Andreas Kerschbaumer

All Publications

• Global recruitment patterns and placebo responses in clinical trials of rheumatoid arthritis. Annals of the rheumatic diseases Kerschbaumer, A., Steiner, M., Pruckner, P., Wildner, B., Maad, M., Smolen, J. S., Aletaha, D. 2025

  Abstract

  Placebo effects pose significant challenges in clinical trials for rheumatoid arthritis (RA). Understanding how socioeconomic factors of recruiting countries influence placebo responses is crucial for improving clinical trial design and outcomes. Here, we investigated the impact of global recruitment patterns on placebo responses in randomised controlled trials of RA.We analysed 124 trials (14 272 patients) investigating targeted therapeutics in RA and assessed how global recruitment patterns are related to placebo response rates using the per-capita gross national income (GNI; weighted by recruiting centres/country) as proxy for socioeconomic status in linear mixed models. Primary outcome was the American College of Rheumatology 20% response placebo response rate. Other socioeconomic metrics utilised were the Human Development Index and out-of-pocket health expenditures. Findings were validated using patient-level data from one global in randomised controlled trial.We identified a negative association of GNI and placebo response rates across all trials (β = -3.7% placebo response per 10 000 international dollars; 95% CI: -5.61 to -1.80; P < .001). Results were confirmed using alternative metrics as well as using geographic data on individual patient level. Importantly, we could demonstrate a meaningful difference of this association when compared to active treatment responses.Our findings indicate that recruiting patients from lower-income countries is associated with higher placebo response rates, whereas active treatment responses remain stable. This may be driven by incentives to recruit patients into trials, such as limited access to therapies in less affluent countries. Addressing these factors is critical for improving trial design and ensuring accurate efficacy assessments.

  View details for DOI 10.1016/j.ard.2025.07.010

  View details for PubMedID 40752975

• Global Recruiting Patterns Affect Placebo Response Rates In Clinical Trials of Psoriatic Arthritis and Plaque Psoriasis. Arthritis & rheumatology (Hoboken, N.J.) Kerschbaumer, A., Steiner, M., Khalili, S., Shehab, A., Jordanov, A., Wildner, B., Maad, M., Smolen, J. S., Aletaha, D. 2025

  Abstract

  Placebo effects are a significant challenge in the conduct of clinical trials. We explored how global recruitment patterns influence the extent of placebo responses in randomized controlled trials of psoriatic arthritis and plaque psoriasis.We conducted an analysis of 51 trials (6,843 patients; 52±5.7% female) in psoriatic arthritis, and 43 trials (5,671 patients; 32±7.1% female) in plaque psoriasis investigating biological and targeted synthetic therapeutics. We investigated to what extent global recruitment patterns are related to the extent of response rates in the placebo arms of these clinical trials by investigating underlying socioeconomic factors using the average per capita gross national income (GNI; weighted for recruiting study centers per country) as proxy of these patterns in linear mixed models.We identified a negative association of GNI and placebo response rates on the primary endpoints across psoriatic arthritis trials (ACR20: β=-5.7% per 10,000 international Dollars; 95% CI: -7.8% to -3.5%; p<0.001) and plaque psoriasis trials (PASI75%: β=-1.1%; 95% CI: -2.0 to -0.3; p=0.011). Sensitivity analyses using other outcome measures and alternative economic metrics, such as the UN Human Development Index and WHO out-of-pocket health expenditures were confirmatory.The global expansion of trial recruitment to less affluent countries may increase placebo rates in studies of psoriatic arthritis and plaque psoriasis. These higher placebo rates may reflect the higher perceived benefit in these countries, leading to regression to the mean after patients have been successfully enrolled.

  View details for DOI 10.1002/art.43302

  View details for PubMedID 40583519

• Impact of pre-existing background therapy on placebo responses in randomised controlled clinical trials of rheumatoid arthritis. Annals of the rheumatic diseases Kerschbaumer, A., Rivai, Z. I., Smolen, J. S., Aletaha, D. 2022; 81 (10): 1374-1378

  Abstract

  Various hypotheses exist for the explanation of placebo response rates in randomised controlled trials (RCTs) of patients with rheumatoid arthritis with IR to methotrexate (MTX). We hypothesised that placebo responses may be related to more consequent intake of MTX during the tightly monitored trial period.We conducted a post hoc analysis of placebo-treated patients included in two RCTs that had allowed inclusion of patients with and without ongoing MTX: the GO-AFTER and the SIRROUND-T trials. We pooled placebo patients of both trials and compared American College of Rheumatology (ACR) 20%/50%/70% response rates and Clinical Disease Activity Index (CDAI) low disease activity (LDA; ie, CDAI ≤10) responses between those receiving placebo on top of continued MTX and those receiving placebo without any background disease modifying antirheumatic drugs (DMARDs).Of 398 placebo patients, 285 continued MTX and 113 had no background DMARDs. Baseline characteristics were similar. At week 16, ACR20 response was achieved by 72/285 (25.3%) of placebo+continued MTX and 14/113 (12.4%) of placebo only patients (nominal p=0.005); for ACR50 these numbers were 25/285 (8.4%) versus 1/113 (0.9%; nominal p=0.003) and for ACR70 they were 8/285 (2.8%) versus 0/113 (0%; nominal p=0.112). Also, more patients with placebo+continued MTX achieved CDAI-LDA at week 16 (25/285; 8.8%) compared with placebo only (2/113; 1.8%; nominal p=0.013).Clinical responses to placebo are higher in patients who continue an insufficient MTX background therapy. This suggests an inadvertently more consequent intake of background therapy during the trial. Background therapy should therefore be effectively aligned before enrollment into a clinical trial.

  View details for DOI 10.1136/annrheumdis-2021-221807

  View details for PubMedID 35725294

• Efficacy outcomes in phase 2 and phase 3 randomized controlled trials in rheumatology. Nature medicine Kerschbaumer, A., Smolen, J. S., Herkner, H., Stefanova, T., Chwala, E., Aletaha, D. 2020; 26 (6): 974-980

  Abstract

  Phase 3 trials are the mainstay of drug development across medicine but have often not met expectations set by preceding phase 2 studies. A systematic meta-analysis evaluated all randomized controlled, double-blind trials investigating targeted disease-modifying anti-rheumatic drugs in rheumatoid and psoriatic arthritis. Primary outcomes of American College of Rheumatology (ACR) 20 responses were compared by mixed-model logistic regression, including exploration of potential determinants of efficacy overestimation. In rheumatoid arthritis, phase 2 trial outcomes systematically overestimated subsequent phase 3 results (odds ratio comparing ACR20 in phase 2 versus phase 3: 1.39, 95% confidence interval: 1.25-1.57, P < 0.001). Data for psoriatic arthritis trials were similar, but not statistically significant (odds ratio comparing ACR20 in phase 2 versus phase 3: 1.35, 95% confidence interval: 0.94-1.94, P = 0.09). Differences in inclusion criteria largely explained the observed differences in efficacy findings. Our findings have implications for all stakeholders in new therapeutic development and testing, as well as potential ethical implications.

  View details for DOI 10.1038/s41591-020-0833-4

  View details for PubMedID 32313250

  View details for PubMedCentralID 3272827

• The effects of structural damage on functional disability in psoriatic arthritis. Annals of the rheumatic diseases Kerschbaumer, A., Baker, D., Smolen, J. S., Aletaha, D. 2017; 76 (12): 2038-2045

  Abstract

  Functional outcomes are central in patients with chronic inflammatory musculoskeletal diseases. In a secondary data analysis of the GO-REVEAL trial (NCT00265096), we investigated wether structural damage is linked to functional impairment in patients with psoriatic arthritis (PsA), a link that is still elusive in this disease.We analysed 363 patients enrolled in the GO-REVEAL study and obtained modified Sharp/van der Heijde Scores (mSvdHS) from X-rays performed at baseline, after 24, 52 and 104 weeks. Using longitudinal analyses, we assessed the effect of total mSvdHS (and its subscores, joint space narrowing (JSN) and erosions (ERO)) on functional status (measured by the Health Assessment Questionnaire) in all patients and in those attaining remission (n=117). Furthermore, we analysed wether structural damage reduces the responsiveness of functional limitations to treatment in a subgroup of responders who had functional impairment at baseline (n=67). Additionally, internal and external validation analyses were performed.The effect of damage on function was seen in the disease activity-adjusted models using total mSvdHS (p=0.005), JSN (p=0.019) and ERO (p=0.001) as well as in the remission analyses for mSvdHS (p=0.029) and JSN (p=0.010), respectively. Functional responsiveness was limited by increasing total mSvdHS (p=0.010), JSN (p=0.002) and ERO (p=0.040). The results were validated using other functional outcomes and in an independent clinical cohort.In PsA, structural damage, particularly JSN, has implications for physical function. Functional outcomes have an irreversible component that is strongly related to the extent of joint destruction. This needs to be considered when targeting functional outcomes in clinical practice.

  View details for DOI 10.1136/annrheumdis-2017-211433

  View details for PubMedID 28835465

• Chasing the target: reports from the Advances in Targeted Therapies meeting, 2024. Annals of the rheumatic diseases Winthrop, K. L., Bathon, J., Kerschbaumer, A., Isaacs, J. D., Mease, P., Gottenberg, J. E., Crow, M. K., Kay, J., Crofford, L., Baraliakos, X., Bykerk, V., Siebert, S., Kloppenburg, M., Aletaha, D., McInnes, I. B., Huizinga, T., Voll, R., Gravallese, E. M., Breedveld, F. C., van Vollenhoven, R., Smolen, J. S. 2025; 84 (6): 927-936

  Abstract

  The Advances in Targeted Therapies annual meeting brings together experts within the field of rheumatology and immunology to highlight and discuss the latest scientific developments and needs in the field. The objective is to highlight unmet scientific needs in the field of rheumatology.The 24th annual Advances in Targeted Therapies meeting convened with more than 100 international clinicians and scientific researchers in rheumatology, immunology, and other specialities relating to all aspects of immune-mediated inflammatory diseases. During the meeting, we held 5 rheumatologic disease-specific discussion sections consisting of experts in each field. These groups included rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (axSpA), osteoarthritis (OA), and systemic lupus erythematosus (SLE). In each group, experts were asked to identify the top 2 to 3 most important overarching and disease-specific scientific unmet needs to be addressed in the next 5 years.The overarching themes across disciplines included the need for precision medicine, improved classification of disease states, and the further identification of targets and associated therapies, including the potential role of chimeric antigen receptor (CAR) T cell therapies. Within RA, the group highlighted the lack of precision medicine and the need for better biomarkers. Further, the lack of targeted therapies against fibroblasts in RA was discussed, with the potential impact of targeting fibroblasts early in the disease as an unmet need. For PsA, there is a continued need for a better definition of disease endotypes and for the categorisation of those with complex and difficult-to-treat (D2T) diseases. The development of bispecific molecules and combination therapeutic approaches remain a high priority. For axSpA, the disease-modifying characteristics of nonsteroid anti-inflammatory drugs need further evaluation, as does the treatment of residual pain and fatigue frequently in the disease. In OA, new therapeutic targets remain an unmet need, and the discussion group prioritised potential experimental strategies that could lead to innovative therapeutic targets. Elucidating the specific signalling and target cells responsible for, or inhibiting, repair will be essential for developing targeted therapies. SLE experts emphasised the need to identify the most predictive biological contributions to disease progression in patients with early clinical precursors of SLE. The role of CAR T cell therapy must be further investigated, along with ancillary biologic studies (eg, immune system profiling) that provide critical insights into disease pathogenesis. Further, there is a need to determine the relationship of patient-relevant symptoms to the pathophysiology of SLE and identify new therapeutic targets for these symptoms.There remain many unmet needs on the road to precision medicine with regard to identifying disease endotypes and biomarkers for disease progression or therapeutic response. For most diseases discussed, a strong unmet need remains with regard to identifying new targets and therapies for those with refractory or D2T disease. The ability to prevent or cure rheumatic disease remains the ultimate unmet need in rheumatology.

  View details for DOI 10.1016/j.ard.2025.02.009

  View details for PubMedID 40240265

• Safety of Janus kinase inhibitors in immune-mediated inflammatory diseases - a systematic literature review informing the 2024 update of an international expert consensus statement. Annals of the rheumatic diseases Konzett, V., Smolen, J. S., Nash, P., Winthrop, K., Aletaha, D., Dörner, T., Fleischmann, R., Tanaka, Y., Primdahl, J., Baraliakos, X., McInnes, I. B., Trauner, M., Sattar, N., de Wit, M., Schoones, J. W., Kerschbaumer, A. 2025; 84 (5): 697-715

  Abstract

  This systematic literature review (SLR) on safety outcomes was performed to inform the 2024 update of the expert consensus statement on the treatment of immune-mediated inflammatory diseases (IMIDs) with Janus kinase inhibitors (JAKi).An update of the 2019 SLR was performed in MEDLINE, Embase, and the Cochrane Library. For safety, randomised, placebo-controlled or active-controlled trials on all JAKi investigated in IMIDs, long-term extension (LTE) studies, pooled trial data analyses, and cohort and claims studies were included.We screened 13,905 records, of which 209 were finally included. Three safety trials and 13 post hoc analyses, 83 efficacy randomised controlled trials (RCTs) with adequate safety reporting, 56 integrated safety analyses and LTE of RCTs, 20 additional conference abstracts on RCT data, as well as 37 real-world cohort studies were presented to the task force. Safety profiles of JAKi were overall consistent across compounds and indications, but impacts of patient profiles, treatment dosing, and other cofactors like background medications on drug safety could be observed. Furthermore, differential effects of variously selective JAKi on distinct adverse events of special interest (AESI) and laboratory outcomes were discerned.A substantial amount of literature was published on JAKi safety since 2019. A comprehensive overview of these data supports the optimal use of JAKi in patients with IMIDs, by consideration and balance of their benefits as well as risks in every patient.

  View details for DOI 10.1016/j.ard.2025.01.024

  View details for PubMedID 39934016

• Expert consensus statement on the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: 2024 update. Annals of the rheumatic diseases Nash, P., Kerschbaumer, A., Konzett, V., Aletaha, D., Dörner, T., Fleischmann, R., McInnes, I., Primdahl, J., Sattar, N., Tanaka, Y., Trauner, M., Winthrop, K., de Wit, M., Askling, J., Baraliakos, X., Boehncke, W. H., Emery, P., Gossec, L., Isaacs, J. D., Krauth, M., Lee, E. B., Maksymowych, W., Pope, J., Scholte-Voshaar, M., Schreiber, K., Schreiber, S., Stamm, T., Taylor, P. C., Takeuchi, T., Tam, L. S., Van den Bosch, F., Westhovens, R., Zeitlinger, M., Smolen, J. S. 2025; 84 (5): 664-679

  Abstract

  In light of the introduction of new Janus kinase inhibitors (JAKi), new indications for JAKi and recent safety considerations that have arisen since the preceding consensus statement on JAKi therapy, a multidisciplinary taskforce was assembled, encompassing patients, health care professionals, and clinicians with expertise in JAKi therapy across specialties. This taskforce, informed by two comprehensive systematic literature reviews, undertook the objective to update the previous expert consensus for using JAKi developed in 2019. The taskforce deliberated on overarching principles, indications, dosage and comedication strategies, warnings and contraindications, screening protocols, monitoring recommendations, and adverse effect profiles. The methodology was based on the European Alliance of Associations for Rheumatology standard operating procedures, with voting on these important elements. Furthermore, an updated research agenda was proposed. The task force did not address when a JAKi should be prescribed but rather considerations once this decision has been made. This update aimed to equip clinicians with the necessary knowledge and guidance for the efficient and safe administration of this expanding and significant class of drugs.

  View details for DOI 10.1016/j.ard.2025.01.032

  View details for PubMedID 40037995

• Efficacy of Janus kinase inhibitors in immune-mediated inflammatory diseases a systematic literature review informing the 2024 update of an international consensus statement. Annals of the rheumatic diseases Konzett, V., Smolen, J. S., Nash, P., Aletaha, D., Winthrop, K., Dörner, T., Fleischmann, R., Tanaka, Y., Primdahl, J., Baraliakos, X., McInnes, I. B., Trauner, M., Sattar, N., de Wit, M., Schoones, J. W., Kerschbaumer, A. 2025; 84 (5): 680-696

  Abstract

  This systematic literature review (SLR) on efficacy outcomes was performed to inform the 2024 update of the expert consensus statement on the treatment of immune-mediated inflammatory diseases (IMIDs) with Janus kinase inhibitors (JAKi).An update of the 2019 SLR was performed in MEDLINE, Embase, and the Cochrane Library. For efficacy, randomised, placebo (PLC)- or active-controlled trials on all JAKi investigated in IMIDs, as well as cohort and claims data for conditions where such studies were not available, were included.In total, 10,556 records were screened, and 182 articles were included in the final analysis, investigating 21 JAKi in 51 IMIDs. Forty-three phase 2 and 59 phase 3 trials as well as 9 strategic trials and 72 pilot or cohort studies and case series were considered. JAKi demonstrated efficacy both in PLC-controlled trials as well as in head-to-head comparisons against active comparators, with 93 of 102 randomised controlled trials (RCTs) meeting their primary endpoints. Since 2019, 8 JAKi have received approval by the Federal Drug Agency and the European Medicine Agency for treatment of 11 IMIDs; of these, for 2, no approved disease-modifying antirheumatic drug (DMARD) therapy had previously been available.JAKi are effective for treating IMIDs, and various compounds have recently been approved. The impact of Janus kinase (JAK) selectivity for distinct JAK-STAT pathways needs further investigation, and few data are also available on sustained disease control upon tapering or withdrawal or on the optimal strategic placement of JAKi in international treatment algorithms.

  View details for DOI 10.1016/j.ard.2025.01.023

  View details for PubMedID 39934019

• Efficacy and safety of pharmacological treatment of psoriatic arthritis: a systematic literature research informing the 2023 update of the EULAR recommendations for the management of psoriatic arthritis. Annals of the rheumatic diseases Kerschbaumer, A., Smolen, J. S., Ferreira, R. J., Bertheussen, H., Baraliakos, X., Aletaha, D., McGonagle, D. G., van der Heijde, D., McInnes, I. B., Esbensen, B. A., Winthrop, K. L., Boehncke, W. H., Schoones, J. W., Gossec, L. 2024; 83 (6): 760-774

  Abstract

  To obtain an overview of recent evidence on efficacy and safety of pharmacological treatments in psoriatic arthritis (PsA).This systematic literature research (SLR) investigated the efficacy and safety of conventional synthetic (cs), biological (b) and targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARDs) in patients with PsA. A systematic database search using Medline, EMBASE, Cochrane CENTRAL was conducted to identify relevant articles published since the previous update in 2019 until 28 December 2022. Efficacy was assessed in trials while for safety observational data were also considered. Adverse events of special interest were infections (including herpes zoster, influenza and tuberculosis), malignancies, major adverse cardiovascular events, venous thromboembolisms, liver disease, laboratory changes and psychiatric adverse events. No meta-analyses were performed.For efficacy, of 3946 articles screened, 38 articles (30 trials) were analysed. The compounds investigated included csDMARDs (leflunomide, methotrexate), bDMARDs inhibiting IL17 (bimekizumab, brodalumab, ixekizumab, izokibep, secukinumab,), IL-23 (guselkumab, risankizumab, tildrakizumab), IL-12/23 (ustekinumab) as well as TNF (adalimumab, certolizumab-pegol, etanercept, infliximab, golimumab) and Janus Kinase inhibitors (JAKi) (brepocitinib, deucravacitinib, tofacitinib, upadacitinib). The compounds investigated were efficacious in improving signs and symptoms of PsA, improving physical functioning and quality of life. For safety, 2055 abstracts were screened, and 24 articles analysed: 15 observational studies and 9 long-term follow-ups of trials, assessing glucocorticoids, TNFi, IL-17i, JAKi, IL-12/23i and PDE4i (apremilast). Safety indicators were generally coherent with the previous SLR in 2019.The results of this SLR informed the task force responsible for the 2023 update of the European Alliance of Associations for Rheumatology recommendations for pharmacological management of PsA.

  View details for DOI 10.1136/ard-2024-225534

  View details for PubMedID 38503473

  View details for PubMedCentralID PMC11103324

• EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2023 update. Annals of the rheumatic diseases Gossec, L., Kerschbaumer, A., Ferreira, R. J., Aletaha, D., Baraliakos, X., Bertheussen, H., Boehncke, W. H., Esbensen, B. A., McInnes, I. B., McGonagle, D., Winthrop, K. L., Balanescu, A., Balint, P. V., Burmester, G. R., Cañete, J. D., Claudepierre, P., Eder, L., Hetland, M. L., Iagnocco, A., Kristensen, L. E., Lories, R., Queiro, R., Mauro, D., Marzo-Ortega, H., Mease, P. J., Nash, P., Wagenaar, W., Savage, L., Schett, G., Shoop-Worrall, S. J., Tanaka, Y., Van den Bosch, F. E., van der Helm-van Mil, A., Zabotti, A., van der Heijde, D., Smolen, J. S. 2024; 83 (6): 706-719

  Abstract

  New modes of action and more data on the efficacy and safety of existing drugs in psoriatic arthritis (PsA) required an update of the EULAR 2019 recommendations for the pharmacological treatment of PsA.Following EULAR standardised operating procedures, the process included a systematic literature review and a consensus meeting of 36 international experts in April 2023. Levels of evidence and grades of recommendations were determined.The updated recommendations comprise 7 overarching principles and 11 recommendations, and provide a treatment strategy for pharmacological therapies. Non-steroidal anti-inflammatory drugs should be used in monotherapy only for mild PsA and in the short term; oral glucocorticoids are not recommended. In patients with peripheral arthritis, rapid initiation of conventional synthetic disease-modifying antirheumatic drugs is recommended and methotrexate preferred. If the treatment target is not achieved with this strategy, a biological disease-modifying antirheumatic drug (bDMARD) should be initiated, without preference among modes of action. Relevant skin psoriasis should orient towards bDMARDs targeting interleukin (IL)-23p40, IL-23p19, IL-17A and IL-17A/F inhibitors. In case of predominant axial or entheseal disease, an algorithm is also proposed. Use of Janus kinase inhibitors is proposed primarily after bDMARD failure, taking relevant risk factors into account, or in case bDMARDs are not an appropriate choice. Inflammatory bowel disease and uveitis, if present, should influence drug choices, with monoclonal tumour necrosis factor inhibitors proposed. Drug switches and tapering in sustained remission are also addressed.These updated recommendations integrate all currently available drugs in a practical and progressive approach, which will be helpful in the pharmacological management of PsA.

  View details for DOI 10.1136/ard-2024-225531

  View details for PubMedID 38499325

  View details for PubMedCentralID PMC11103320

• Unmet need in rheumatology: reports from the Advances in Targeted Therapies meeting, 2023. Annals of the rheumatic diseases Winthrop, K. L., Mease, P., Kerschbaumer, A., Voll, R. E., Breedveld, F. C., Smolen, J. S., Gottenberg, J. E., Baraliakos, X., Kiener, H. P., Aletaha, D., Isaacs, J. D., Buch, M. H., Crow, M. K., Kay, J., Crofford, L., van Vollenhoven, R. F., Ospelt, C., Siebert, S., Kloppenburg, M., McInnes, I. B., Huizinga, T. W., Gravallese, E. M. 2024; 83 (4): 409-416

  Abstract

  The Advances in Targeted Therapies meets annually, convening experts in the field of rheumatology to both provide scientific updates and identify existing scientific gaps within the field. To review the major unmet scientific needs in rheumatology. The 23rd annual Advances in Targeted Therapies meeting convened with more than 100 international basic scientists and clinical researchers in rheumatology, immunology, infectious diseases, epidemiology, molecular biology and other specialties relating to all aspects of immune-mediated inflammatory diseases. We held breakout sessions in five rheumatological disease-specific groups including: rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (axSpa), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and vasculitis, and osteoarthritis (OA). In each group, experts were asked to identify and prioritise current unmet needs in clinical and translational research. An overarching theme across all disease states is the continued need for clinical trial design innovation with regard to therapeutics, endpoint and disease endotypes. Within RA, unmet needs comprise molecular classification of disease pathogenesis and activity, pre-/early RA strategies, more refined pain profiling and innovative trials designs to deliver on precision medicine. Continued scientific questions within PsA include evaluating the genetic, immunophenotypic, clinical signatures that predict development of PsA in patients with psoriasis, and the evaluation of combination therapies for difficult-to-treat disease. For axSpA, there continues to be the need to understand the role of interleukin-23 (IL-23) in pathogenesis and the genetic relationship of the IL-23-receptor polymorphism with other related systemic inflammatory diseases (eg, inflammatory bowel disease). A major unmet need in the OA field remains the need to develop the ability to reliably phenotype and stratify patients for inclusion in clinical trials. SLE experts identified a number of unmet needs within clinical trial design including the need for allowing endpoints that reflect pharmacodynamic/functional outcomes (eg, inhibition of type I interferon pathway activation; changes in urine biomarkers). Lastly, within SSc and vasculitis, there is a lack of biomarkers that predict response or disease progression, and that allow patients to be stratified for therapies. There remains a strong need to innovate clinical trial design, to identify systemic and tissue-level biomarkers that predict progression or response to therapy, endotype disease, and to continue developing therapies and therapeutic strategies for those with treatment-refractory disease. This document, based on expert consensus, should provide a roadmap for prioritising scientific endeavour in the field of rheumatology.

  View details for DOI 10.1136/ard-2023-224916

  View details for PubMedID 38123338

• Evidence on treat to target strategies in polymyalgia rheumatica and giant cell arteritis: a systematic literature review. Rheumatology (Oxford, England) Hysa, E., Bond, M., Ehlers, L., Camellino, D., Falzon, L., Dejaco, C., Buttgereit, F., Aletaha, D., Kerschbaumer, A. 2024; 63 (2): 285-297

  Abstract

  To inform an international task force about current evidence on Treat to Target (T2T) strategies in PMR and GCA.A systematic literature research (SLR) was conducted in Medline, EMBASE, Cochrane Library, clinicaltrials.gov from their inception date to May 2022, and in the EULAR/ACR abstract database (2019-2021). Randomised clinical trials (RCTs) and non-randomised interventional studies published in English and answering at least one of the eleven PICO questions on T2T strategies, treatment targets and outcomes, framed by the taskforce, were identified. Study selection process, data extraction and risk of bias assessment were conducted independently by two investigators.Of 7809 screened abstracts, 397 were selected for detailed review and 76 manuscripts were finally included (31 RCTs, eight subgroup/exploratory analyses of RCTs and 37 non-randomised interventional studies). No study comparing a T2T strategy against standard of care was identified. In PMR RCTs, the most frequently applied outcomes concerned treatment (90.9% of RCTs), particularly the cumulative glucocorticoids (GC) dose and GC tapering, followed by clinical, laboratory and safety outcomes (63.3% each). Conversely, the most commonly reported outcomes in RCTs in GCA were prevention of relapses (72.2%), remission as well as treatment-related and safety outcomes (67.0% each).This SLR provides evidence and highlights the knowledge gaps on T2T strategies in PMR and GCA, informing the task force developing T2T recommendations for these diseases.

  View details for DOI 10.1093/rheumatology/kead471

  View details for PubMedID 37672017

  View details for PubMedCentralID PMC10836985

• Selectivity, efficacy and safety of JAKinibs: new evidence for a still evolving story. Annals of the rheumatic diseases Bonelli, M., Kerschbaumer, A., Kastrati, K., Ghoreschi, K., Gadina, M., Heinz, L. X., Smolen, J. S., Aletaha, D., O'Shea, J., Laurence, A. 2024; 83 (2): 139-160

  Abstract

  Fundamental insight gained over the last decades led to the discovery of cytokines as pivotal drivers of inflammatory diseases such as rheumatoid arthritis, psoriasis/psoriasis arthritis, inflammatory bowel diseases, atopic dermatitis and spondylarthritis. A deeper understanding of the pro-inflammatory and anti-inflammatory effects of various cytokines has prompted new cytokine-targeting therapies, which revolutionised the treatment options in the last years for patients with inflammatory disorders. Disease-associated immune responses typically involve a complex interplay of multiple cytokines. Therefore, blockade of one single cytokine does not necessarily lead to a persistent remission in all patients with inflammatory disorders and fostered new therapeutic strategies targeting intracellular pathways shared by multiple cytokines. By inhibiting JAK-STAT signalling pathways common to families of cytokines, JAK-inhibitors (JAKinibs) have created a new paradigm for the treatment of inflammatory diseases. Multiple agents have been approved for various disorders and more are being investigated for several new indications. Second-generation selective JAKinibs have been devised with the aim to achieve an increased selectivity and a possible reduced risk of side effects. In the current review, we will summarise the current body of evidence of pan versus selective JAKinibs and the most recent insights on new side effects and indications, including COVID-19.

  View details for DOI 10.1136/ard-2023-223850

  View details for PubMedID 37923366

  View details for PubMedCentralID PMC10850682

• Definition of rheumatoid arthritis flare based on SDAI and CDAI. Annals of the rheumatic diseases Konzett, V., Kerschbaumer, A., Smolen, J. S., Kristianslund, E. K., Provan, S. A., Kvien, T. K., Aletaha, D. 2024; 83 (2): 169-176

  Abstract

  To develop and validate definitions for disease flares in rheumatoid arthritis (RA) based on the quantitative Simplified and Clinical Disease Activity Indices (SDAI, CDAI).We analysed RA treatment courses from the Norwegian disease-modifying antirheumatic drug registry (NOR-DMARD) and the Vienna RA cohort. In a receiver operating curve analysis, we determined flare definitions for absolute changes in SDAI and CDAI based on a semiquantitative patient anchor. NOR-DMARD was sampled into an 80%-training cohort for cut point derivation and a 20%-test cohort for internal validation. The definitions were then externally validated in the independent Vienna RA cohort and tested regarding their performance on longitudinal, content, face, and construct validity.We analysed 4256 treatment courses from NOR-DMARD and 2557 from the Vienna RA cohort. The preliminary definitions for absolute changes in SDAI and CDAI for flare are an increase of 4.7 and 4.5, respectively. The definitions performed well in the test and external validation cohorts, and showed clinical face and construct validity, as flares significantly impact both functional ( ∆ Health Assessment Questionnaire flare vs no-flare +0.43; p<0.001) and structural ( ∆ modified Sharp Score 43% higher after flare; p<0.001) disease outcomes, and reflect consistent worsening across all disease core sets, both patient reported and objective.We here provide novel definitions for flare in RA based on SDAI and CDAI, validated in two large independent real-world cohorts. In times of highly effective medications for RA, and consideration of their tapering, these definitions will be useful for guiding decision making in clinical practice and designing clinical trials.

  View details for DOI 10.1136/ard-2023-224742

  View details for PubMedID 37890977

• Treat-to-target recommendations in giant cell arteritis and polymyalgia rheumatica. Annals of the rheumatic diseases Dejaco, C., Kerschbaumer, A., Aletaha, D., Bond, M., Hysa, E., Camellino, D., Ehlers, L., Abril, A., Appenzeller, S., Cid, M. C., Dasgupta, B., Duftner, C., Grayson, P. C., Hellmich, B., Hočevar, A., Kermani, T. A., Matteson, E. L., Mollan, S. P., Neill, L., Ponte, C., Salvarani, C., Sattui, S. E., Schmidt, W. A., Seo, P., Smolen, J. S., Thiel, J., Toro-Gutiérrez, C. E., Whitlock, M., Buttgereit, F. 2024; 83 (1): 48-57

  Abstract

  To develop treat-to-target (T2T) recommendations in giant cell arteritis (GCA) and polymyalgia rheumatica (PMR).A systematic literature review was conducted to retrieve data on treatment targets and outcomes in GCA/PMR as well as to identify the evidence for the effectiveness of a T2T-based management approach in these diseases. Based on evidence and expert opinion, the task force (29 participants from 10 countries consisting of physicians, a healthcare professional and a patient) developed recommendations, with consensus obtained through voting. The final level of agreement was provided anonymously.Five overarching principles and six-specific recommendations were formulated. Management of GCA and PMR should be based on shared decisions between patient and physician recognising the need for urgent treatment of GCA to avoid ischaemic complications, and it should aim at maximising health-related quality of life in both diseases. The treatment targets are achievement and maintenance of remission, as well as prevention of tissue ischaemia and vascular damage. Comorbidities need to be considered when assessing disease activity and selecting treatment.These are the first T2T recommendations for GCA and PMR. Treatment targets, as well as strategies to assess, achieve and maintain these targets have been defined. The research agenda highlights the gaps in evidence and the need for future research.

  View details for DOI 10.1136/ard-2022-223429

  View details for PubMedID 36828585

  View details for PubMedCentralID PMC10803996

• Determination of the most appropriate ACR response definition for contemporary drug approval trials in rheumatoid arthritis. Annals of the rheumatic diseases Konzett, V., Kerschbaumer, A., Smolen, J. S., Aletaha, D. 2024; 83 (1): 58-64

  Abstract

  To evaluate which American College of Rheumatology (ACR) response definition (ACR20, 50 or 70) should primarily be used for efficacy claims in future drug approval trials of rheumatoid arthritis (RA).We systematically searched EMBASE, Medline and the Cochrane Library for randomised controlled RA drug approval trials of biological and targeted synthetic disease-modifying antirheumatic drugs (DMARDs). We included full-text articles reporting ACR response rates for multiple time points over a 24-week placebo-controlled period and visualised normalised response trajectories over time in different patient populations. Using mixed-effect logistic regression, we calculated the proportion of ACR responders per outcome and time point, and compared the discriminant validity of these metrics at multiple time points.We screened 12 680 records and included 45 in the final analysis. Discriminative capacity of the ACR20 was high across all time points, whereas ACR50 and ACR70 showed highest discrimination towards the end of the placebo-controlled periods. This effect could be observed in all patient populations and compound groups. Faster response to treatment was observed in DMARD naïve patient populations when compared with DMARD insufficient responders.ACR20 remains the most powerful discriminator between active treatment and placebo, especially when early discrimination is of primary interest. At the same time, our results support the selection of more stringent thresholds if later time points shall be evaluated, given their comparable discriminant but higher clinical face validity.

  View details for DOI 10.1136/ard-2023-224477

  View details for PubMedID 37758287

• Consensus statement on blocking interleukin-6 receptor and interleukin-6 in inflammatory conditions: an update. Annals of the rheumatic diseases Aletaha, D., Kerschbaumer, A., Kastrati, K., Dejaco, C., Dougados, M., McInnes, I. B., Sattar, N., Stamm, T. A., Takeuchi, T., Trauner, M., van der Heijde, D., Voshaar, M., Winthrop, K. L., Ravelli, A., Betteridge, N., Burmester, G. R., Bijlsma, J. W., Bykerk, V., Caporali, R., Choy, E. H., Codreanu, C., Combe, B., Crow, M. K., de Wit, M., Emery, P., Fleischmann, R. M., Gabay, C., Hetland, M. L., Hyrich, K. L., Iagnocco, A., Isaacs, J. D., Kremer, J. M., Mariette, X., Merkel, P. A., Mysler, E. F., Nash, P., Nurmohamed, M. T., Pavelka, K., Poor, G., Rubbert-Roth, A., Schulze-Koops, H., Strangfeld, A., Tanaka, Y., Smolen, J. S. 2023; 82 (6): 773-787

  Abstract

  Targeting interleukin (IL)-6 has become a major therapeutic strategy in the treatment of immune-mediated inflammatory disease. Interference with the IL-6 pathway can be directed at the specific receptor using anti-IL-6Rα antibodies or by directly inhibiting the IL-6 cytokine. This paper is an update of a previous consensus document, based on most recent evidence and expert opinion, that aims to inform on the medical use of interfering with the IL-6 pathway.A systematic literature research was performed that focused on IL-6-pathway inhibitors in inflammatory diseases. Evidence was put in context by a large group of international experts and patients in a subsequent consensus process. All were involved in formulating the consensus statements, and in the preparation of this document.The consensus process covered relevant aspects of dosing and populations for different indications of IL-6 pathway inhibitors that are approved across the world, including rheumatoid arthritis, polyarticular-course and systemic juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still's disease, Castleman's disease, chimeric antigen receptor-T-cell-induced cytokine release syndrome, neuromyelitis optica spectrum disorder and severe COVID-19. Also addressed were other clinical aspects of the use of IL-6 pathway inhibitors, including pretreatment screening, safety, contraindications and monitoring.The document provides a comprehensive consensus on the use of IL-6 inhibition to treat inflammatory disorders to inform healthcare professionals (including researchers), patients, administrators and payers.

  View details for DOI 10.1136/ard-2022-222784

  View details for PubMedID 35953263

• Influence of active versus placebo control on treatment responses in randomised controlled trials in rheumatoid arthritis. Annals of the rheumatic diseases Kerschbaumer, A., Stimakovits, N. M., Smolen, J. S., Stefanova, T., Chwala, E., Aletaha, D. 2023; 82 (4): 476-482

  Abstract

  To investigate whether treatment effects of pharmaceutical compounds compared with placebo controls are systematically different to the effects of the same compounds compared with active treatment controls in rheumatoid arthritis (RA) clinical trials.We systematically identified randomised controlled trials (RCTs) in RA, and matched active treatment arms with comparable regimens, populations, background therapy, and outcome reporting, by the nature of their control group (active comparator or placebo). Medline, EMBASE and CENTRAL were used to identify RCTs investigating disease modifying anti-rheumatic drug therapies until December 2021. Using mixed-model logistic regression we estimated OddsRatios (OR) for achieving an American College of Rheumatology (ACR) 20/50/70% response at weeks 12 and 24. Risk of bias was assessed using the Cochrane Tool.We screened 8328 studies and included 40 for analysis after detailed review of 590 manuscripts; unique compounds had significantly higher responses in active comparator trials compared with their effects observed in placebo controlled trials, with ORs of 1.67 (95% CI 1.46 to 1.91; p<0.001) for ACR20, 1.50 (95% CI 1.29 to 1.75; p<0.001) for ACR50 and 1.65 (95% CI 1.30 to 2.10; p<0.001) for ACR70 (week 12); corresponding ORs for ACR 20, 50, and 70 (week 24) were 1.93 (95% CI 1.50 to 2.48; p<0.001), 1.75 (95% CI 1.32 to 2.33; p<0.001) and 1.68 (95% CI 1.21 to 2.34; p<0.001), respectively. Sensitivity analyses showed consistent results.Placebo controlled trials lead to smaller effect sizes of active compounds in RCTs compared with the same compound in head-to-head trials. This difference may be explained by potential nocebo effects in placebo-controlled settings and needs to be considered when interpreting head-to-head and placebo-controlled trials, by patients, investigators, sponsors and regulatory agencies.

  View details for DOI 10.1136/ard-2022-223349

  View details for PubMedID 36627167

• Safety and immunogenicity of a third COVID-19 vaccination in patients with immune-mediated inflammatory diseases compared with healthy controls. Annals of the rheumatic diseases Kartnig, F., Mrak, D., Simader, E., Tobudic, S., Radner, H., Mandl, P., Göschl, L., Hommer, N., Mayer, M., Hofer, P., Hummel, T., Deimel, T., Geßl, I., Puchner, A., Kerschbaumer, A., Thalhammer, R., Handisurya, A., Kain, R., Winkler, S., Smolen, J. S., Stiasny, K., Perkmann, T., Haslacher, H., Aberle, J. H., Aletaha, D., Heinz, L. X., Sieghart, D., Bonelli, M. 2023; 82 (2): 292-300

  Abstract

  A third COVID-19 vaccination is recommended for immunosuppressed patients. However, data on immunogenicity and safety of a third COVID-19 vaccination in patients with immune-mediated inflammatory diseases (IMIDs) are sparse and therefore addressed within this clinical trial.60 immunosuppressed patients and 48 healthy controls (HCs) received a third vaccination with an mRNA vaccine. The primary endpoint was defined as the presence of antibody levels against the receptor-binding domain (RBD)>1500 BAU/mL in patients with IMIDs versus HCs. Further endpoints included differences in neutralising antibodies and cellular immune responses after the third vaccination. Reactogenicity was recorded for 7 days, and safety was evaluated until week 4.Rate of individuals with anti-RBD antibodies>1500 BAU/mL was not significantly different after the third vaccination between patients with IMIDs and HCs (91% vs 100% p=0.101). Anti-RBD and neutralising antibody levels were significantly lower in patients with IMIDs after the third vaccination than in HCs (p=0.002 and p=0.016, respectively). In contrast, fold increase in antibody levels between week 0 and 4 was higher in patients with IMIDs. Treatment with biological (b) disease-modifying anti-rheumatic drugs (DMARD) or combination of bDMARDs and conventional synthetic DMARDs was associated with reduced antibody levels. Enhanced cellular immune response to wild type and Omicron peptide stimulation was observed after the third vaccination. No serious adverse event was attributed to the third vaccination.Our clinical trial data support the immunogenicity and safety of a third COVID-19 vaccination in patients with IMIDs. However, effects of DMARD therapy on immunogenicity should be considered.EudraCT No: 2021-002693-10.

  View details for DOI 10.1136/ard-2022-222682

  View details for PubMedID 36109141

• Efficacy of synthetic and biological DMARDs: a systematic literature review informing the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis. Annals of the rheumatic diseases Kerschbaumer, A., Sepriano, A., Bergstra, S. A., Smolen, J. S., van der Heijde, D., Caporali, R., Edwards, C. J., Verschueren, P., de Souza, S., Pope, J. E., Takeuchi, T., Hyrich, K. L., Winthrop, K. L., Aletaha, D., Stamm, T. A., Schoones, J. W., Landewé, R. B. 2023; 82 (1): 95-106

  Abstract

  To update the evidence on efficacy of DMARDs (disease-modifying antirheumatic drugs) and inform the taskforce of the 2022 update of the European Alliance of Associations for Rheumatology (EULAR) recommendations for management of rheumatoid arthritis (RA).This systematic literature review (SLR) investigated the efficacy of conventional synthetic (cs), biological (b), biosimilar and targeted synthetic (ts)DMARDs in patients with RA. Medline, EMBASE, Cochrane CENTRAL and Web of Science were used to identify all relevant articles published since the previous update in 2019 to 14 January 2022.Of 8969 search results, 169 articles were selected for detailed review and 47 were finally included. Trials investigated the efficacy of csDMARDs, bDMARDs and tsDMARDs, DMARD switching, tapering and trials investigating different treatment strategies. The compounds investigated were csDMARDs (methotrexate (MTX), leflunomide, sulfasalazine, hydroxychloroquine), bDMARDs (abatacept, adalimumab, certolizumab-pegol, denosumab, etanercept, infliximab, levilimab, olokizumab, opineracept, rituximab, sarilumab, tocilizumab) and tsDMARDs (baricitinib, filgotinib, tofacitinib, upadacitinib). The efficacy of csDMARDs+ short-term glucocorticoids in early RA was confirmed and similar to bDMARD+MTX combination therapy. Interleukin-6 pathway inhibition was effective in trials on olokizumab and levilimab. Janus kinase inhibitor (JAKi) was efficacious in different patient populations. After insufficient response to JAKi, patients could respond to TNFi treatment. Tapering of DMARDs was feasible for a proportion of patients, who were able to taper therapy while remaining in low disease activity or remission.The results of this SLR, together with one SLR on safety of DMARD and one on glucocorticoids, informed the taskforce of the 2022 update of the EULAR recommendations for pharmacological management of RA.

  View details for DOI 10.1136/ard-2022-223365

  View details for PubMedID 36368906

• Safety of synthetic and biological DMARDs: a systematic literature review informing the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis. Annals of the rheumatic diseases Sepriano, A., Kerschbaumer, A., Bergstra, S. A., Smolen, J. S., van der Heijde, D., Caporali, R., Edwards, C. J., Verschueren, P., de Souza, S., Pope, J., Takeuchi, T., Hyrich, K., Winthrop, K. L., Aletaha, D., Stamm, T., Schoones, J. W., Landewé, R. B. 2023; 82 (1): 107-118

  Abstract

  To perform a systematic literature review (SLR) concerning the safety of synthetic(s) and biological (b) disease-modifying antirheumatic drugs (DMARDs) to inform the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis (RA).SLR of observational studies comparing safety outcomes of any DMARD with another intervention in RA. A comparator group was required for inclusion. For treatments yet without, or limited, registry data, randomised controlled trials (RCTs) were used.Fifty-nine observational studies addressed the safety of DMARDs. Two studies (unclear risk of bias (RoB)) showed an increased risk of serious infections with bDMARDs compared with conventional synthetic (cs)DMARDs. Herpes zoster infections occurred more with JAKi than csDMARDs (adjusted HR (aHR): 3.66) and bDMARDs (aHR: 1.9-2.3) (four studies, two low RoB). The risk of malignancies was similar across bDMARDs (five studies) and with tofacitinib compared with bDMARDs (one study, low RoB). The risk of major adverse cardiovascular events (MACE) was similar with bDMARDs and tofacitinib (two studies, one low RoB). Thirty studies reported safety from RCTs, with one, designed to evaluate safety, showing that malignancies (HR (95% CI): 1.48 (1.04 to 2.09)) and MACE (HR (95% CI): 1.33 (0.91 to 1.94)) occurred numerically more frequently with tofacitinib (5 mg and 10 mg doses combined) than with TNFi in patients with cardiovascular risk factors. In this study, the risk of venous thromboembolism (VTE) was higher with tofacitinib 10 mg than with TNFi.The safety profile of bDMARDs was further demonstrated. Whether the difference in incidence of malignancies, MACE and VTE between tofacitinib and TNFi applies to other JAKi needs further evaluation.

  View details for DOI 10.1136/ard-2022-223357

  View details for PubMedID 36376026

• EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Annals of the rheumatic diseases Smolen, J. S., Landewé, R. B., Bergstra, S. A., Kerschbaumer, A., Sepriano, A., Aletaha, D., Caporali, R., Edwards, C. J., Hyrich, K. L., Pope, J. E., de Souza, S., Stamm, T. A., Takeuchi, T., Verschueren, P., Winthrop, K. L., Balsa, A., Bathon, J. M., Buch, M. H., Burmester, G. R., Buttgereit, F., Cardiel, M. H., Chatzidionysiou, K., Codreanu, C., Cutolo, M., den Broeder, A. A., El Aoufy, K., Finckh, A., Fonseca, J. E., Gottenberg, J. E., Haavardsholm, E. A., Iagnocco, A., Lauper, K., Li, Z., McInnes, I. B., Mysler, E. F., Nash, P., Poor, G., Ristic, G. G., Rivellese, F., Rubbert-Roth, A., Schulze-Koops, H., Stoilov, N., Strangfeld, A., van der Helm-van Mil, A., van Duuren, E., Vliet Vlieland, T. P., Westhovens, R., van der Heijde, D. 2023; 82 (1): 3-18

  Abstract

  To provide an update of the EULAR rheumatoid arthritis (RA) management recommendations addressing the most recent developments in the field.An international task force was formed and solicited three systematic literature research activities on safety and efficacy of disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids (GCs). The new evidence was discussed in light of the last update from 2019. A predefined voting process was applied to each overarching principle and recommendation. Levels of evidence and strengths of recommendation were assigned to and participants finally voted on the level of agreement with each item.The task force agreed on 5 overarching principles and 11 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); GCs; biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab including biosimilars), abatacept, rituximab, tocilizumab, sarilumab and targeted synthetic (ts) DMARDs, namely the Janus kinase inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib. Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering in sustained clinical remission is provided. Safety aspects, including risk of major cardiovascular events (MACEs) and malignancies, costs and sequencing of b/tsDMARDs were all considered. Initially, MTX plus GCs is recommended and on insufficient response to this therapy within 3-6 months, treatment should be based on stratification according to risk factors; With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD should be added to the csDMARD; after careful consideration of risks of MACEs, malignancies and/or thromboembolic events tsDMARDs may also be considered in this phase. If the first bDMARD (or tsDMARD) fails, any other bDMARD (from another or the same class) or tsDMARD (considering risks) is recommended. With sustained remission, DMARDs may be tapered but should not be stopped. Levels of evidence and levels of agreement were high for most recommendations.These updated EULAR recommendations provide consensus on RA management including safety, effectiveness and cost.

  View details for DOI 10.1136/ard-2022-223356

  View details for PubMedID 36357155

• Efficacy, duration of use and safety of glucocorticoids: a systematic literature review informing the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis. Annals of the rheumatic diseases Bergstra, S. A., Sepriano, A., Kerschbaumer, A., van der Heijde, D., Caporali, R., Edwards, C. J., Verschueren, P., de Souza, S., Pope, J. E., Takeuchi, T., Hyrich, K. L., Winthrop, K. L., Aletaha, D., Stamm, T. A., Schoones, J. W., Smolen, J. S., Landewé, R. B. 2023; 82 (1): 81-94

  Abstract

  This systematic literature review (SLR) regarding the efficacy, duration of use and safety of glucocorticoids (GCs), was performed to inform the 2022 update of the EULAR recommendations for the management of rheumatoid arthritis (RA). Studies on GC efficacy were identified from a separate search on the efficacy of disease-modifying antirheumatic drugs (DMARDs). A combined search was performed for the duration of use and safety of GCs in RA patients. Dose-defined and time-defined GC treatment of any dose and duration (excluding intra-articular GCs) prescribed in combination with other DMARDs were considered. Results are presented descriptively. Two included studies confirmed the efficacy of GC bridging as initial therapy, with equal efficacy after 2 years of initial doses of 30 mg/day compared with 60 mg/day prednisone. Based on a recently performed SLR, in clinical trials most patients starting initial GC bridging are able to stop GCs within 12 (22% patients continued on GCs) to 24 months (10% patients continued on GCs). The safety search included 12 RCTs and 21 observational studies. Well-known safety risks of GC use were confirmed, including an increased risk of osteoporotic fractures, serious infections, diabetes and mortality. Data on cardiovascular outcomes were Inconsistent. Overall, safety risks increased with increasing dose and/or duration, but evidence on which dose is safe was conflicting. In conclusion, this SLR has confirmed the efficacy of GCs in the treatment of RA. In clinical trials, most patients have shown to be able to stop GCs within 12-24 months. Well-known safety risks of GC use have been confirmed, but with heterogeneity between studies.

  View details for DOI 10.1136/ard-2022-223358

  View details for PubMedID 36410794

• Immunogenicity and safety of a fourth COVID-19 vaccination in rituximab-treated patients: an open-label extension study. Annals of the rheumatic diseases Mrak, D., Simader, E., Sieghart, D., Mandl, P., Radner, H., Perkmann, T., Haslacher, H., Mayer, M., Koblischke, M., Hofer, P., Göschl, L., Kartnig, F., Deimel, T., Kerschbaumer, A., Hummel, T., Kornek, B., Thalhammer, R., Stiasny, K., Winkler, S., Smolen, J. S., Aberle, J. H., Aletaha, D., Heinz, L. X., Bonelli, M. 2022; 81 (12): 1750-1756

  Abstract

  Patients under rituximab therapy are at high risk for a severe COVID-19 disease course. Humoral immune responses to SARS-CoV-2 vaccination are vastly diminished in B-cell-depleted patients, even after a third vaccine dose. However, it remains unclear whether these patients benefit from a fourth vaccination and whether continued rituximab therapy affects antibody development.In this open-label extension trial, 37 rituximab-treated patients who received a third dose with either a vector or mRNA-based vaccine were vaccinated a fourth time with an mRNA-based vaccine (mRNA-1273 or BNT162b2). Key endpoints included the humoral and cellular immune response as well as safety after a fourth vaccination.The number of patients who seroconverted increased from 12/36 (33%) to 21/36 (58%) following the fourth COVID-19 vaccination. In patients with detectable antibodies to the spike protein's receptor-binding domain (median: 8.0 binding antibody units (BAU)/mL (quartiles: 0.4; 13.8)), elevated levels were observed after the fourth vaccination (134.0 BAU/mL (quartiles: 25.5; 1026.0)). Seroconversion and antibody increase were strongly diminished in patients who received rituximab treatment between the third and the fourth vaccination. The cellular immune response declined 12 weeks after the third vaccination, but could only be slightly enhanced by a fourth vaccination. No unexpected safety signals were detected, one serious adverse event not related to vaccination occurred.A fourth vaccine dose is immunogenic in a fraction of rituximab-treated patients. Continuation of rituximab treatment reduced humoral immune response, suggesting that rituximab affects a second booster vaccination. It might therefore be considered to postpone rituximab treatment in clinically stable patients.2021-002348-57.

  View details for DOI 10.1136/ard-2022-222579

  View details for PubMedID 35977809

• Heterologous vector versus homologous mRNA COVID-19 booster vaccination in non-seroconverted immunosuppressed patients: a randomized controlled trial. Nature communications Mrak, D., Sieghart, D., Simader, E., Tobudic, S., Radner, H., Mandl, P., Göschl, L., Koblischke, M., Hommer, N., Wagner, A., Mayer, M., Schubert, L., Hartl, L., Kozbial, K., Hofer, P., Kartnig, F., Hummel, T., Kerschbaumer, A., Deimel, T., Puchner, A., Gudipati, V., Thalhammer, R., Munda, P., Uyanik-Ünal, K., Zuckermann, A., Novacek, G., Reiberger, T., Garner-Spitzer, E., Reindl-Schwaighofer, R., Kain, R., Winkler, S., Smolen, J. S., Stiasny, K., Fischer, G. F., Perkmann, T., Haslacher, H., Zeitlinger, M., Wiedermann, U., Aberle, J. H., Aletaha, D., Heinz, L. X., Bonelli, M. 2022; 13 (1): 5362

  Abstract

  Impaired response to COVID-19 vaccination is of particular concern in immunosuppressed patients. To determine the best vaccination strategy for this vulnerable group we performed a single center, 1:1 randomized blinded clinical trial. Patients who failed to seroconvert upon two mRNA vaccinations (BNT162b2 or mRNA-1273) are randomized to receive either a third dose of the same mRNA or the vector vaccine ChAdOx1 nCoV-19. Primary endpoint is the difference in SARS-CoV-2 spike antibody seroconversion rate between vector and mRNA vaccinated patients four weeks after the third dose. Secondary outcomes include cellular immune responses. Seroconversion rates at week four are significantly higher in the mRNA (homologous vaccination, 15/24, 63%) as compared to the vector vaccine group (heterologous vaccination, 4/22, 18%). SARS-CoV-2-specific T-cell responses are reduced but could be increased after a third dose of either vector or mRNA vaccine. In a multivariable logistic regression analysis, patient age and vaccine type are associated with seroconversion. No serious adverse event is attributed to COVID-19 booster vaccination. Efficacy and safety data underline the importance of a booster vaccination and support the use of a homologous mRNA booster vaccination in immunosuppressed patients.Trial registration: EudraCT No.: 2021-002693-10.

  View details for DOI 10.1038/s41467-022-33036-y

  View details for PubMedID 36097029

  View details for PubMedCentralID PMC9467419

• A systematic literature review informing the consensus statement on efficacy and safety of pharmacological treatment with interleukin-6 pathway inhibition with biological DMARDs in immune-mediated inflammatory diseases. RMD open Kastrati, K., Aletaha, D., Burmester, G. R., Chwala, E., Dejaco, C., Dougados, M., McInnes, I. B., Ravelli, A., Sattar, N., Stamm, T. A., Takeuchi, T., Trauner, M., van der Heijde, D., Voshaar, M. J., Winthrop, K., Smolen, J. S., Kerschbaumer, A. 2022; 8 (2)

  Abstract

  Informing an international task force updating the consensus statement on efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) selectively targeting interleukin-6 (IL-6) pathway in the context of immune-mediated inflammatory diseases.A systematic literature research of all publications on IL-6 axis inhibition with bDMARDs published between January 2012 and December 2020 was performed using MEDLINE, EMBASE and Cochrane CENTRAL databases. Efficacy and safety outcomes were assessed in clinical trials including their long-term extensions and observational studies. Meeting abstracts from ACR, EULAR conferences and results on clinicaltrials.gov were taken into consideration.187 articles fulfilled the inclusion criteria. Evidence for positive effect of IL-6 inhibition was available in various inflammatory diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still's disease, cytokine release syndrome due to chimeric antigen receptor T cell therapy and systemic sclerosis-associated interstitial lung disease. Newcomers like satralizumab and anti-IL-6 ligand antibody siltuximab have expanded therapeutic approaches for Castleman's disease and neuromyelitis optica, respectively. IL-6 inhibition did not provide therapeutic benefits in psoriatic arthritis, ankylosing spondylitis and certain connective tissue diseases. In COVID-19, tocilizumab (TCZ) has proven to be therapeutic in advanced disease. Safety outcomes did not differ from other bDMARDs, except higher risks of diverticulitis and lower gastrointestinal perforations. Inconsistent results were observed in several studies investigating the risk for infections when comparing TCZ to TNF-inhibitors.IL-6 inhibition is effective for treatment of several inflammatory diseases with a safety profile that is widely comparable to other bDMARDs.

  View details for DOI 10.1136/rmdopen-2022-002359

  View details for PubMedID 36260501

  View details for PubMedCentralID PMC9462104

• Response to: 'Correspondence on 'EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2019 update' by Fallon et al. Annals of the rheumatic diseases Baraliakos, X., Gossec, L., McInnes, I., Kerschbaumer, A., de Wit, M., Dougados, M., Primdahl, J., van der Heijde, D., Smolen, J. S. 2022; 81 (9): e174

  View details for DOI 10.1136/annrheumdis-2020-218676

  View details for PubMedID 32963050

• Response to: 'Comment on: 'EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2019 update' by Gossec et al' by Wei et al. Annals of the rheumatic diseases Gossec, L., Baraliakos, X., McInnes, I., Kerschbaumer, A., de Wit, M., Dougados, M., Primdahl, J., van der Heijde, D., Smolen, J. S. 2022; 81 (8): e139

  View details for DOI 10.1136/annrheumdis-2020-218456

  View details for PubMedID 32873555

• Torque Teno Virus quantification for monitoring of immunomodulation with biologic compounds in the treatment of rheumatoid arthritis. Rheumatology (Oxford, England) Studenic, P., Bond, G., Kerschbaumer, A., Bécède, M., Pavelka, K., Karateev, D., Stieger, J., Puchner, R., Mueller, R. B., Puchhammer-Stöckl, E., Durechova, M., Loiskandl, M., Perkmann, T., Olejarova, M., Luchikhina, E., Steiner, C. W., Bonelli, M., Smolen, J. S., Aletaha, D. 2022; 61 (7): 2815-2825

  Abstract

  RA patients who fail to respond to MTX can receive biologic dMARDs (bDMARDs). The Torque Teno Virus (TTV) is a potential novel candidate for monitoring of immunosuppression. We explore TTV in these patients and its association with clinical response to bDMARDs.The BioBio Study is a multicentre randomized open-label trial, including RA patients with insufficient response to MTX. Patients were randomized to either TNFi (infliximab, INF), anti-IL-6 (tocilizumab, TCZ), CTLA4-Ig (abatacept, ABA) or anti-CD20 (rituximab, RTX) in addition to MTX. PCR was used to quantify TTV in the peripheral blood.TTV was measured in 95 patients (INF, n = 23; TCZ, n = 22; ABA, n = 27; RTX; n = 23). TTV increased by a median of 4.5 × 104 copies/ml [c/ml; interquartile range (IQR) 0-7.5 × 105] after 3 months. TTV levels at month 3 were associated with the Simplified Disease Activity Index (SDAI) (P = 0.03) and the Clinical Disease Activity Index (CDAI) response (P = 0.026) at month 6. A TTV cut-off level of 1.2 × 106 c/ml at month 3 had a positive likelihood ratio of 2.7 for prediction of an 85% reduction in SDAI at month 6.Our data suggest that TTV levels increase upon TNF, CD20 and costimulation blockade and are associated with the clinical response to bDMARDs in RA patients.ClinicalTrials.gov; https://clinicaltrials.gov; NCT01638715.

  View details for DOI 10.1093/rheumatology/keab839

  View details for PubMedID 34792562

• Systematic literature review of observational cohorts and clinical trials into the success rate of glucocorticoid discontinuation after their use as bridging therapy in patients with rheumatoid arthritis. Annals of the rheumatic diseases van Ouwerkerk, L., Palmowski, A., Nevins, I. S., Buttgereit, F., Verschueren, P., Smolen, J. S., Landewé, R. B., Bijlsma, J. J., Kerschbaumer, A., Westhovens, R., Huizinga, T. W., Allaart, C. F., Bergstra, S. A. 2022; 81 (7): 937-943

  Abstract

  To investigate the success rate of glucocorticoid (GC) discontinuation during follow-up in observational cohorts and clinical trials using temporary GC as part of initial therapy ('bridging') in newly diagnosed patients with rheumatoid arthritis (RA).Systematic literature searches were conducted to identify observational cohorts and clinical trials including patients with RA treated with initial GC bridging therapy, defined as discontinuation of GC within 1 year. Patient percentages still using GC were considered the reverse of successful discontinuation. Random effects meta-analyses were performed stratified by time point.The scoping literature search for observational cohort studies could not identify studies answering the research question. The literature search for clinical trials identified 7160 abstracts, resulting in 10 included studies, with varying type and dose of GC and varying tapering schedules, of which 4 reported sufficient data on GC discontinuation or use after the bridging phase. The pooled proportion of patients who were still or again using GC was 22% (95% CI 8% to 37%, based on four trials) at 12 months and 10% at 24 months (95% CI -1 to 22, based on two trials). Heterogeneity was substantial (I²≥65%).The success rate of GC discontinuation after bridging as part of initial treatment of RA has been described in a limited number of studies. Reports on observational cohorts did not answer the research question. In clinical trials, protocolised discontinuation was mostly successful, although 22% of the patients who started GC bridging therapy still or again used GC at 12 months, and 10% at 24 months.

  View details for DOI 10.1136/annrheumdis-2022-222338

  View details for PubMedID 35470162

• Tocilizumab in patients with new onset polymyalgia rheumatica (PMR-SPARE): a phase 2/3 randomised controlled trial. Annals of the rheumatic diseases Bonelli, M., Radner, H., Kerschbaumer, A., Mrak, D., Durechova, M., Stieger, J., Husic, R., Mandl, P., Smolen, J. S., Dejaco, C., Aletaha, D. 2022; 81 (6): 838-844

  Abstract

  Polymyalgia rheumatica is the second most common inflammatory rheumatic disease of people >50 years. Glucocorticoid therapy is highly effective, but many patients require treatment for several years. Effective glucocorticoid sparing agents are still needed.In this double-blind, multi-centre phase 2/3 clinical trial, we randomly assigned 36 patients with new onset polymyalgia rheumatica from three centres to receive subcutaneous tocilizumab (162 mg per week) or placebo for 16 weeks (1:1 ratio). All patients received oral prednisone, tapered from 20 mg to 0 mg over 11 weeks.The primary endpoint was the proportion of patients in glucocorticoid-free remission at week 16; key secondary endpoints, including time to first relapse and cumulative glucocorticoid dose at weeks 16 and 24, were evaluated.From 20 November 2017 to 28 October 2019 39 patients were screened for eligibility; 19 patients received tocilizumab and 17 placebo. Glucocorticoid-free remission at week 16 was achieved in 12 out of 19 patients on tocilizumab (63.2%) and 2 out of 17 patients receiving placebo (11.8%, p=0.002), corresponding to an OR of 12.9 (95 % CI: 2.2 to 73.6) in favour of tocilizumab. Mean (±SD) time to first relapse was 130±13 and 82±11 days (p=0.007), respectively, and the median (IQR) cumulative glucocorticoid dose was 727 (721-842) mg and 935 (861-1244) mg (p=0.003), respectively. Serious adverse events were observed in five placebo patients and one tocilizumab patient.In patients with new onset polymyalgia rheumatica undergoing rapid glucocorticoid tapering, tocilizumab was superior to placebo regarding sustained glucocorticoid-free remission, time to relapse and cumulative glucocorticoid dose.NCT03263715.

  View details for DOI 10.1136/annrheumdis-2021-221126

  View details for PubMedID 35210264

• Segmental endobronchial valve therapy for a vasculitis-induced emphysema. Respiratory medicine case reports Bal, C., Göschl, L., Milos, R. I., Gerstbrein, K., Kerschbaumer, A., Idzko, M., Gompelmann, D. 2022; 37: 101650

  Abstract

  A 53-year old female patient with history of hypocomplementaemic urticarial vasculitis syndrome (HUVS) and polyarteritis nodosa presented with progressive dyspnoea on exertion due to emphysema. Lung function revealed a severe obstructive ventilator disorder with a forced expiratory volume in 1 second of 22% of predicted, and a significant hyperinflation with a residual volume of 321% of predicted. Multi-detector computed tomography (MDCT) scan and quantitative CT analysis (StratX software) confirmed a lower lobe predominant emphysema. Considering the young age, the very severely impaired lung function, the relatively low nicotine abuse, the exclusion of alpha-1 antitrypsin deficiency, together with the known diagnosis of HUVS, the emphysema was more likely due to the vasculitis than to a typical chronic obstructive lung disease. MDCT scan showed that particularly the segment 8 of the right lower lobe was severely emphysematous destroyed and hyperinflated. Invasive Chartis® measurement revealed no significant collateral ventilation of the isolated segment 8 of the right lower lobe, so that an endobronchial valve placement was performed. Three months following intervention, the MDCT scan revealed a complete collapse of the segment 8 on the right, which was associated with a significant clinical benefit and a mild reduction of the hyperinflation in the lung function test.

  View details for DOI 10.1016/j.rmcr.2022.101650

  View details for PubMedID 35494554

  View details for PubMedCentralID PMC9048058

• Perceptions and experiences of individuals at-risk of rheumatoid arthritis (RA) knowing about their risk of developing RA and being offered preventive treatment: systematic review and thematic synthesis of qualitative studies. Annals of the rheumatic diseases Siddle, H. J., Chapman, L. S., Mankia, K., Zăbălan, C., Kouloumas, M., Raza, K., Falahee, M., Kerry, J., Kerschbaumer, A., Aletaha, D., Emery, P., Richards, S. H. 2022; 81 (2): 159-168

  Abstract

  There is increasing interest in identifying individuals at-risk of rheumatoid arthritis (RA) and initiating early treatment to prevent or delay the onset of arthritis. We aimed to describe the perceptions and experiences of at-risk individuals and to inform the conduct of clinical trials and studies, and clinical practice.A systematic review and thematic synthesis of qualitative studies was conducted. Two review authors independently screened studies for inclusion, appraised their methodological quality using the Critical Appraisal Skills Programme checklist and assessed confidence in the findings using the Grading of Recommendations Assessment, Development and Evaluation-Confidence in Evidence from Reviews of Qualitative Research approach.Seven studies involving 115 individuals at-risk of developing RA were included. Three major themes (seven subthemes) were identified: understanding the risk of developing RA (knowledge of RA and identification of potential risk factors); preventive interventions to reduce the risk of developing RA (understanding the value and role of preventive interventions, and engagement with preventive interventions); and perceptions of predictive testing for RA (benefits of predictive testing, decision to undertake predictive testing and concerns about predictive testing). Moderate confidence in most review findings was evident.While there are clear benefits in informing individuals at-risk of RA about their risk following predictive testing and offering preventive treatment, there are potential barriers to engagement, intensified by the burden of uncertainty. Identification of the optimum approaches for presenting risk information, including the risks and benefits of engaging with preventive interventions, is urgently needed to support individuals at-risk of RA in their decision making.CRD42021236034.

  View details for DOI 10.1136/annrheumdis-2021-221160

  View details for PubMedID 34750103

  View details for PubMedCentralID PMC8762008

• Intercepting psoriatic arthritis in patients with psoriasis: buy one get one free? Annals of the rheumatic diseases McGonagle, D. G., Zabotti, A., Watad, A., Bridgewood, C., De Marco, G., Kerschbaumer, A., Aletaha, D. 2022; 81 (1): 7-10

  View details for DOI 10.1136/annrheumdis-2021-221255

  View details for PubMedID 34810194

• EULAR points to consider for conducting clinical trials and observational studies in individuals at risk of rheumatoid arthritis. Annals of the rheumatic diseases Mankia, K., Siddle, H. J., Kerschbaumer, A., Alpizar Rodriguez, D., Catrina, A. I., Cañete, J. D., Cope, A. P., Daien, C. I., Deane, K. D., El Gabalawy, H., Finckh, A., Holers, V. M., Koloumas, M., Ometto, F., Raza, K., Zabalan, C., van der Helm-van Mil, A., van Schaardenburg, D., Aletaha, D., Emery, P. 2021; 80 (10): 1286-1298

  Abstract

  Despite growing interest, there is no guidance or consensus on how to conduct clinical trials and observational studies in populations at risk of rheumatoid arthritis (RA).An European League Against Rheumatism (EULAR) task force formulated four research questions to be addressed by systematic literature review (SLR). The SLR results informed consensus statements. One overarching principle, 10 points to consider (PTC) and a research agenda were proposed. Task force members rated their level of agreement (1-10) for each PTC.Epidemiological and demographic characteristics should be measured in all clinical trials and studies in at-risk individuals. Different at-risk populations, identified according to clinical presentation, were defined: asymptomatic, musculoskeletal symptoms without arthritis and early clinical arthritis. Study end-points should include the development of subclinical inflammation on imaging, clinical arthritis, RA and subsequent achievement of arthritis remission. Risk factors should be assessed at baseline and re-evaluated where appropriate; they include genetic markers and autoantibody profiling and additionally clinical symptoms and subclinical inflammation on imaging in those with symptoms and/or clinical arthritis. Trials should address the effect of the intervention on risk factors, as well as progression to clinical arthritis or RA. In patients with early clinical arthritis, pharmacological intervention has the potential to prevent RA development. Participants' knowledge of their RA risk may inform their decision to participate; information should be provided using an individually tailored approach.These consensus statements provide data-driven guidance for rheumatologists, health professionals and investigators conducting clinical trials and observational studies in individuals at risk of RA.

  View details for DOI 10.1136/annrheumdis-2021-220884

  View details for PubMedID 34362746

  View details for PubMedCentralID PMC8458095

• A core set of risk factors in individuals at risk of rheumatoid arthritis: a systematic literature review informing the EULAR points to consider for conducting clinical trials and observational studies in individuals at risk of rheumatoid arthritis. RMD open Mankia, K., Siddle, H., Di Matteo, A., Alpízar-Rodríguez, D., Kerry, J., Kerschbaumer, A., Aletaha, D., Emery, P. 2021; 7 (3)

  Abstract

  There is significant interest in determining risk factors in individuals at risk of rheumatoid arthritis (RA). A core set of risk factors for clinical arthritis development has not been defined.A literature search and systematic literature review (SLR) was conducted to identify risk factors in individuals at risk of RA using Medline, Embase, PubMed and Central databases.3854 articles were identified by the literature search. After screening of titles, 138 abstracts were reviewed and 96 articles finally included. Fifty-three articles included data on risk factors including autoantibodies, subclinical inflammation on imaging, clinical features, serum and cellular biomarkers and genetic markers. Risk factors were dependent on the at-risk population. There was good evidence for serum anticitrullinated protein antibodies (ACPA) levels, as risk factors for arthritis in all at-risk populations (n=13 articles). Subclinical inflammation on ultrasound (n=12) and MRI (n=6) was reported as a risk factor in multiple studies in at-risk individuals with musculoskeletal (MSK) symptoms and undifferentiated arthritis (UA). Clinical features were reported as a risk factor in at-risk individuals with MSK symptoms and UA (n=13). Other risk factors, including serum and cellular markers were less frequently reported.Risk factors for arthritis development in RA are specific to the at-risk population. Serum ACPA confers risk in all populations; subclinical inflammation on imaging and clinical features confer risk in at-risk individuals with MSK symptoms. This SLR informed the EULAR taskforce for points to consider on conducting clinical trials and studies in individuals at risk of RA.

  View details for DOI 10.1136/rmdopen-2021-001768

  View details for PubMedID 34531306

  View details for PubMedCentralID PMC8449955

• Points to consider for the treatment of immune-mediated inflammatory diseases with Janus kinase inhibitors: a consensus statement. Annals of the rheumatic diseases Nash, P., Kerschbaumer, A., Dörner, T., Dougados, M., Fleischmann, R. M., Geissler, K., McInnes, I., Pope, J. E., van der Heijde, D., Stoffer-Marx, M., Takeuchi, T., Trauner, M., Winthrop, K. L., de Wit, M., Aletaha, D., Baraliakos, X., Boehncke, W. H., Emery, P., Isaacs, J. D., Kremer, J., Lee, E. B., Maksymowych, W. P., Voshaar, M., Tam, L. S., Tanaka, Y., van den Bosch, F., Westhovens, R., Xavier, R., Smolen, J. S. 2021; 80 (1): 71-87

  Abstract

  Janus kinase inhibitors (JAKi) have been approved for use in various immune-mediated inflammatory diseases. With five agents licensed, it was timely to summarise the current understanding of JAKi use based on a systematic literature review (SLR) on efficacy and safety.Existing data were evaluated by a steering committee and subsequently reviewed by a 29 person expert committee leading to the formulation of a consensus statement that may assist the clinicians, patients and other stakeholders once the decision is made to commence a JAKi. The committee included patients, rheumatologists, a gastroenterologist, a haematologist, a dermatologist, an infectious disease specialist and a health professional. The SLR informed the Task Force on controlled and open clinical trials, registry data, phase 4 trials and meta-analyses. In addition, approval of new compounds by, and warnings from regulators that were issued after the end of the SLR search date were taken into consideration.The Task Force agreed on and developed four general principles and a total of 26 points for consideration which were grouped into six areas addressing indications, treatment dose and comedication, contraindications, pretreatment screening and risks, laboratory and clinical follow-up examinations, and adverse events. Levels of evidence and strengths of recommendations were determined based on the SLR and levels of agreement were voted on for every point, reaching a range between 8.8 and 9.9 on a 10-point scale.The consensus provides an assessment of evidence for efficacy and safety of an important therapeutic class with guidance on issues of practical management.

  View details for DOI 10.1136/annrheumdis-2020-218398

  View details for PubMedID 33158881

  View details for PubMedCentralID PMC7788060

• Hand X-ray examination in two planes is not required for radiographic assessment of hand osteoarthritis. Therapeutic advances in musculoskeletal disease Staats, K., Sunk, I. G., Weidekamm, C., Kerschbaumer, A., Bécède, M., Supp, G., Stamm, T., Windhager, R., Smolen, J. S., Bobacz, K. 2020; 12: 1759720X20934934

  Abstract

  Radiographic imaging is essential in the diagnosis of hand osteoarthritis (HOA); however, it is unknown whether a multiplanar examination would add essential information to dorso-palmar (dp) views alone. This study evaluated whether an additional radiographic view would aid clinicians in the diagnostic process of HOA.The dp radiographs of both hands from 159 HOA patients were assessed according to the scores described by Kellgren and Lawrence (K/L). In oblique view images, structures similar to classic ostophytes (OPs) were found, namely bony proliferations on the dorsal and/or ventral margins of joints, and were documented as dorsal/ventral OPs (dvOPs). Function and pain were assessed by applying standardised read-out systems. Logistic regression analysis and Mann-Whitney tests were implemented.The presence of dvOPs was associated with the degree of joint damage; however, dp views were sufficient to estimate radiographic changes. Only a few joints showed dvOPs as the only structural alteration; nevertheless, in almost all cases, classical radiographic OA changes were found in dp views of other joints of the same or the contralateral hand. The presence of dvOPs did not affect joint function or pain according to established scores, but was associated with radiographic progression in distal interphalangeal joints.This is the first study to confirm that additional radiographic planes, oblique/lateral views, are not necessary in the diagnostic process in HOA in daily clinical practice. Nevertheless, the presence of dvOPs reflect more severe joint damage and is associated with radiographic progression in HOA; hence, oblique/lateral views could be a useful tool for academic purposes.

  View details for DOI 10.1177/1759720X20934934

  View details for PubMedID 32655702

  View details for PubMedCentralID PMC7333491

• Is Methotrexate as Efficacious as Etanercept in Psoriatic Arthritis Patients? Comment on the Article by Mease et al. Arthritis & rheumatology (Hoboken, N.J.) Kerschbaumer, A., Smolen, J. S., Aletaha, D. 2020; 72 (7): 1227-1229

  View details for DOI 10.1002/art.41274

  View details for PubMedID 32336032

• Safety of synthetic and biological DMARDs: a systematic literature review informing the 2019 update of the EULAR recommendations for the management of rheumatoid arthritis. Annals of the rheumatic diseases Sepriano, A., Kerschbaumer, A., Smolen, J. S., van der Heijde, D., Dougados, M., van Vollenhoven, R., McInnes, I. B., Bijlsma, J. W., Burmester, G. R., de Wit, M., Falzon, L., Landewé, R. 2020; 79 (6): 760-770

  Abstract

  To perform a systematic literature review (SLR) concerning the safety of synthetic (s) and biological (b) disease-modifying anti rheumatic dugs (DMARDs) to inform the 2019 update of the EULAR recommendations for the management of rheumatoid arthritis (RA).An SLR of observational studies comparing safety outcomes of any DMARD with another intervention for the management of RA. A comparator group was required for inclusion. For treatments still without registry data (eg, sarilumab and the Janus kinase (JAK) inhibitors baricitinib, upadacitinib), randomised controlled trials (RCTs) and long-term extensions (LTEs) were used. Risk of bias (RoB) was assessed according to standard procedures.Forty-two observational studies fulfilled the inclusion criteria, addressing safety outcomes with bDMARDs and sDMARDs. Nine studies showed no difference in the risk of serious infections across bDMARDs and two studies (high RoB) showed an increased risk with bDMARDs compared with conventional synthetic (cs) DMARDs (adjusted incidence rate ratio 3.1-3.9). The risk of Herpes zoster infection was similar across bDMARDs, but one study showed an increased risk with tofacitinib compared with abatacept (adjusted HR (aHR) 2.0). Five studies showed no increased risk of cancer for bDMARDs compared with csDMARDs. An increased risk of lower intestinal perforation was found for tocilizumab compared with csDMARDs (aHR 4.5) and tumour necrosis factor inhibitor (TNFi) (aHR 2.6-4.0). Sixty manuscripts reported safety data from RCTs/LTEs. Overall, no unexpected safety outcomes were found, except for the possibly increased risk of venous thromboembolism (VTE) with JAK inhibitors.Data obtained by this SLR confirm the known safety profile of bDMARDs. The risk of VTE in RA, especially in patients on JAK inhibitors, needs further evaluation.

  View details for DOI 10.1136/annrheumdis-2019-216653

  View details for PubMedID 32033941

• Efficacy of pharmacological treatment in rheumatoid arthritis: a systematic literature research informing the 2019 update of the EULAR recommendations for management of rheumatoid arthritis. Annals of the rheumatic diseases Kerschbaumer, A., Sepriano, A., Smolen, J. S., van der Heijde, D., Dougados, M., van Vollenhoven, R., McInnes, I. B., Bijlsma, J. W., Burmester, G. R., de Wit, M., Falzon, L., Landewé, R. 2020; 79 (6): 744-759

  Abstract

  To inform the 2019 update of the European League against Rheumatism (EULAR) recommendations for the management of rheumatoid arthritis (RA).A systematic literature research (SLR) to investigate the efficacy of any disease-modifying antirheumatic drug (DMARD) (conventional synthetic (cs)DMARD, biological (b) and biosimilar DMARD, targeted synthetic (ts)DMARD) or glucocorticoid (GC) therapy in patients with RA was done by searching MEDLINE, Embase and the Cochrane Library for articles published between 2016 and 8 March 2019.234 abstracts were selected for detailed assessment, with 136 finally included. They comprised the efficacy of bDMARDs versus placebo or other bDMARDs, efficacy of Janus kinase (JAK) inhibitors (JAKi) across different patient populations and head-to-head of different bDMARDs versus JAKi or other bDMARDs. Switching of bDMARDs to other bDMARDs or tsDMARDs, strategic trials and tapering studies of bDMARDs, csDMARDs and JAKi were assessed. The drugs evaluated included abatacept, adalimumab, ABT-122, baricitinib, certolizumab pegol, SBI-087, CNTO6785, decernotinib, etanercept, filgotinib, golimumab, GCs, GS-9876, guselkumab, hydroxychloroquine, infliximab, leflunomide, mavrilimumab, methotrexate, olokizumab, otilimab, peficitinib, rituximab, sarilumab, salazopyrine, secukinumab, sirukumab, tacrolimus, tocilizumab, tofacitinib, tregalizumab, upadacitinib, ustekinumab and vobarilizumab. The efficacy of many bDMARDs and tsDMARDs was shown. Switching to another tumour necrosis factor inhibitor (TNFi) or non-TNFi bDMARDs after TNFi treatment failure is efficacious. Tapering of DMARDs is possible in patients achieving long-standing stringent clinical remission; in patients with residual disease activity (including patients in LDA) the risk of flares is increased during the tapering. Biosimilars are non-inferior to their reference products.This SLR informed the task force regarding the evidence base of various therapeutic regimen for the development of the update of EULAR's RA management recommendation.

  View details for DOI 10.1136/annrheumdis-2019-216656

  View details for PubMedID 32033937

  View details for PubMedCentralID PMC7286044

• EULAR recommendations for the management of psoriatic arthritis with pharmacological therapies: 2019 update. Annals of the rheumatic diseases Gossec, L., Baraliakos, X., Kerschbaumer, A., de Wit, M., McInnes, I., Dougados, M., Primdahl, J., McGonagle, D. G., Aletaha, D., Balanescu, A., Balint, P. V., Bertheussen, H., Boehncke, W. H., Burmester, G. R., Canete, J. D., Damjanov, N. S., Kragstrup, T. W., Kvien, T. K., Landewé, R. B., Lories, R. J., Marzo-Ortega, H., Poddubnyy, D., Rodrigues Manica, S. A., Schett, G., Veale, D. J., Van den Bosch, F. E., van der Heijde, D., Smolen, J. S. 2020; 79 (6): 700-712

  Abstract

  To update the European League Against Rheumatism (EULAR) recommendations for the pharmacological treatment of psoriatic arthritis (PsA).According to the EULAR standardised operating procedures, a systematic literature review was followed by a consensus meeting to develop this update involving 28 international taskforce members in May 2019. Levels of evidence and strengths of recommendations were determined.The updated recommendations comprise 6 overarching principles and 12 recommendations. The overarching principles address the nature of PsA and diversity of both musculoskeletal and non-musculoskeletal manifestations; the need for collaborative management and shared decision-making is highlighted. The recommendations provide a treatment strategy for pharmacological therapies. Non-steroidal anti-inflammatory drugs and local glucocorticoid injections are proposed as initial therapy; for patients with arthritis and poor prognostic factors, such as polyarthritis or monoarthritis/oligoarthritis accompanied by factors such as dactylitis or joint damage, rapid initiation of conventional synthetic disease-modifying antirheumatic drugs is recommended. If the treatment target is not achieved with this strategy, a biological disease-modifying antirheumatic drugs (bDMARDs) targeting tumour necrosis factor (TNF), interleukin (IL)-17A or IL-12/23 should be initiated, taking into account skin involvement if relevant. If axial disease predominates, a TNF inhibitor or IL-17A inhibitor should be started as first-line disease-modifying antirheumatic drug. Use of Janus kinase inhibitors is addressed primarily after bDMARD failure. Phosphodiesterase-4 inhibition is proposed for patients in whom these other drugs are inappropriate, generally in the context of mild disease. Drug switches and tapering in sustained remission are addressed.These recommendations provide stakeholders with an updated consensus on the pharmacological management of PsA, based on a combination of evidence and expert opinion.

  View details for DOI 10.1136/annrheumdis-2020-217159

  View details for PubMedID 32434812

  View details for PubMedCentralID PMC7286048

• EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Annals of the rheumatic diseases Smolen, J. S., Landewé, R. B., Bijlsma, J. W., Burmester, G. R., Dougados, M., Kerschbaumer, A., McInnes, I. B., Sepriano, A., van Vollenhoven, R. F., de Wit, M., Aletaha, D., Aringer, M., Askling, J., Balsa, A., Boers, M., den Broeder, A. A., Buch, M. H., Buttgereit, F., Caporali, R., Cardiel, M. H., De Cock, D., Codreanu, C., Cutolo, M., Edwards, C. J., van Eijk-Hustings, Y., Emery, P., Finckh, A., Gossec, L., Gottenberg, J. E., Hetland, M. L., Huizinga, T. W., Koloumas, M., Li, Z., Mariette, X., Müller-Ladner, U., Mysler, E. F., da Silva, J. A., Poór, G., Pope, J. E., Rubbert-Roth, A., Ruyssen-Witrand, A., Saag, K. G., Strangfeld, A., Takeuchi, T., Voshaar, M., Westhovens, R., van der Heijde, D. 2020; 79 (6): 685-699

  Abstract

  To provide an update of the European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) management recommendations to account for the most recent developments in the field.An international task force considered new evidence supporting or contradicting previous recommendations and novel therapies and strategic insights based on two systematic literature searches on efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) since the last update (2016) until 2019. A predefined voting process was applied, current levels of evidence and strengths of recommendation were assigned and participants ultimately voted independently on their level of agreement with each of the items.The task force agreed on 5 overarching principles and 12 recommendations concerning use of conventional synthetic (cs) DMARDs (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GCs); biological (b) DMARDs (tumour necrosis factor inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, sarilumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (the Janus kinase (JAK) inhibitors tofacitinib, baricitinib, filgotinib, upadacitinib). Guidance on monotherapy, combination therapy, treatment strategies (treat-to-target) and tapering on sustained clinical remission is provided. Cost and sequencing of b/tsDMARDs are addressed. Initially, MTX plus GCs and upon insufficient response to this therapy within 3 to 6 months, stratification according to risk factors is recommended. With poor prognostic factors (presence of autoantibodies, high disease activity, early erosions or failure of two csDMARDs), any bDMARD or JAK inhibitor should be added to the csDMARD. If this fails, any other bDMARD (from another or the same class) or tsDMARD is recommended. On sustained remission, DMARDs may be tapered, but not be stopped. Levels of evidence and levels of agreement were mostly high.These updated EULAR recommendations provide consensus on the management of RA with respect to benefit, safety, preferences and cost.

  View details for DOI 10.1136/annrheumdis-2019-216655

  View details for PubMedID 31969328

• Pharmacological treatment of psoriatic arthritis: a systematic literature research for the 2019 update of the EULAR recommendations for the management of psoriatic arthritis. Annals of the rheumatic diseases Kerschbaumer, A., Smolen, J. S., Dougados, M., de Wit, M., Primdahl, J., McInnes, I., van der Heijde, D., Baraliakos, X., Falzon, L., Gossec, L. 2020; 79 (6): 778-786

  Abstract

  To perform an update of a review of the efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) in psoriatic arthritis (PsA).This is a systematic literature research of 2015-2018 publications on all DMARDs in patients with PsA, searching Medline, Embase and the Cochrane Library. Efficacy was assessed in randomised controlled trials. For safety, cohort studies, case-control studies and long-term extensions (LTEs) were analysed.56 publications (efficacy: n=33; safety n=23) were analysed. The articles were on tumour necrosis factor (TNF) inhibitors (n=6; golimumab, etanercept and biosimilars), interleukin (IL)-17A inhibitors (n=10; ixekizumab, secukinumab), IL-23-p19 inhibitors (n=2; guselkumab, risankizumab), clazakizumab (IL-6 inhibitor), abatacept (CD80/86 inhibitor) and ABT-122 (anti-TNF/IL-17A), respectively. One study compared ustekinumab (IL-12/23i) with TNF inhibitor therapy in patients with entheseal disease. Three articles investigated DMARD tapering. Trials on targeted synthetic DMARDs investigated apremilast (phosphodiesterase-4 inhibitor) and Janus kinase inhibitors (JAKi; tofacitinib, filgotinib). Biosimilar comparison with bio-originator showed non-inferiority. Safety was evaluated in 13 LTEs, 9 cohort studies and 1 case-control study investigating malignancies, infections, infusion reactions, multiple sclerosis and major cardiovascular events, as well as efficacy and safety of vaccination. No new safety signals were identified; however, warnings on the risk of venous thromboembolic events including pulmonary embolism when using JAKi were issued by regulators based on other studies.Many drugs in PsA are available and have demonstrated efficacy against placebo. Efficacy varies across PsA manifestations. Safety must also be taken into account. This review informed the development of the European League Against Rheumatism 2019 updated PsA management recommendations.

  View details for DOI 10.1136/annrheumdis-2020-217163

  View details for PubMedID 32381564

• Targeting p19 in psoriatic arthritis: more than just another therapeutic approach? Lancet (London, England) Kerschbaumer, A., Aletaha, D. 2020; 395 (10230): 1091-1093

  View details for DOI 10.1016/S0140-6736(20)30525-0

  View details for PubMedID 32178770

• Risk profiling for a refractory course of rheumatoid arthritis. Seminars in arthritis and rheumatism Bécède, M., Alasti, F., Gessl, I., Haupt, L., Kerschbaumer, A., Landesmann, U., Loiskandl, M., Supp, G. M., Smolen, J. S., Aletaha, D. 2019; 49 (2): 211-217

  Abstract

  Despite modern therapeutics and treatment strategies, a subset of rheumatoid arthritis (RA) patients remains insufficiently responsive to multiple therapies. Here, we identify predictors of such refractory RA ("reRA").Patients from a longitudinal academic clinical database with reRA (defined as failing to reach the treatment target of at least low disease activity with ≥3 DMARD courses, including ≥1 biological, over a total of ≥18 months) were compared to patients who did respond within the first two treatments (treatment amenable RA, "taRA"). We performed logistic regression analysis to identify risk factors for refractory disease, and several sensitivity analyses concerning different potential definitions for reRA to confirm the robustness of the results; key findings were also validated in an independent community cohort.We enrolled 412 patients, of whom 70 were reRA and 102 taRA; 240 patients fulfilled neither definition. ReRA patients were more frequently female (92.9 vs. 70.6%, p < 0.001), younger (44.37 vs. 51.14 years, p = 0.002), and had higher CDAI levels at first presentation (26.06 vs. 15.39, p < 0.001). Treatment delay was significantly longer for reRA than for taRA (3.17 vs. 1.45 years, p = 0.001). In multivariable analyses, treatment delay, female gender and higher disease activity remained as independent predictors of refractory disease. Based on the identified predictors, we developed a matrix model for risk of future reRA.Our data identified delay to initial treatment, female gender and higher disease activity as important predictors of a later refractory course of RA. Delay of treatment initiation is the single most important modifiable risk factor of refractory disease.

  View details for DOI 10.1016/j.semarthrit.2019.02.004

  View details for PubMedID 30799033

• Disease activity assessment in patients with psoriatic arthritis. Best practice & research. Clinical rheumatology Kerschbaumer, A., Smolen, J. S., Aletaha, D. 2018; 32 (3): 401-414

  Abstract

  Psoriatic arthritis (PsA) is an inflammatory disease in patients with a personal or family history of psoriasis. While synovitis is the major hallmark, enthesitis, dactylitis, axial inflammation, and skin and nail involvement are variable in prevalence and severity. The assessment of disease activity is important to determine the treatment target ("Treat-to-Target") as well as early response to therapy, because a prolonged ineffective medication may not only be associated with an adverse disease outcome but constitutes a waste of individual and/or societal expenses. Various measures of disease activity have been established for all manifestations individually ('uni-dimensional approach') or by combining such measures into a single umbrella score ('multi-dimensional approach'). Because pathogeneses and therapeutic responsiveness differ among individual domains, a uni-dimensional approach is preferred. The major uni-dimensional index is the Disease Activity index for PSoriatic Arthritis, which provides a continuous scale and allows calculating disease activity at any point in time, determining response to therapy and defining disease activity states, such as remission, as a treatment target. The assessment of the various domains by individual and combined indices is discussed.

  View details for DOI 10.1016/j.berh.2018.08.004

  View details for PubMedID 31171311

• Tofacitinib for Psoriatic Arthritis. The New England journal of medicine Aletaha, D., Kerschbaumer, A., Smolen, J. S. 2018; 378 (8): 775

  View details for DOI 10.1056/NEJMc1715189

  View details for PubMedID 29469555

• The Case | Myeloid bodies in the kidney biopsy of a patient with systemic lupus erythematosus. Kidney international Bojic, M., Kozakowski, N., Bécède, M., Kerschbaumer, A., Bobacz, K. 2017; 92 (1): 271-272

  View details for DOI 10.1016/j.kint.2016.12.025

  View details for PubMedID 28647000

• Fever of unknown origin (FUO) revised. Wiener klinische Wochenschrift Unger, M., Karanikas, G., Kerschbaumer, A., Winkler, S., Aletaha, D. 2016; 128 (21-22): 796-801

  Abstract

  Fever of unknown origin (FUO) was originally characterised in 1961 by Petersdorf and Beeson as a disease condition of temperature exceeding 38.3 °C on at least three occasions over a period of at least three weeks, with no diagnosis made despite one week of inpatient investigation. However, since underlying diseases are often reported for classical FUO, these presentations may not be considered to be of "unknown origin". Rather, the aetiology of prolonged fever may resolve, or not resolve. The definition of fever with unresolved cause (true FUO) is difficult, as it is a moving target, given the constant advancement of imaging and biomarker analysis. Therefore, the prevalence of fever with unresolved cause (FUO) is unknown.In this review, we report such a case of prolonged fever, which initially has presented as classical FUO, and discuss current literature. Furthermore, we will give an outlook, how a prospective study on FUO will allow to solve outstanding issues like the utility of different diagnostic investigations, and the types and prevalence of various underlying diseases.

  View details for DOI 10.1007/s00508-016-1083-9

  View details for PubMedID 27670857

  View details for PubMedCentralID PMC5104815

• An overview of psoriatic arthritis - epidemiology, clinical features, pathophysiology and novel treatment targets. Wiener klinische Wochenschrift Kerschbaumer, A., Fenzl, K. H., Erlacher, L., Aletaha, D. 2016; 128 (21-22): 791-795

  Abstract

  Psoriatic arthritis is a chronic inflammatory joint disease occurring in a subgroup of patients suffering from psoriasis. This article gives an overview of the complexity of psoriatic arthritis, looking at several aspects of this heterogeneous disease, such as epidemiology, important clinical features and comorbidities as well as current concepts of the pathophysiology and subsequent insights in novel treatment targets.

  View details for DOI 10.1007/s00508-016-1111-9

  View details for PubMedID 27822746

  View details for PubMedCentralID PMC5104808