clinical deterioration, as compared with 65 of 146 in the placebo group (44.5%) (P = 0.017). Acne and hirsutism were reported in 33% and 16%, respectively, of the prasterone group and in 14% and 2%, respectively, of the placebo group (P < 0.05 for both comparisons). However, most cases of acne and hirsutism were mild and did not require withdrawal from therapy. Myalgias and oral stomatitis were reported less frequently in the prasterone group (22% and 15%, respectively) than in the placebo group (36% and 23%, respectively) (P < 0.05 for both comparisons). Serum levels of high-density lipoprotein cholesterol, triglycerides, and C3 complement significantly decreased, while levels of testosterone and, to a lesser extent, estradiol increased in the prasterone group.In adult women with active SLE, administration of prasterone at a dosage of 200 mg/day improved or stabilized signs and symptoms of disease and was generally well tolerated.

  View details for DOI 10.1002/art.20427

  View details for Web of Science ID 000223799200017

• Demyelination and inhibition of tumor necrosis factor (TNF) CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Magnano, M. D., Robinson, W. H., Genovese, M. C. 2004; 22 (5): S134-S140

  Abstract

  The development of tumor necrosis factor alpha (TNFalpha) inhibitor therapy is arguably the most significant achievement in the treatment of rheumatic diseases to date. One serious potential side effect associated with these agents is the onset of neurologic signs and symptoms. In this paper we will examine the relationship of TNFalpha antagonism and demyelinating disease. Reviewing early laboratory and animal models, we discuss the mechanism of TNFalpha in central nervous system (CNS) injury and repair. Two negative studies of TNFa inhibitor therapy in the treatment of refractory multiple sclerosis (MS) are considered. From the manufacturers' clinical development programs and post-marketing adverse event reporting data, we report the current incidence of demyelinating symptoms associated with each of the commercially available anti-TNFa agents. Comparing these reports to the incidence of MS in society as a whole, we find the rate of new cases of neurologic disease in exposed patients is not different from the rate of expected cases. Finally we explore arguments that support and refute a potential biologic relationship between TNFa neutralization and demyelinating disease.

  View details for Web of Science ID 000224406600021

  View details for PubMedID 15552527

• Arthritis antigen microarray analysis reveals associations of distinct autoantibody profiles with markers of disease activity and severity in RA. 68th Annual Scientific Meeting of the American-College-of-Rheumatology/39th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals Hueber, W., Kidd, B., Lee, B. J., Genovese, M., Bruce, B., Fries, J., van Venrooij, W., Robinson, W. H. WILEY-BLACKWELL. 2004: S651–S651

  View details for Web of Science ID 000223799001807

• A randomized, blinded, parallel group, placebo-controlled, pilot study evaluating the effect of Pvac treatment in patients with diffuse systemic sclerosis 68th Annual Scientific Meeting of the American-College-of-Rheumatology/39th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals Genovese, M. C., Boyle, D., Chakravarty, E., Tutuncu, Z., Thorburn, C., Halilhodzic, M., KROLL, S., Stewart, S., Baughman, J., Kavanaugh, A. WILEY-BLACKWELL. 2004: S636–S636

  View details for Web of Science ID 000223799001763

• Effects of prasterone on disease activity and symptoms in women with active systemic lupus erythematosus. Arthritis and rheumatism Petri, M. A., Mease, P. J., Merrill, J. T., Lahita, R. G., Iannini, M. J., Yocum, D. E., Ginzler, E. M., Katz, R. S., Gluck, O. S., Genovese, M. C., van Vollenhoven, R., Kalunian, K. C., Manzi, S., Greenwald, M. W., Buyon, J. P., Olsen, N. J., Schiff, M. H., Kavanaugh, A. F., Caldwell, J. R., Ramsey-Goldman, R., St Clair, E. W., Goldman, A. L., Egan, R. M., Polisson, R. P., Moder, K. G., Rothfield, N. F., Spencer, R. T., Hobbs, K., Fessler, B. J., Calabrese, L. H., Moreland, L. W., Cohen, S. B., Quarles, B. J., Strand, V., Gurwith, M., Schwartz, K. E. 2004; 50 (9): 2858-2868

  Abstract

  To determine whether prasterone administration results in improvement or stabilization of systemic lupus erythematosus (SLE) disease activity and its symptoms.Women with active SLE were treated with prasterone 200 mg/day plus standard SLE treatments or with placebo plus standard SLE treatments for up to 12 months in this randomized, double-blind investigation conducted at 27 centers. Standard SLE treatments included prednisone (/=6 weeks prior to enrollment and remain unchanged during protocol treatment. Responders were patients who experienced no clinical deterioration and had improvement or stabilization over the duration of the study in 2 disease activity measures (the SLE Disease Activity Index [SLEDAI] and the Systemic Lupus Activity Measure) and 2 quality of life measures (patient's global assessment and the Krupp Fatigue Severity Scale).A total of 381 women with SLE were enrolled. Among patients with clinically active disease at baseline (SLEDAI score >2), 86 of 147 in the prasterone group (58.5%) demonstrated improvement or stabilization without clinical deterioration, as compared with 65 of 146 in the placebo group (44.5%) (P = 0.017). Acne and hirsutism were reported in 33% and 16%, respectively, of the prasterone group and in 14% and 2%, respectively, of the placebo group (P < 0.05 for both comparisons). However, most cases of acne and hirsutism were mild and did not require withdrawal from therapy. Myalgias and oral stomatitis were reported less frequently in the prasterone group (22% and 15%, respectively) than in the placebo group (36% and 23%, respectively) (P < 0.05 for both comparisons). Serum levels of high-density lipoprotein cholesterol, triglycerides, and C3 complement significantly decreased, while levels of testosterone and, to a lesser extent, estradiol increased in the prasterone group.In adult women with active SLE, administration of prasterone at a dosage of 200 mg/day improved or stabilized signs and symptoms of disease and was generally well tolerated.

  View details for PubMedID 15452837

• Combination leflunomide and methotrexate (MTX) therapy for patients with active rheumatoid arthritis failing MTX monotherapy: Open-label extension of a randomized, double-blind, placebo controlled trial JOURNAL OF RHEUMATOLOGY Kremer, J., Genovese, M., Cannon, G. W., Caldwell, J., Cush, J., Furst, D. E., Luggen, M., Keystone, E. D., Bathon, J., Kavanaugh, A., Ruderman, E., Coleman, P., Curtis, D., Kopp, E., Kantor, S., Weisman, M., Waltuck, J., Lindsley, H. B., Markenson, J., Crawford, B., Fernando, I., Simpson, K., Strand, V. 2004; 31 (8): 1521-1531

  Abstract

  To obtain additional safety and efficacy data on leflunomide (LEF) treatment in combination with methotrexate (MTX) therapy in an open-label extension study in patients with rheumatoid arthritis (RA).Following a 24 week, randomized, double-blind trial of adding placebo (PLA) or LEF to stable MTX therapy, patients could enter a 24 week extension. Subjects randomized to LEF and MTX continued treatment [(LEF/LEF) + MTX]. Subjects randomized to PLA and MTX switched to LEF (10 mg/day, no loading dose) and MTX [(PLA/LEF) + MTX]. The double-blind regarding initial randomization was maintained.For subjects in the extension phase, American College of Rheumatology 20% (ACR20) responder rates for the (LEF/LEF) + MTX group were maintained from Week 24 (57/96, 59.4%) to Week 48 (53/96, 55.2%). ACR20 responder rates improved in patients switched to LEF from PLA at Week 24 [(PLA/LEF) + MTX] from 25.0% (24/96) at Week 24 to 57.3% (55/96) at Week 48. Patients in the extension who switched from PLA to LEF without a loading dose exhibited a lower incidence of elevated transaminases compared to patients initially randomized to LEF. Diarrhea and nausea were less frequent during the open-label extension in patients who did not receive a LEF loading dose.Response to therapy was maintained to 48 weeks of treatment in patients who continued to receive LEF and MTX during the extension. Importantly, ACR20 response rates after 24 weeks of LEF therapy were similar between patients switched from PLA to LEF without loading dose, and those who received a loading does of LEF (100 mg/day x 2 days) at randomization. Fewer adverse events were reported in patients switched to LEF without a loading dose.

  View details for Web of Science ID 000223004900010

  View details for PubMedID 15290730

• The efficacy of switching from etanercept to infliximab in patients with rheumatoid arthritis JOURNAL OF RHEUMATOLOGY Hansen, K. E., Hildebrand, J. P., Genovese, M. C., Cush, J. J., Patel, S., Cooley, D. A., Cohen, S. B., Gangnon, R. E., Schiff, M. H. 2004; 31 (6): 1098-1102

  Abstract

  To describe the degree of clinical benefit in patients with rheumatoid arthritis (RA) who receive infliximab therapy after lack of efficacy with etanercept.In a retrospective study among 6 centers primarily designed to assess the safety of infliximab in combination with leflunomide, a standardized chart review form was used to collect data on 93 patients with RA. During that study, it was noted that some of these patients had switched from etanercept to infliximab. In this study, we compared the response of subjects switching from etanercept to infliximab (n = 20) to that of subjects receiving infliximab with no prior tumor necrosis factor (TNF) therapy (n = 73).The swollen and tender joint count, patient and physician global assessments, morning stiffness, and C-reactive protein all improved substantially in both groups, with no statistical difference in the degree of benefit between the groups. At the time of chart review, switchers had received a statistically higher dose of infliximab than controls (4.4 vs 3.19 mg/kg; p = 0.006) with a total of 5.7 and 5 infusions, respectively.In this retrospective study, previous lack of efficacy with etanercept did not predict lack of efficacy with infliximab. Indeed, the degree of clinical improvement was similar in both groups, although switchers were receiving a higher dose of infliximab at the time of chart review. Our findings suggest that clinical response may differ between anti-TNF agents, and lack of response to one agent may not predict a lack of response to another.

  View details for Web of Science ID 000221823500015

  View details for PubMedID 15170921

• Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate ARTHRITIS AND RHEUMATISM Genovese, M. C., Cohen, S., Moreland, L., Lium, D., Robbins, S., Newmark, R., Bekker, P. 2004; 50 (5): 1412-1419

  Abstract

  To determine the potential for additive or synergistic effects of combination therapy with the selective anti-tumor necrosis factor alpha agent etanercept and the anti-interleukin-1 agent anakinra.Two hundred forty-four patients in whom rheumatoid arthritis (RA) was active despite methotrexate therapy were treated with subcutaneous etanercept only (25 mg twice weekly), full-dosage etanercept (25 mg twice weekly) plus anakinra (100 mg/day), or half-dosage etanercept (25 mg once weekly) plus anakinra (100 mg/day) for 6 months in a double-blind study at 41 centers in the US. Patients had never previously received anticytokine therapy. Patient response was measured with the American College of Rheumatology (ACR) core set criteria, a health-related quality-of-life questionnaire, and the Disease Activity Score. Safety was assessed by the number of adverse events and clinical laboratory values. Plasma concentrations of both agents and antibody formation against both agents were also assessed.Combination therapy with etanercept plus anakinra provided no treatment benefit over etanercept alone, regardless of the regimen, but was associated with an increased safety risk. Thirty-one percent of the patients treated with full-dosage etanercept plus anakinra achieved an ACR 50% response, compared with 41% of the patients treated with etanercept only. This result was not statistically significant (P = 0.914). The incidence of serious infections (0% for etanercept alone, 3.7-7.4% for combination therapy), injection-site reactions, and neutropenia was increased with combination therapy. Combination therapy had no effect on the pharmacokinetics or immunogenicity of either agent.Combination therapy with etanercept and anakinra provides no added benefit and an increased risk compared with etanercept alone and is not recommended for the treatment of patients with RA.

  View details for DOI 10.1002/art.20221

  View details for Web of Science ID 000221340900008

  View details for PubMedID 15146410

• Treatment of rheumatoid arthritis with etanercept RHEUMATIC DISEASE CLINICS OF NORTH AMERICA Genovese, M. C., Kremer, J. M. 2004; 30 (2): 311-?

  Abstract

  Etanercept is effective in the treatment of rheumatoid arthritis (RA)when used as monotherapy and in combination with methotrexate(MTX). Radiographic progression of disease was slowed significantly when the drug was used for a 24-month period and was statistically significantly better than MTX. In addition to its use in RA,etanercept is approved by the U.S. Food and Drug Administration for other rheumatologic conditions, including psoriatic arthritis,ankylosing spondylitis, and juvenile chronic arthritis.

  View details for DOI 10.1016/j.rdc.2004.01.004

  View details for Web of Science ID 000221971000007

  View details for PubMedID 15172043

• Associations between rheumatoid arthritis and malignancy RHEUMATIC DISEASE CLINICS OF NORTH AMERICA Chakravarty, E. F., Genovese, M. C. 2004; 30 (2): 271-?

  Abstract

  There are many complex associations between rheumatoid arthritis(RA) and malignancy. Patients with rheumatic diseases on the whole appear to be at increased risk for the development of certain malignancies. The data from several studies are persuasive that the presence of RA conveys an increased risk for the development of lymphoproliferative disorders and may convey a decreased risk for the development of malignancies of the digestive tract. Understanding the complex interrelationships between RA and malignancy will lead to more accurate diagnosis of underlying pathology, more effective treatment of symptoms and underlying disease, and appropriate surveillance for the development of later complications.

  View details for DOI 10.1016/j.rdc.2004.01.007

  View details for Web of Science ID 000221971000004

  View details for PubMedID 15172040

• The safety and efficacy of leflunomide in combination with infliximab in rheumatoid arthritis ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH Hansen, K. E., Cush, J., Singhal, A., Cooley, D. A., Cohen, S., Patel, S. R., Genovese, M., Sundaramurthy, S., Schiff, M. 2004; 51 (2): 228-232

  Abstract

  To report the safety and efficacy of leflunomide (LEF) in combination with infliximab (INF) for the treatment of rheumatoid arthritis.In an open, multicenter, retrospective study, data were collected on the safety and efficacy of LEF and INF.Eighty-eight patients received the combination of LEF and INF for an average of 6.6 months and a total exposure of 581 patient-months. The mean duration of LEF was 17 +/- 9 months (range 3-32 months; median 18.5 months) with an average of 4.8 INF infusions per patient. In all but 3 subjects, LEF was used initially and INF was added later. Infusion reactions occurred in 3 patients (0.7% of all infusions). A total of 34% of subjects experienced adverse events and in 6 (6.8% of the group) these were deemed serious. Ten infections occurred when patients were taking the combination; 9 patients recovered fully and 1 died of bacterial pneumonia. A lifetime smoker developed lung cancer and another patient was found to have colon cancer.The adverse events noted within the combination therapy group were in keeping with the known risks of each drug when used individually. Limited data were available on efficacy, but a general improvement in disease control was noted with the combination of drugs, which for most patients involved the addition of INF to previous use of LEF.

  View details for DOI 10.1002/art.20228

  View details for Web of Science ID 000220764600012

  View details for PubMedID 15077264

• Unlocking the "PAD" lock on rheumatoid arthritis ANNALS OF THE RHEUMATIC DISEASES Utz, P. J., Genovese, M. C., Robinson, W. H. 2004; 63 (4): 330-332

  View details for DOI 10.1136/ard.2003.015990

  View details for Web of Science ID 000220198000002

  View details for PubMedID 15020322

  View details for PubMedCentralID PMC1754966

• Articular cartilage of knee: Normal patterns at MR imaging that mimic disease in healthy subjects and patients with osteoarthritis RADIOLOGY Yoshioka, H., Stevens, K., Genovese, M., Dillingham, M. F., Lang, P. 2004; 231 (1): 31-38

  Abstract

  To evaluate normal magnetic resonance (MR) imaging findings that may mimic articular cartilage diseases in healthy subjects and patients with osteoarthritis of the knee.Sagittal fat-suppressed intermediate-weighted fast spin-echo (FSE) (repetition time msec/echo time [TE] msec, 4,000/13), sagittal T2-weighted FSE (4,000/39), and sagittal fat-suppressed three-dimensional (3D) spoiled gradient-echo (SPGR) (60/5, 40 degrees flip angle) MR images were acquired in 28 patients and four volunteers. FSE images with a TE of 13 msec were considered "short-TE images"; those with a TE of 39 msec were considered "long-TE images." Presence of normal MR imaging appearance of articular cartilage was determined by one author. Contrast between cartilage and adjacent structures (meniscus, joint capsule, synovial fluid, muscle) was calculated in posterior regions of the femoral condyle on images obtained with each sequence; Wilcoxon signed rank testing was performed.The following appearances were observed in patients with knee osteoarthritis (on short-TE FSE, long-TE FSE, and SPGR MR images, respectively): (a) ambiguity of surface contour in posterior region of the femoral condylar cartilage (in zero, zero, and 20 patients), (b) linear area of high signal intensity in deep zone adjacent to subchondral bone of femoral condyle (in zero, zero, and 26 patients), (c) pseudolaminar appearance in posterior region of femoral condylar cartilage (in seven, nine, and 24 patients), (d) truncation artifact in patellofemoral compartment (in seven, six, and 27 patients), (e) susceptibility artifact on cartilage surface caused by air or metal (in three, three, and 11 patients), (f) decreased signal intensity in distal part of trochlear cartilage (in 28, 28, and 28 patients), (g) cartilage thinning adjacent to the anterior horn of the lateral meniscus (in 19, 19, and 21 patients), and (h) focal cartilage flattening in posterior region of femoral condyle (in 16, 16, and nine patients). Cartilage-meniscus and cartilage-synovial fluid contrast was significantly higher on fat-suppressed FSE than on fat-suppressed 3D SPGR MR images (P <.001).Fat-suppressed FSE and 3D SPGR MR images showed nonuniform signal intensity arising from articular cartilage and cartilage thinning, both of which could mimic disease.

  View details for DOI 10.1148/radiol.2311020453

  View details for Web of Science ID 000220394300006

  View details for PubMedID 15068938

• A randomized, controlled trial of interferon-beta-1a (Avonex (R)) in patients with rheumatoid arthritis: a pilot study [ISRCTN03626626] ARTHRITIS RESEARCH & THERAPY Genovese, M. C., Chakravarty, E. F., Krishnan, E., Moreland, L. W. 2004; 6 (1): R73-R77

  Abstract

  The objective of this study was to evaluate the safety and possible efficacy of IFN-beta-1a for the treatment of patients with rheumatoid arthritis (RA). Twenty-two patients with active RA were enrolled in a phase II randomized, double-blind, placebo-controlled trial of 30 microg IFN-beta-1a by weekly self-injection for 24 weeks. The primary outcome of the study was safety. Secondary outcomes included the proportion of patients achieving an American College of Rheumatology (ACR) 20 response at 24 weeks. There were no significant differences in adverse events reported in the two groups. Fewer than 20% of patients in each arm of the study achieved an ACR 20 response at 24 weeks (P = 0.71). Sixty-nine percent of patients receiving IFN-beta and 67% receiving placebo terminated the study early, most of them secondary to a perceived lack of efficacy. Overall, IFN-beta-1a had a safety profile similar to that of placebo. There were no significant differences in the proportion of patients achieving an ACR 20 response between the two groups.

  View details for DOI 10.1186/ar1026

  View details for Web of Science ID 000187021500012

  View details for PubMedCentralID PMC400417

• Interleukin 1 receptor antagonist inhibits localized bone formation in vivo JOURNAL OF RHEUMATOLOGY Ma, T., Miyanishi, K., Trindade, M. C., Genovese, M., Regula, D., Smith, R. L., Goodman, S. B. 2003; 30 (12): 2547-2552

  Abstract

  To test the in vivo effects of interleukin 1 receptor antagonist (IL-1ra) on bone formation and tissue ingrowth using an implantable bone ingrowth chamber that can be infused with test solutions.The bone ingrowth chamber was implanted in the proximal tibia of 10 mature NZW rabbits unilaterally. After an initial osseointegration period, the chambers were emptied of tissue and infused with either 0.05% bovine serum albumin (BSA) in phosphate buffered saline (PBS) or an IL-1ra solution for 4-week periods, which were separated by 4-week periods of no infusion. Tissue samples harvested from each chamber were snap-frozen and examined by histology and immunohistochemistry.The chambers were filled with longitudinally-oriented woven bone in a fibrovascular stroma during periods of infusion of 0.05% BSA in PBS or during periods without infusion. In contrast, infusion of IL-1ra for 4 weeks prevented tissue ingrowth in 4 of 6 chambers, and in 2 chambers exhibiting tissue ingrowth, bone formation was decreased. Bone formation remained at a lower level during the subsequent two 4-week periods without infusion after IL-1ra was discontinued, compared to samples prior to the IL-1ra treatment.The results showed that tissue ingrowth and bone formation were suppressed in an in vivo model by continuous infusion of IL-1ra at an early phase of tissue regeneration and differentiation.

  View details for PubMedID 14719192

• Synovial proteome microarrays identify deiminated proteins as targets of the autoantibody response in Rheumatoid Arthritis 67th Annual Scientific Meeting of the American-College-of-Rheumatology/38th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals Hueber, W., Lee, B. J., Genovese, M. C., Bruce, B., van Venrooij, W. J., Smolen, J. S., Steinman, L., Utz, P. J., Robinson, W. H. WILEY-BLACKWELL. 2003: S429–S429

  View details for Web of Science ID 000185432801113

• The Early Rheumatoid Arthritis (ERA) Trial comparing the efficacy and safety of etanercept and methotrexate CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Bathon, J. M., Genovese, M. C. 2003; 21 (5): S195-S197

  Abstract

  The Early Rheumatoid Arthritis (ERA) trial compared monotherapy with etanercept or methotrexate in patients with early erosive rheumatoid arthritis. Over the initial period of 12, and subsequently 24, months both treatments were associated with a profound reduction in radiographic progression of joint damage, as well as a reduction in signs and symptoms of disease. Etanercept showed slight superiority to methotrexate in reducing subsequent radiographic erosions and in the rapidity of the clinical response. Both therapies proved to be safe and well tolerated and, importantly, the relative safety and tolerance of a rapidly escalated dosing regimen for methotrexate was demonstrated. In summary, early aggressive treatment of RA is associated with clinical and radiographic benefit that can be demonstrated after a relatively short period of treatment.

  View details for Web of Science ID 000185970100035

  View details for PubMedID 14969076

• COX-2 selective inhibitors and bone INTERNATIONAL JOURNAL OF IMMUNOPATHOLOGY AND PHARMACOLOGY Goodman, S. B., Ma, T., Genovese, M., Smith, R. L. 2003; 16 (3): 201-205

  Abstract

  Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed medications for relief of pain and inflammation. Recent animal studies using models of fracture healing and bone ingrowth suggest that NSAIDs (both non-selective NSAIDs and selective COX-2 inhibitors) adversely affect these bone-related processes. The dose and time-relationships of these medications and their resulting effects on bone have not yet been fully elucidated. Furthermore, whether COX-2 inhibitors and non-selective NSAIDs lead to clinically relevant adverse effects on bone healing in humans is unknown.

  View details for PubMedID 14611721

• Imaging of the articular cartilage in osteoarthritis of the knee joint: 3D spatial-spectral spoiled gradient-echo vs. fat-suppressed 3D spoiled gradient-echo MR imaging JOURNAL OF MAGNETIC RESONANCE IMAGING Yoshioka, H., Alley, M., Steines, D., Stevens, K., Rubesova, E., Genovese, M., Dillingham, M. F., Lang, P. 2003; 18 (1): 66-71

  Abstract

  To compare three-dimensional (3D) spatial-spectral (SS) spoiled gradient-recalled acquisition in the steady state (SPGR) imaging with fat-suppressed 3D SPGR sequences in MR imaging of articular cartilage of the knee joint in patients with osteoarthritis.MR images of six patients with osteoarthritis of the knee were prospectively examined with a 1.5T MR scanner. For quantitative analyses, the signal-to-noise ratios, contrast-to-noise ratios, and contrast of cartilage and adjacent structures including meniscus, synovial fluid, muscle, fat tissue, and bone marrow were measured.In patients with osteoarthritis, 3DSS-SPGR images demonstrated higher spatial resolution and higher mean signal-to-noise (S/N) ratios (cartilage, 24.9; synovial fluid, 12.3; muscle, 20.7; meniscus, 21.6), with shorter acquisition times (7 minutes 20 seconds), when compared to fat-suppressed 3D SPGR images (cartilage, 22.3; synovial fluid, 10.8; muscle, 16.7; meniscus, 13.4).3DSS-SPGR imaging is a promising method for evaluating cartilage pathology in patients with osteoarthritis of the knee and has the potential to replace fat-suppressed 3D SPGR imaging.

  View details for DOI 10.1002/jmri.10320

  View details for PubMedID 12815641

• CTLA4IG (BMS-188667) in a phase IIB, multi-center, randomized, double-blind, placebo controlled study in rheumatoid arthritis patients receiving etanercept: Association between clinical response and key biomarkers Annual European Congress of Rheumatology Schiff, M., Genovese, M., Nuamah, I., Becker, J., Weinblatt, M. BMJ PUBLISHING GROUP. 2003: 178–178

  View details for Web of Science ID 000224551400565

• Modulation of bone ingrowth and tissue differentiation by local infusion of interleukin-10 in the presence of ultra-high molecular weight polyethylene (UHMWPE) wear particles. Journal of biomedical materials research. Part A Goodman, S., Trindade, M., Ma, T., Lee, M., Wang, N., Ikenou, T., Matsuura, I., Miyanishi, K., Fox, N., Regula, D., Genovese, M., Klein, J., Bloch, D., Smith, R. L. 2003; 65 (1): 43-50

  Abstract

  Interleukin-10 (IL-10) is a cytokine that plays a major role in suppressing the inflammatory response, particularly cell-mediated immunity that is characteristic of the TH1 response. The purpose of this study was to determine whether local infusion of IL-10 could mitigate the suppression of bone ingrowth associated with polyethylene wear particles. Drug test chambers were implanted in the proximal tibia of 20 mature New Zealand White rabbits. The DTC provided a continuous 1 x 1 x 5-mm canal for tissue ingrowth. After a 6-week period for osseointegration, the DTC was then connected to an osmotic diffusion pump. IL-10 at doses of 0.1-100 ng/mL (0.25 microL/h) was infused with or without ultra-high molecular weight polyethylene particles (0.5 +/- 0.2 microm diameter, 10(12) particles/mL) present in the chamber for a 3- or 6-week period. The tissue in the chamber was harvested after each treatment; sections were stained with hematoxylin and eosin for morphometric analysis. Osteoclast-like cells were identified by immunohistochemical staining using a monoclonal antibody directed against the alpha chain of the vitronectin receptor, CD51. Osteoblasts were identified using alkaline phosphatase staining. In dose-response studies, infusion of 1 ng/mL IL-10 yielded the greatest bone ingrowth in the presence of particles. The addition of polyethylene particles evoked a marked foreign body reaction and fibrosis; bone ingrowth was significantly suppressed (p = 0.0003). Bone ingrowth was increased by over 48% with infusion of IL-10 for the final 3 weeks of a 6-week ultra-high molecular weight polyethylene particle exposure compared with particles alone (p = 0.027). IL-10 is a cytokine that plays a major role in suppressing the inflammatory response, especially cell-mediated immunity that is characteristic of the TH1 response. Local infusion of immune-modulating cytokines such as IL-10 may prove to be useful in abating particle-induced periprosthetic osteolysis.

  View details for PubMedID 12635153

• Modulation of bone ingrowth and tissue differentiation by local infusion of interleukin-10 in the presence of ultra-high molecular weight polyethylene (UHMWPE) wear particles JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A Goodman, S., Trindade, M., Ma, T., Lee, M., Wang, N., Ikenou, T., Matsuura, I., Miyanishi, K., Fox, N., Regula, D., Genovese, M., Klein, J., Bloch, D., Smith, R. L. 2003; 65A (1): 43-50

  Abstract

  Interleukin-10 (IL-10) is a cytokine that plays a major role in suppressing the inflammatory response, particularly cell-mediated immunity that is characteristic of the TH1 response. The purpose of this study was to determine whether local infusion of IL-10 could mitigate the suppression of bone ingrowth associated with polyethylene wear particles. Drug test chambers were implanted in the proximal tibia of 20 mature New Zealand White rabbits. The DTC provided a continuous 1 x 1 x 5-mm canal for tissue ingrowth. After a 6-week period for osseointegration, the DTC was then connected to an osmotic diffusion pump. IL-10 at doses of 0.1-100 ng/mL (0.25 microL/h) was infused with or without ultra-high molecular weight polyethylene particles (0.5 +/- 0.2 microm diameter, 10(12) particles/mL) present in the chamber for a 3- or 6-week period. The tissue in the chamber was harvested after each treatment; sections were stained with hematoxylin and eosin for morphometric analysis. Osteoclast-like cells were identified by immunohistochemical staining using a monoclonal antibody directed against the alpha chain of the vitronectin receptor, CD51. Osteoblasts were identified using alkaline phosphatase staining. In dose-response studies, infusion of 1 ng/mL IL-10 yielded the greatest bone ingrowth in the presence of particles. The addition of polyethylene particles evoked a marked foreign body reaction and fibrosis; bone ingrowth was significantly suppressed (p = 0.0003). Bone ingrowth was increased by over 48% with infusion of IL-10 for the final 3 weeks of a 6-week ultra-high molecular weight polyethylene particle exposure compared with particles alone (p = 0.027). IL-10 is a cytokine that plays a major role in suppressing the inflammatory response, especially cell-mediated immunity that is characteristic of the TH1 response. Local infusion of immune-modulating cytokines such as IL-10 may prove to be useful in abating particle-induced periprosthetic osteolysis.

  View details for DOI 10.1002/jbm.a.10279

  View details for Web of Science ID 000182453600007

• Allele and antigen-specific treatment of rheumatoid arthritis: A double blind, placebo controlled phase 1 trial JOURNAL OF RHEUMATOLOGY Kavanaugh, A., Genovese, M., Baughman, J., Kivitz, A., Bulpitt, K., Olsen, N., Weisman, M., Matteson, E., Furst, D., van Vollenhoven, R., Anderson, J., Cohen, S., Wei, N., Meijerink, J., Jacobs, C., Mocci, S. 2003; 30 (3): 449-454

  Abstract

  Human cartilage glycoprotein 39 (HC gp-39) appears to be a relevant autoantigen in patients with rheumatoid arthritis (RA). Administration of major histocompatibility complex (MHC) Class II complexed antigens without requisite costimulatory signals can induce immunologic tolerance. We evaluated the safety, pharmacokinetics, and preliminary efficacy of AG4263 in patients with RA. AG4263 is a soluble complex of native HLA-DR4 (beta*0401) complexed to Org 36601, a 13-mer peptide derived from HC gp-39 (also referred to as CDP263).Thirty-one HLA-DRB1*0401 positive patients with persistent RA disease activity despite concurrent methotrexate were randomized to 7 infusions of AG4263 (n = 24) or placebo (n = 7) over 6 weeks. The initial dose of 0.5 micro g/kg was escalated in subsequent cohorts to a maximum of 150 micro g/kg. Safety analyses included recording of adverse events and measurement of CD4/CD8 counts, reactivity to recall antigens, and development of antibodies to HLA-DR4. Efficacy was assessed using the Paulus 20 criteria.Treatment was well tolerated, with injection site reaction the most common adverse event. There was no loss of reactivity to recall antigens, change in cell counts, or antibodies to HLA-DR. The mean half-life of AG4263 was 12.5 h. Some evidence of clinical response was seen; responses were more common among patients receiving the highest doses of AG4263 and among those with baseline T cell reactivity to CDP263.AG4263 was safe, well tolerated, and without evidence of generalized immune suppression. Along with the observed trend toward clinical efficacy, the results suggest that this therapeutic approach warrants further investigation in patients with RA.

  View details for Web of Science ID 000181372100006

  View details for PubMedID 12610799

• Multiplex autoantibody profiling using 'synovial proteome' microarrays identifies citrulline-modified peptides as major targets of the autoimmune response in rheumatoid arthritis 3rd World Congress of the Global-Arthritis-Research-Network (GARN) Hueber, W., Lee, B. J., Genovese, M., van Venrooij, W., Steinman, L., Utz, P. J., Robinson, W. H. BIOMED CENTRAL LTD. 2003: S31–S31

  View details for DOI 10.1186/ar900

  View details for Web of Science ID 000220116700101

• Rheumatic syndromes associated with malignancy CURRENT OPINION IN RHEUMATOLOGY Chakravarty, E., Genovese, M. C. 2003; 15 (1): 35-43

  Abstract

  The relation between rheumatic syndromes and an underlying malignancy is a complex one. As a result of autoimmunity, an aberrant immune response, or the use of immunomodulatory drugs, many of the rheumatic diseases appear to pose an increased risk for the development of malignancy. Unfortunately, for many of the same reasons, the presence of an underlying malignancy can result in the development of features of rheumatic disease. Awareness of the associations between rheumatic syndromes and malignancy will aid the clinician in the accurate diagnosis of underlying pathology, more effective treatment of both the symptoms and underlying disease, and appropriate surveillance for the development of later complications.

  View details for Web of Science ID 000180055000007

  View details for PubMedID 12496508

• Concomitant leflunomide therapy in patients with active rheumatoid arthritis despite stable doses of methotrexate - A randomized, double-blind, placebo-controlled trial ANNALS OF INTERNAL MEDICINE Kremer, J. M., Genovese, M. C., Cannon, G. W., Caldwell, J. R., Cush, J. J., Furst, D. E., Luggen, M. E., Keystone, E., Weisman, M. H., Bensen, W. M., Kaine, J. L., Ruderman, E. M., Coleman, P., Curtis, D. L., Kopp, E. J., Kantor, S. M., Waltuck, J., Lindsley, H. B., Markenson, J. A., Strand, V., Crawford, B., Fernando, I., Simpson, K., Bathon, J. M. 2002; 137 (9): 726-733

  Abstract

  Disease-modifying antirheumatic drugs may confer greater benefits when combined with the antimetabolite methotrexate.To evaluate the efficacy and safety of leflunomide versus placebo when added to ongoing, stable-dose methotrexate therapy in patients with persistently active rheumatoid arthritis.24-week, multicenter, randomized, double-blind, placebo-controlled trial.20 centers in the United States and Canada.Patients with persistent rheumatoid arthritis, as defined by American College of Rheumatology (ACR) criteria, despite receiving methotrexate for at least 6 months.Leflunomide or matching placebo added to existing methotrexate therapy.The primary efficacy variable was the rate of achievement of 20% improvement in ACR criteria (ACR20) at the end of the study. The Health Assessment Questionnaire Disability Index was assessed at each visit, and the Medical Outcomes Study 36-Item Short Form was completed as an end point analysis.In the leflunomide and placebo groups, 46.2% and 19.5% of patients, respectively, met ACR20 criteria at 24 weeks (P < 0.001). Clinical improvement was demonstrated by statistically significant mean changes in individual components of the ACR20 response criteria. Discontinuation rates were similar in both treatment groups (23.1% in the leflunomide group and 24.8% in the placebo group), as were the overall incidences of adverse events (89.2% vs. 89.5%, respectively). Adverse events were predominantly mild or moderate.Combination therapy with leflunomide and methotrexate provides statistically significant clinical benefit in patients with active rheumatoid arthritis who are receiving methotrexate therapy. Leflunomide plus methotrexate is generally well tolerated and can be used safely with appropriate liver enzyme and hematologic monitoring.

  View details for Web of Science ID 000179052400003

  View details for PubMedID 12416946

• COX-2 selective NSAID decreases bone ingrowth in vivo JOURNAL OF ORTHOPAEDIC RESEARCH Goodman, S., Ma, T., Trindade, M., Ikenoue, T., Matsuura, I., Wong, N., Fox, N., Genovese, M., Regula, D., Smith, R. L. 2002; 20 (6): 1164-1169

  Abstract

  Whether non-steroidal anti-inflammatory drug (NSAID)-induced suppression of bone ingrowth is due to cyclooxygenase-1 (COX-1) inhibition, cyclooxygenase-2 (COX-2) inhibition, or through a yet unidentified pathway is unknown. In this study, the effects of a non-specific COX-1 and COX-2 inhibitor, versus a specific COX-2 inhibitor on bone ingrowth and tissue differentiation are examined in vivo. Harvest chambers were implanted unilaterally in the tibiae of eight mature, New Zealand white rabbits. After a 6-week period for osseointegration of the chamber, the following oral treatments were given for 4 weeks each, followed by a harvest in each case: drinking water with no NSAID (control 1), Naproxen sodium--a COX-1 and COX-2 non-specific inhibitor at a dose of 110 mg/kg/day in the drinking water, drinking water with no NSAID (control 2), and Rofecoxib-a COX-2 inhibitor at a dose of 12.5 mg/day inserted directly into the rabbit's mouth. Harvested specimens were snap frozen, cut into serial 6 microm sections and stained with hematoxylin and eosin for general morphological characterization, and alkaline phosphatase (osteoblast marker). Sections were also processed for immunoperoxidase staining using monoclonal antibodies to identify cells expressing the vitronectin receptor (osteoclast-like cells). With drinking water alone, the percentage of bone ingrowth averaged 24.8 +/- 2.9% and 29.9 +/- 4.5% respectively. Naproxen sodium in the drinking water and oral Rofecoxib decreased bone ingrowth significantly (15.9 +/- 3.3%. p = 0.031 and 18.5 +/- 2+/-4%, p = 0.035 compared to drinking water respectively). Both Naproxen sodium (p = 0.026) and Rofecoxib (p = 0.02) decreased the number of CD51 positive osteoclast-like cells per section compared with drinking water alone. Rofecoxib decreased the area of osteoblasts per section area (p = 0.014) compared to controls, although the value for Naproxen sodium did not reach statistical significance. The results of the present study suggest that bone formation is suppressed by oral administration of an NSAID which contains a COX-2 inhibitor. COX-2 inhibitors currently taken for arthritis and other conditions may potentially delay fracture healing and bone ingrowth.

  View details for PubMedID 12472224

• The efficacy of switching from etanercept to infliximab in patients with rheumatoid arthritis. 66th Annual Scientific Meeting of the American-College-of-Rheumatology/37th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals Hansen, K. E., Cush, J. J., Patel, S., Genovese, M. C., Schiff, M. WILEY-BLACKWELL. 2002: S538–S538

  View details for Web of Science ID 000178421801469

• Central nervous system lupus and pregnancy: 11-year experience at a single center. journal of maternal-fetal & neonatal medicine El-Sayed, Y. Y., Lu, E. J., Genovese, M. C., Lambert, R. E., Chitkara, U., Druzin, M. L. 2002; 12 (2): 99-103

  Abstract

  To describe the pregnancy outcomes in women with central nervous system (CNS) manifestations of lupus.Between 1991 and 2002, the outcome of five pregnancies in four patients with CNS lupus were retrospectively reviewed. All patients had an established history of systemic lupus erythematosus (SLE), and either a history of CNS lupus or active CNS lupus. Pregnancy outcomes assessed included term and preterm birth, intrauterine growth restriction, abnormal antepartum testing, perinatal mortality, pre-eclampsia and other maternal morbidities.Evidence of active CNS lupus symptoms developed in three of the five pregnancies. Two pregnancies were complicated by early onset pre-eclampsia, abnormal antepartum testing and extreme prematurity, with one subsequent neonatal death. The remaining three pregnancies had good neonatal outcomes, but were complicated by severe maternal post-pregnancy exacerbations, and the eventual death of one patient.CNS lupus in pregnancy represents an especially severe manifestation of SLE, and may involve great maternal and fetal risks.

  View details for PubMedID 12420839

• Etanercept versus methotrexate in patients with early rheumatoid arthritis - Two-year radiographic and clinical outcomes ARTHRITIS AND RHEUMATISM Genovese, M. C., Bathon, J. M., Martin, R. W., Fleischmann, R. M., Tesser, J. R., Schiff, M. H., Keystone, E. C., Wasko, M. C., Moreland, L. W., Weaver, A. L., Markenson, J., Cannon, G. W., Spencer-Green, G., Finck, B. K. 2002; 46 (6): 1443-1450

  Abstract

  To compare the clinical and radiographic outcomes in patients with rheumatoid arthritis (RA) who received monotherapy with either etanercept or methotrexate (MTX) for 2 years and to assess the safety of this therapy.In the Enbrel ERA (early rheumatoid arthritis) trial, 632 patients with early, active RA were randomized to receive either twice-weekly subcutaneous etanercept (10 mg or 25 mg) or weekly oral MTX (mean dosage 19 mg per week) for at least 1 year in a double-blind manner. Following the blinded phase of the trial, 512 patients continued to receive the therapy to which they had been randomized for up to 1 additional year, in an open-label manner. Radiograph readers remained blinded to treatment group assignment and the chronologic order of images.At 24 months, more 25-mg etanercept patients than MTX patients met American College of Rheumatology 20% improvement criteria (72% and 59%, respectively; P = 0.005), and more had no increase in total score and erosion scores on the Sharp scale (P = 0.017 and P = 0.012, respectively). The mean changes in total Sharp score and erosion score in the 25-mg etanercept group (1.3 and 0.66 units, respectively) were significantly lower than those in the MTX group (3.2 and 1.86 units, respectively; P = 0.001). Significantly more patients in the 25-mg etanercept group (55%) than in the MTX group (37%) had at least 0.5 units of improvement in the Health Assessment Questionnaire disability index (P < 0.001). Fewer patients in the etanercept group than in the MTX group experienced adverse events or discontinued treatment because of adverse events.Etanercept as monotherapy was safe and was superior to MTX in reducing disease activity, arresting structural damage, and decreasing disability over 2 years in patients with early, aggressive RA.

  View details for DOI 10.1002/art.10308

  View details for PubMedID 12115173

• Long-term followup of patients treated with total lymphoid irradiation for lupus nephritis ARTHRITIS AND RHEUMATISM Genovese, M. C., Uhrin, Z., Bloch, D. A., Oehlert, J., Sibley, R. K., Myers, B., Strober, S. 2002; 46 (4): 1014-1018

  Abstract

  To describe the long-term survival, renal condition, and morbidity outcomes in patients who received total lymphoid irradiation (TLI) for the treatment of lupus nephritis.Twenty-one patients with biopsy-proven, diffuse membranoproliferative glomerulonephritis and significant proteinuria of >2.5 grams/day received TLI from 1980 to 1987 at Stanford University Medical Center. All patients had previously failed to respond to treatment with high-dose corticosteroids or therapy with corticosteroids plus immunosuppressive agents (azathioprine, cyclophosphamide, or chlorambucil).The mean duration of followup since TLI was 10.7 years. Fifteen of 21 patients (71%) remained alive at the time of this assessment. Nine of the 21 patients (43%) survived without developing end-stage renal disease (ESRD). The probability of long-term survival without ESRD and without need for additional immunosuppressive agents after TLI was 19% (4 of 21). Factors predicting renal failure at the time of TLI included elevated creatinine levels, increased interstitial fibrosis on renal biopsy, and increased fractional excretion of immunoglobulin and albumin. Malignancies were found in 4 patients, and opportunistic infections occurred in 7 patients.Overall, patients with lupus nephritis treated with TLI do not appear to have better 10-year survival with lower incidence of ESRD compared with patients in published series treated with conventional immunosuppressive therapies. However, in this series of patients, treatment with conventional immunosuppressive therapies had been unsuccessful and given the limited number of adverse events and the efficacy seen in some patients, TLI appears to be a reasonable therapeutic option for the treatment of severe lupus nephritis among patients who fail to respond under standard cytotoxic regimens.

  View details for Web of Science ID 000174946500022

  View details for PubMedID 11953979

• Autoantigen microarrays for multiplex characterization of autoantibody responses NATURE MEDICINE Robinson, W. H., DiGennaro, C., Hueber, W., Haab, B. B., KAMACHI, M., Dean, E. J., Fournel, S., Fong, D., Genovese, M. C., de Vegvar, H. E., Skriner, K., Hirschberg, D. L., Morris, R. I., Muller, S., Pruijn, G. J., van Venrooij, W. J., Smolen, J. S., Brown, P. O., Steinman, L., Utz, P. J. 2002; 8 (3): 295-301

  Abstract

  We constructed miniaturized autoantigen arrays to perform large-scale multiplex characterization of autoantibody responses directed against structurally diverse autoantigens, using submicroliter quantities of clinical samples. Autoantigen microarrays were produced by attaching hundreds of proteins, peptides and other biomolecules to the surface of derivatized glass slides using a robotic arrayer. Arrays were incubated with patient serum, and spectrally resolvable fluorescent labels were used to detect autoantibody binding to specific autoantigens on the array. We describe and characterize arrays containing the major autoantigens in eight distinct human autoimmune diseases, including systemic lupus erythematosus and rheumatoid arthritis. This represents the first report of application of such technology to multiple human disease sera, and will enable validated detection of antibodies recognizing autoantigens including proteins, peptides, enzyme complexes, ribonucleoprotein complexes, DNA and post-translationally modified antigens. Autoantigen microarrays represent a powerful tool to study the specificity and pathogenesis of autoantibody responses, and to identify and define relevant autoantigens in human autoimmune diseases.

  View details for Web of Science ID 000174139500036

  View details for PubMedID 11875502

• Expression of the chemokine receptors CCR4, CCR5, and CXCR3 by human tissue-infiltrating lymphocytes AMERICAN JOURNAL OF PATHOLOGY Kunkel, E. J., Boisvert, J., Murphy, K., Vierra, M. A., Genovese, M. C., Wardlaw, A. J., Greenberg, H. B., Hodge, M. R., Wu, L. J., BUTCHER, E. C., Campbell, J. J. 2002; 160 (1): 347-355

  Abstract

  Differential expression of adhesion molecules and chemokine receptors has been useful for identification of peripheral blood memory lymphocyte subsets with distinct tissue and microenvironmental tropisms. Expression of CCR4 by circulating memory CD4(+) lymphocytes is associated with cutaneous and other systemic populations while expression of CCR9 is associated with a small intestine-homing subset. CCR5 and CXCR3 are also expressed by discrete memory CD4(+) populations in blood, as well as by tissue-infiltrating lymphocytes from a number of sites. To characterize the similarities and differences among tissue-infiltrating lymphocytes, and to shed light on the specialization of lymphocyte subsets that mediate inflammation and immune surveillance in particular tissues, we have examined the expression of CCR4, CXCR3, and CCR5 on CD4(+) lymphocytes directly isolated from a wide variety of normal and inflamed tissues. Extra-lymphoid tissues contained only memory lymphocytes, many of which were activated (CD69(+)). As predicted by classical studies, skin lymphocytes were enriched in CLA expression whereas intestinal lymphocytes were enriched in alpha(4)beta(7) expression. CCR4 was expressed at high levels by skin-infiltrating lymphocytes, at lower levels by lung and synovial fluid lymphocytes, but never by intestinal lymphocytes. Only the high CCR4 levels characteristic of skin lymphocytes were associated with robust chemotactic and adhesive responses to TARC, consistent with a selective role for CCR4 in skin lymphocyte homing. In contrast, CXCR3 and CCR5 were present on the majority of lymphocytes from each non-lymphoid tissue examined, suggesting that these receptors are unlikely to determine tissue specificity, but rather, may play a wider role in tissue inflammation.

  View details for Web of Science ID 000173231700038

  View details for PubMedID 11786428

• Rules of chemokine receptor association with T cell polarization in vivo JOURNAL OF CLINICAL INVESTIGATION Kim, C. H., Rott, L., Kunkel, E. J., Genovese, M. C., Andrew, D. P., Wu, L. J., BUTCHER, E. C. 2001; 108 (9): 1331-1339

  Abstract

  Current concepts of chemokine receptor (CKR) association with Th1 and Th2 cell polarization and effector function have largely ignored the diverse nature of effector and memory T cells in vivo. Here, we systematically investigated the association of 11 CKRs, singly or in combination, with CD4 T cell polarization. We show that Th1, Th2, Th0, and nonpolarized T cells in blood and tissue can express any of the CKRs studied but that each CKR defines a characteristic pool of polarized and nonpolarized CD4 T cells. Certain combinations of CKRs define populations that are markedly enriched in major subsets of Th1 versus Th2 cells. For example, although Th0, Th1, and Th2 cells are each found among blood CD4 T cells coordinately expressing CXCR3 and CCR4, Th1 but not Th2 cells can be CXCR3(+)CCR4(-), and Th2 but only rare Th1 cells are CCR4(+)CXCR3(-). Contrary to recent reports, although CCR7(-) cells contain a higher frequency of polarized CD4 T cells, most Th1 and Th2 effector cells are CCR7(+) and thus may be capable of lymphoid organ homing. Interestingly, Th1-associated CKRs show little or no preference for Th1 cells except when they are coexpressed with CXCR3. We conclude that the combinatorial expression of CKRs, which allow tissue- and subset-dependent targeting of effector cells during chemotactic navigation, defines physiologically significant subsets of polarized and nonpolarized T cells.

  View details for PubMedID 11696578

• Demyelinating and neurologic events reported in association with tumor necrosis factor alpha antagonism - By what mechanisms could tumor necrosis factor alpha antagonists improve rheumatoid arthritis but exacerbate multiple sclerosis? ARTHRITIS AND RHEUMATISM Robinson, W. H., Genovese, M. C., Moreland, L. W. 2001; 44 (9): 1977-1983

  View details for Web of Science ID 000172491200004

  View details for PubMedID 11592357

• Treatment of rheumatoid arthritis with total lymphoid irradiation - Long-term survival ARTHRITIS AND RHEUMATISM Uhrin, Z., Wang, B. W., Matsuda, Y., Strober, S., Genovese, M. C. 2001; 44 (7): 1525-1528

  Abstract

  Total lymphoid irradiation (TLI) has been used to treat rheumatoid arthritis (RA) since the 1970s. This study reviews long-term (15-20-year) mortality outcomes of patients treated with TLI for RA at Stanford University Medical Center and compares these outcomes with those in patients treated with disease-modifying antirheumatic drugs (DMARDs).Fifty-three patients with RA were treated with full-dose TLI at Stanford University Medical Center. All had failed previous therapy with gold salts and penicillamine. One hundred six control patients were selected from the Arthritis, Rheumatism, and Aging Medical Information Systems database and were matched with the patients for age, sex, disease duration, and mean Health Assessment Questionnaire (HAQ) score. Survival was analyzed using Kaplan-Meier methods and Cox proportional hazards regression.No significant difference in age and sex was found between TLI-treated patients and controls. TLI-treated patients had more education (mean 13.4 years versus 11.8 years; P = 0.016) and received more DMARDs prior to TLI (mean 2.1 versus 1.3; P = 0.0001). TLI-treated patients had lower mean HAQ scores at the time of TLI (2.0 versus 2.4; P = 0.0002). TLI had no significant overall effect on survival in treated patients compared with controls (P = 0.62). The survival curves appeared to cross over at approximately 11 years of followup, with better early survival in the TLI group and better late survival in the control group. There was a total of 25 deaths in the TLI group. There were 45 deaths in the control group, with causes of death available for 20 patients. There were 3 patients with lymphoma and 2 with myelodysplastic syndrome in the TLI group, and none in the control group. The most common cause of death in both groups was infection.TLI had no significant effect on overall survival, with trends toward higher early mortality in controls and trends toward higher late mortality in TLI-treated patients. Overall, there was no difference in mortality, but it appears that there may have been more lymphoproliferative malignancies in the TLI cohort. We would recommend that TLI be used cautiously for patients with refractory RA in whom the benefits outweigh the risks.

  View details for Web of Science ID 000172491000008

  View details for PubMedID 11465702

• Combination therapy of leflunomide (LEF) & methotrexate (MTX) is effective & well tolerated in RA patients inadequately responding to MTX alone Kremer, J. M., Genovese, M., Cannon, G. W., Caldwell, J. R., Cush, J. J., Bathon, J. J RHEUMATOL PUBL CO. 2001: 105–105

  View details for Web of Science ID 000169889200408

• Bonzo/CXCR6 expression defines type 1-polarized T-cell subsets with extralymphoid tissue homing potential JOURNAL OF CLINICAL INVESTIGATION Kim, C. H., Kunkel, E. J., Boisvert, J., Johnston, B., Campbell, J. J., Genovese, M. C., Greenberg, H. B., BUTCHER, E. C. 2001; 107 (5): 595-601

  Abstract

  Chemokine receptor expression is finely controlled during T-cell development. We show that newly identified chemokine receptor Bonzo/CXCR6 is expressed by subsets of Th1 or T-cytotoxic 1 (Tc1) cells, but not by Th2 or Tc2 cells, establishing Bonzo as a differential marker of polarized type 1 T cells in vitro and in vivo. Priming of naive T cells by dendritic cells induces expression of Bonzo on T cells. IL-12 enhances this dendritic cell-dependent upregulation, while IL-4 inhibits it. In blood, 35-56% of Bonzo+ CD4 T cells are Th1 cells, and 60-65% of Bonzo+ CD8 T cells are Tc1 cells, while few Bonzo+ cells are type 2 T cells. Almost all Bonzo+ Tc1 cells contain preformed granzyme A and display cytotoxic effector phenotype. Most Bonzo+ T cells lack L-selectin and/or CCR7, homing receptors for lymphoid tissues. Instead, Bonzo+ T cells are dramatically enriched among T cells in tissue sites of inflammation, such as rheumatoid joints and inflamed livers. Bonzo may be important in trafficking of effector T cells that mediate type 1 inflammation, making it a potential target for therapeutic modulation of inflammatory diseases.

  View details for Web of Science ID 000167337800009

  View details for PubMedID 11238560

  View details for PubMedCentralID PMC199429

• Current management of rheumatoid arthritis HOSPITAL PRACTICE Genovese, M. C., Davis, J. S. 2001; 36 (2): 21-?

  View details for Web of Science ID 000166876100003

  View details for PubMedID 11220358

• CCR7 expression and memory T cell diversity in humans JOURNAL OF IMMUNOLOGY Campbell, J. J., Murphy, K. E., Kunkel, E. J., Brightling, C. E., Soler, D., Shen, Z. M., Boisvert, J., Greenberg, H. B., Vierra, M. A., Goodman, S. B., Genovese, M. C., Wardlaw, A. J., BUTCHER, E. C., Wu, L. J. 2001; 166 (2): 877-884

  Abstract

  CCR7, along with L-selectin and LFA-1, mediates homing of T cells to secondary lymphoid organs via high endothelial venules (HEV). CCR7 has also been implicated in microenvironmental positioning of lymphocytes within secondary lymphoid organs and in return of lymphocytes and dendritic cells to the lymph after passage through nonlymphoid tissues. We have generated mAbs to human CCR7, whose specificities correlate with functional migration of lymphocyte subsets to known CCR7 ligands. We find that CCR7 is expressed on the vast majority of peripheral blood T cells, including most cells that express adhesion molecules (cutaneous lymphocyte Ag alpha(4)beta(7) integrin) required for homing to nonlymphoid tissues. A subset of CD27(neg) memory CD4 T cells from human peripheral blood is greatly enriched in the CCR7(neg) population, as well as L-selectin(neg) cells, suggesting that these cells are incapable of homing to secondary lymphoid organs. Accordingly, CD27(neg) T cells are rare within tonsil, a representative secondary lymphoid organ. All resting T cells within secondary lymphoid organs express high levels of CCR7, but many activated cells lack CCR7. CCR7 loss in activated CD4 cells accompanies CXC chemokine receptor (CXCR)5 gain, suggesting that the reciprocal expression of these two receptors may contribute to differential positioning of resting vs activated cells within the organ. Lymphocytes isolated from nonlymphoid tissues (such as skin, lung, or intestine) contain many CD27(neg) cells lacking CCR7. The ratio of CD27(neg)/CCR7(neg) cells to CD27(pos)/CCR7(pos) cells varies from tissue to tissue, and may correlate with the number of cells actively engaged in Ag recognition within a given tissue.

  View details for Web of Science ID 000166259600023

  View details for PubMedID 11145663

• A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis NEW ENGLAND JOURNAL OF MEDICINE Bathon, J. M., Martin, R. W., Fleischmann, R. M., Tesser, J. R., Schiff, M. H., Keystone, E. C., Genovese, M. C., Wasko, M. C., Moreland, L. W., Weaver, A. L., Markenson, J., Finck, B. K. 2000; 343 (22): 1586-1593

  Abstract

  Etanercept, which blocks the action of tumor necrosis factor, reduces disease activity in patients with long-standing rheumatoid arthritis. Its efficacy in reducing disease activity and preventing joint damage in patients with active early rheumatoid arthritis is unknown.We treated 632 patients with early rheumatoid arthritis with either twice-weekly subcutaneous etanercept (10 or 25 mg) or weekly oral methotrexate (mean, 19 mg per week) for 12 months. Clinical response was defined as the percent improvement in disease activity according to the criteria of the American College of Rheumatology. Bone erosion and joint-space narrowing were measured radiographically and scored with use of the Sharp scale. On this scale, an increase of 1 point represents one new erosion or minimal narrowing.As compared with patients who received methotrexate, patients who received the 25-mg dose of etanercept had a more rapid rate of improvement, with significantly more patients having 20 percent, 50 percent, and 70 percent improvement in disease activity during the first six months (P<0.05). The mean increase in the erosion score during the first 6 months was 0.30 in the group assigned to receive 25 mg of etanercept and 0.68 in the methotrexate group (P= 0.001), and the respective increases during the first 12 months were 0.47 and 1.03 (P=0.002). Among patients who received the 25-mg dose of etanercept, 72 percent had no increase in the erosion score, as compared with 60 percent of patients in the methotrexate group (P=0.007). This group of patients also had fewer adverse events (P=0.02) and fewer infections (P= 0.006) than the group that was treated with methotrexate.As compared with oral methotrexate, subcutaneous [corrected] etanercept acted more rapidly to decrease symptoms and slow joint damage in patients with early active rheumatoid arthritis.

  View details for Web of Science ID 000165511000001

  View details for PubMedID 11096165

• A novel chemokine ligand for CCR10 and CCR3 expressed by epithelial cells in mucosal tissues. Journal of immunology Pan, J., Kunkel, E. J., Gosslar, U., Lazarus, N., Langdon, P., Broadwell, K., Vierra, M. A., Genovese, M. C., BUTCHER, E. C., Soler, D. 2000; 165 (6): 2943-2949

  Abstract

  Mucosae-associated epithelial chemokine (MEC) is a novel chemokine whose mRNA is most abundant in salivary gland, with strong expression in other mucosal sites, including colon, trachea, and mammary gland. MEC is constitutively expressed by epithelial cells; MEC mRNA is detected in cultured bronchial and mammary gland epithelial cell lines and in epithelia isolated from salivary gland and colon using laser capture microdissection, but not in the endothelial, hemolymphoid, or fibroblastic cell lines tested. Although MEC is poorly expressed in skin, its closest homologue is the keratinocyte-expressed cutaneous T cell-attracting chemokine (CTACK; CCL27), and MEC supports chemotaxis of transfected lymphoid cells expressing CCR10, a known CTACK receptor. In contrast to CTACK, however, MEC also supports migration through CCR3. Consistent with this, MEC attracts eosinophils in addition to memory lymphocyte subsets. These results suggest an important role for MEC in the physiology of extracutaneous epithelial tissues, including diverse mucosal organs.

  View details for PubMedID 10975800

• Cutting edge: A novel chemokine ligand for CCR10 and CCR3 expressed by epithelial cells in mucosal tissues JOURNAL OF IMMUNOLOGY Pan, J. L., Kunkel, E. J., Gosslar, U., Lazarus, N., Langdon, P., Broadwell, K., Vierra, M. A., Genovese, M. C., BUTCHER, E. C., Soler, D. 2000; 165 (6): 2943-2949

  Abstract

  Mucosae-associated epithelial chemokine (MEC) is a novel chemokine whose mRNA is most abundant in salivary gland, with strong expression in other mucosal sites, including colon, trachea, and mammary gland. MEC is constitutively expressed by epithelial cells; MEC mRNA is detected in cultured bronchial and mammary gland epithelial cell lines and in epithelia isolated from salivary gland and colon using laser capture microdissection, but not in the endothelial, hemolymphoid, or fibroblastic cell lines tested. Although MEC is poorly expressed in skin, its closest homologue is the keratinocyte-expressed cutaneous T cell-attracting chemokine (CTACK; CCL27), and MEC supports chemotaxis of transfected lymphoid cells expressing CCR10, a known CTACK receptor. In contrast to CTACK, however, MEC also supports migration through CCR3. Consistent with this, MEC attracts eosinophils in addition to memory lymphocyte subsets. These results suggest an important role for MEC in the physiology of extracutaneous epithelial tissues, including diverse mucosal organs.

  View details for Web of Science ID 000165938100004

• Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: Epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity JOURNAL OF EXPERIMENTAL MEDICINE Kunkel, E. J., Campbell, J. J., Haraldsen, G., Pan, J. L., Boisvert, J., Roberts, A. I., Ebert, E. C., Vierra, M. A., Goodman, S. B., Genovese, M. C., Wardlaw, A. J., Greenberg, H. B., Parker, C. M., Butcher, E. C., Andrew, D. P., Agace, W. W. 2000; 192 (5): 761-767

  Abstract

  The immune system has evolved specialized cellular and molecular mechanisms for targeting and regulating immune responses at epithelial surfaces. Here we show that small intestinal intraepithelial lymphocytes and lamina propria lymphocytes migrate to thymus-expressed chemokine (TECK). This attraction is mediated by CC chemokine receptor (CCR)9, a chemoattractant receptor expressed at high levels by essentially all CD4(+) and CD8(+) T lymphocytes in the small intestine. Only a small subset of lymphocytes in the colon are CCR9(+), and lymphocytes from other tissues including tonsils, lung, inflamed liver, normal or inflamed skin, inflamed synovium and synovial fluid, breast milk, and seminal fluid are universally CCR9(-). TECK expression is also restricted to the small intestine: immunohistochemistry reveals that intense anti-TECK reactivity characterizes crypt epithelium in the jejunum and ileum, but not in other epithelia of the digestive tract (including stomach and colon), skin, lung, or salivary gland. These results imply a restricted role for lymphocyte CCR9 and its ligand TECK in the small intestine, and provide the first evidence for distinctive mechanisms of lymphocyte recruitment that may permit functional specialization of immune responses in different segments of the gastrointestinal tract. Selective expression of chemokines by differentiated epithelium may represent an important mechanism for targeting and specialization of immune responses.

  View details for PubMedID 10974041

• A double-blind, placebo-controlled, clinical trial of dehydroepiandrosterone in severe systemic lupus erythematosus LUPUS van Vollenhoven, R. F., Park, J. L., Genovese, M. C., West, J. P., McGuire, J. L. 1999; 8 (3): 181-187

  Abstract

  To determine if dehydroepiandrosterone (DHEA) is beneficial in severe systemic lupus erythematosus (SLE).A double-blinded, placebo-controlled, randomized clinical trial in 21 patients with severe and active SLE, manifestated primarily by nephritis, serositis or hematological abnormalities. In addition to conventional treatment with corticosteroids +/- immunosuppressives, patients received DHEA 200 mg/d vs. placebo for 6 months, followed by a 6-month open label period. The primary outcome was a prospectively defined responder analysis, based on a quantitatively specified improvement of the principal severe lupus manifestation at 6 months.Nineteen patients were available for evaluation at 6 months. Baseline imbalance between the groups was noted, with the DHEA group having greater disease activity at baseline (P<0.05 by physician's global assessment). Eleven patients were responders: 7/9 patients on DHEA vs. 4/10 patients on placebo (P<0.10). Of the secondary outcomes, mean improvement in SLE disease activity index (SLE-DAI) score was greater in the DHEA group (-10.3+/-3.1 vs. -3.9+/-1.4. P<0.07). Bone mineral density at the lumbo-sacral spine showed significant reduction in the placebo group, but was maintained in the DHEA group.DHEA therapy, when added to conventional treatment for severe SLE, may at most have a small added benefit with respect to lupus outcomes, but baseline imbalances in the study population limit the generalizability of the results. DHEA appears to have a protective effect with respect to corticosteroid-induced osteopenia in such patients.

  View details for Web of Science ID 000080473900004

  View details for PubMedID 10342710

• Joint and soft-tissue injection - A useful adjuvant to systemic and local treatment POSTGRADUATE MEDICINE Genovese, M. C. 1998; 103 (2): 125-?

  Abstract

  Joint and soft-tissue injection can augment systemic and local conservative treatment and have long-lasting benefits. Inflammatory and crystalline arthritis, synovitis, tendinitis, bursitis, and many other conditions respond well to injection. Corticosteroid preparations should be chosen on the basis of solubility and potency desired and the size of structure to be injected. Injections should not be made directly into a ligament or tendon and should be limited to every third or fourth month. With attention to the usual cautions required with corticosteroid use and avoidance of contraindications (e.g., bacteremia, fracture), injection is usually safe and effective, particularly as a bridging technique to long-term therapy.

  View details for Web of Science ID 000071888100014

  View details for PubMedID 9479311

• Dehydroepiandrosterone (DHEA) in severe systemic lupus erythematosus. Results of a double-blinded, placebo controlled pilot study. Genovese, M. C., Hendrickson, C. L., Park, J., Powell, M. J., McGuire, J. L., VANVOLLENHOVEN, R. F. WILEY-BLACKWELL. 1997: 168–68

  View details for Web of Science ID A1997XY63400168

• Running and osteoarthritis of the knee: A 12 year longitudinal study. Lane, N. E., Oehlert, J., Ward, M., Genovese, M., Bloch, D., Fries, J. F. WILEY-BLACKWELL. 1997: 1242–42

  View details for Web of Science ID A1997XY63401239

• Fever, rash, and arthritis in a woman with silicone gel breast implants WESTERN JOURNAL OF MEDICINE Genovese, M. C. 1997; 167 (3): 149-158

  View details for Web of Science ID A1997XW74200003

  View details for PubMedID 9308407

• Lemierre's syndrome SOUTHERN MEDICAL JOURNAL Lee, B. K., LOPEZ, F., Genovese, M., Loutit, J. S. 1997; 90 (6): 640-643

  Abstract

  Lemierre's syndrome is an acute medical condition characterized by anaerobic oropharyngeal infection leading to septic thrombophlebitis of the internal jugular vein. The illness is often complicated by septic pulmonary emboli and distant metastatic infections. Treatment consists of surgical drainage of purulent collections and long-term intravenous antibiotic therapy. Although Lemierre's syndrome is rare, it is potentially fatal and remains an important entity for clinicians to recognize and treat appropriately.

  View details for Web of Science ID A1997XE84400013

  View details for PubMedID 9191743

• INCIDENCE OF AND RISK-FACTORS FOR HOSPITALIZATIONS IN SYSTEMIC LUPUS-ERYTHEMATOSUS - A PROSPECTIVE-STUDY OF THE HOPKINS LUPUS COHORT JOURNAL OF RHEUMATOLOGY Petri, M., Genovese, M. 1992; 19 (10): 1559-1559

  Abstract

  To determine the incidence of and risk factors for hospitalization in systemic lupus erythematosus (SLE).A prospective study of hospitalizations in 1989 and 1990 in the Hopkins Lupus Cohort was conducted.Of 261 patients with SLE in the Hopkins Cohort, 147 (56.3%) were hospitalized in 1989 or 1990. The incidence of hospitalization was 0.69 admissions/person-year. The mean length of stay was 9.6 days +/- 12.7 (SD). Activity of SLE accounted for 35% of admissions. Risk factors for hospitalization for active lupus in 1990 included activity of SLE in 1989 (measured by either the highest physician's global assessment in 1989, p = 0.004, highest lupus activity index (LAI) score in 1989, p = 0.002, or highest systemic lupus erythematosus disease activity index score in 1989, p = 0.008), an average prednisone dose greater than 10 mg in 1989 (p = 0.002), and the presence of neurologic lupus in 1989 (p = 0.02). Medical admissions other than for active SLE accounted for an additional 27% of admissions; one-half of these admissions (47%) were for complications of SLE and/or its treatment, with coronary artery disease the most common (21% of medical admissions). Infections were responsible for 14% of admissions. The majority of infections were bacterial (90%). Risk factors for hospitalization for infection in 1990 included active SLE in 1989 (p = 0.03), average prednisone dose of greater than 10 mg in 1989 (p = 0.04), immunosuppressive drug use in 1989 (p = 0.003), neurologic SLE in 1989 (p = 0.02) and previous hospitalization in 1989 (p = 0.03).Hospitalization is common in the Hopkins Lupus Cohort, with active SLE (35%), infection (14%, infection and/or active SLE; 11%, infection alone) and medical complications of SLE (13%) as the 3 most common causes.

  View details for Web of Science ID A1992JT98300014

  View details for PubMedID 1464868

• DEFINITION, INCIDENCE, AND CLINICAL DESCRIPTION OF FLARE IN SYSTEMIC LUPUS-ERYTHEMATOSUS - A PROSPECTIVE COHORT STUDY ARTHRITIS AND RHEUMATISM Petri, M., Genovese, M., Engle, E., Hochberg, M. 1991; 34 (8): 937-944

  Abstract

  The course of systemic lupus erythematosus (SLE) is characterized by exacerbations (or flares) and remissions of disease activity. As part of an ongoing prospective cohort study, 3 disease activity indices, the physician's global assessment, the Lupus Activity Index, and the University of Toronto SLE Disease Activity Index, have been recorded, at least quarterly since 1987, on 185 SLE patients. We developed a definition of SLE flare and a description of its clinical epidemiology. Disease flare was defined as a change of greater than or equal to 1.0 in the physician's global assessment of disease activity (measured on a 0-3 scale) from the previous visit or from a visit within the last 93 days. Of the 185 patients, 98 (53%) had greater than or equal to 1 flare; the total number of flares was 146. The incidence of flare was 0.65 per patient-year of followup. The median time from the first study visit to a flare was 12 months. Flares were frequently characterized by constitutional symptoms, musculoskeletal involvement, cutaneous involvement, and decreasing levels of C3 and C4. At the time of flare, the mean University of Toronto SLE Disease Activity Index score increased by 3.0 and the mean Lupus Activity Index score (modified to omit the physician's global assessment) increased by 0.26. Overall, 44.8% of the flares prompted a change in treatment. Patients who experienced flares fulfilled more of the SLE criteria at entry and had been followed up for a longer duration after entry into the study, compared with those who did not have flares.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1991GA98800001

  View details for PubMedID 1859487