Bio


Dr. Chung is an Associate Professor of Medicine (Immunology and Rheumatology) and Dermatology at Stanford University School of Medicine. Dr. Chung initiated and developed the Stanford Scleroderma Program which focuses on three major goals: 1) To provide outstanding, comprehensive, multi-disciplinary care for patients with systemic sclerosis and related diseases; 2) To maintain a detailed clinical database and biorepository of SSc tissue samples to perform collaborative epidemiological and translational studies; 3) To conduct industry-sponsored and investigator-initiated clinical trials of novel therapeutic agents for the treatment of SSc. The Scleroderma Program has grown dramatically since its conception, and Dr. Chung now leads a team of over 15 clinicians and researchers focused on SSc patient care and research. Dr. Chung has a vast amount of experience in SSc clinical trial design and enrollment, and has completed five investigator-initiated clinical trials, all of which included collaborative translational studies to better understand the mechanism of action of novel agents in the SSc population.

Clinical Focus


  • Immunology and Rheumatology
  • Rheumatology
  • Scleroderma, Systemic
  • Connective Tissue Diseases

Academic Appointments


Administrative Appointments


  • Member, Pulmonary Hypertension Association Scientific Leadership Council (2014 - Present)
  • Abstract Reviewer, Scleroderma World Congress Meeting (2013 - 2013)
  • Member, Medical Advisory Board for Scleroderma Foundation (2012 - Present)
  • Secretary/Clerk, Scleroderma Clinical Trials Consortium (2011 - Present)
  • Lead Guest Editor, International Journal of Rheumatology, Special Issues on Systemic Sclerosis (2010 - 2011)
  • Abstract Reviewer, American College of Rheumatology Annual Meeting (2010 - 2010)
  • Instructor, Meet the Professor session at the American College of Rheumatology Annual Meeting (2008 - 2008)
  • Medical Advisor, Scleroderma Foundation Northern California Chapter (2008 - Present)
  • Grant Reviewer, The Raynaud's & Scleroderma Association (2007 - 2007)
  • Contributor, Scleroderma Research Foundation Insights newsletter (2006 - 2006)
  • Proposal Reviewer, Department of Defense, Peer Reviewed Medical Research Program (2006 - 2006)
  • Protocol Reviewer, FWF Austrian Science Fund (2005 - 2005)
  • Contributor, American College of Rheumatology Fellows Reading List (2004 - 2004)
  • Co-director, Internal Medicine Residency Support Group, Stanford University School of Medicine (2002 - 2002)

Honors & Awards


  • Department of Medicine, Division of Immunology & Rheumatology Teaching Award, Stanford School of Medicine (2014)
  • Office of Diversity and Leadership Faculty Fellow, Stanford University School of Medicine (2012)
  • Travel Award, Scleroderma Clinical Trials Consortium (2007)
  • Distinguished Fellow Award, American College of Rheumatology (2006)
  • Faculty Fellowship, Center for Clinical Immunology at Stanford (2006)
  • Dean's Postdoctoral Research Fellowship Award, Stanford University (2005)
  • Attendee, Clinical Immunology Society Spring School (2005)
  • Katherine McCormick Fund for Women Travel Grant, Stanford University (2004)
  • Departmental Award in Internal Medicine, Ohio State University College of Medicine (2000)
  • Frederick H. Shillito Award for Project: An Epidemiologic Study of Dengue Fever in Puerto Rico, Ohio State University School of Public Health Research (2000)
  • Janet M. Glasgow Memorial Award, Ohio State University College of Medicine (2000)
  • Alpha Omega Alpha Honor Medical Society, Ohio State University College of Medicine (2000)
  • High Honors in Molecular Biology, Princeton University (1996)
  • Phi Beta Kappa Society, Princeton University (1996)

Boards, Advisory Committees, Professional Organizations


  • Associate Program Director for Rheumatology Fellowship, Stanford University (2014 - Present)
  • Preceptor for residents on Women's Health Clerkship, Stanford University (2009 - Present)
  • Mentor at Fellows-in-training Scholarship Educational Session, American College of Rheumatology Annual Meeting (2013 - 2013)
  • Director of Women's Rheumatology Clinic, Women's Health Center of Excellence, Palo Alto Veteran Affairs Health Care System (2009 - Present)
  • Preceptor for medical students in Ambulatory Medicine Clerkship at the Palo Alto Veteran Affairs Hospital, Stanford University School of Medicine (2006 - Present)
  • Rheumatology didactic sessions for fellows, residents, and medical students, Stanford University School of Medicine (2006 - Present)
  • Preceptor for fellows, residents, and medical students in Rheumatology Clinic, Palo Alto Veteran Affairs Hospital (2006 - Present)
  • Preceptor for fellows and residents in Rheumatologic Dermatology Clinic, Stanford University School of Medicine (2006 - Present)
  • Rheumatology consult attending for fellows and residents, Stanford University Hospital and Palo Alto Veteran Affairs Hospital (2006 - Present)
  • Internal Medicine ward attending for residents and medical students, Palo Alto Veteran Affairs Hospital (2006 - Present)
  • Rheumatology lecture series for Internal Medicine residents, Stanford University School of Medicine (2005 - Present)
  • Lecture series for Dermatology residents, Stanford University School of Medicine (2005 - Present)

Professional Education


  • Medical Education:Ohio State University College of Medicine Registrar (2000) OH
  • Fellowship:Stanford University School of Medicine (2006) CA
  • Board Certification: Rheumatology, American Board of Internal Medicine (2005)
  • Residency:Stanford University School of Medicine (2003) CA
  • AB, Princeton University, Molecular Biology (1996)
  • MD, Ohio State University, Medicine (2000)
  • MS, Stanford University, Epidemiology (2007)

Patents


  • Lorinda Chung, Howard Chang, William Robinson, David Fiorentino. "United States Patent 61/147,983 Profiling for Determination of Response to Treatment for Inflammatory Disease", Leland Stanford Junior University School of Medicine, Jan 28, 2009

Current Research and Scholarly Interests


My research interests focus on all aspects of systemic sclerosis. I am currently involved in clinical, translational, and epidemiologic research in these areas, and dedicate a substantial portion of my research time to investigator-initiated and multi-center clinical trials of novel therapeutics for the treatment of systemic sclerosis. I collaborate closely with the Department of Dermatology and multiple divisions in the Department of Medicine (Pulmonary, Cardiology, Gastroenterology) in the ongoing study of molecular and clinical responses to novel therapeutics for the treatment of systemic sclerosis, with the goal of identifying useful biomarkers from skin and blood samples. I am especially interested in the vascular disease related to systemic sclerosis, including investigating the pathogenesis, biomarkers, and potential treatments for pulmonary arterial hypertension and digital ulceration. In addition to research, I am devoted to providing superb care to patients with systemic sclerosis and related rheumatic diseases. I am absolutely committed to further developing the Stanford Scleroderma Center of Excellence where we will provide outstanding comprehensive patient care, and we will perform state-of-the-art research to better understand the pathogenesis of systemic sclerosis, and ultimately to develop new treatments for this devastating disease. Lastly, I am actively involved in teaching and mentoring medical students, housestaff, and fellows and encouraging the brightest minds of the future to pursue careers in scleroderma research.

Clinical Trials


  • A Pilot Study to Evaluate the Safety and Efficacy of Oral Treprostinil in the Treatment of Calcinosis in Patients With Systemic Sclerosis Recruiting

    This is a prospective open-label trial that will enroll 12 patients with systemic sclerosis (SSc) and at least one calcinotic lesion of the hands that is palpable on physical examination and also measureable on hand radiographs, at one single center. Each subject will receive treprostinil orally for 12 months, and follow-up evaluations will be performed every 3 months. Our main objective is to determine whether oral treprostinil is safe, and effective in reducing calcinosis in patients with SSc. We hypothesize that calcinosis is a result of microvascular injury and ischemic damage, and that therefore treprostinil may be beneficial in the treatment of calcinosis in patients with SSc.

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  • A Study of Subcutaneous Abatacept to Treat Diffuse Cutaneous Systemic Sclerosis Recruiting

    The study hypothesis is that SC abatacept is safe and shows evidence of efficacy (improvement in modified Rodnan score [mRSS]) in patients with diffuse cutaneous systemic sclerosis (dcScc) compared to matching placebo.

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  • Functional Luminal Imaging Probe (FLIP) Topography Use in Patients With Scleroderma and Trouble Swallowing Recruiting

    FLIP topography has been FDA cleared to evaluate a variety of esophageal conditions, but has never been evaluated in patients with scleroderma. The investigators hope to evaluate this technology in patients who have scleroderma and various esophageal symptoms, and compare to non-scleroderma patients.

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  • Rituximab for Treatment of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension (SSc-PAH) Recruiting

    Systemic sclerosis-associated pulmonary arterial hypertension (SSc-PAH) is a serious, life-threatening manifestation of systemic sclerosis (SSc), an autoimmune disease of the connective tissue characterized by scarring (fibrosis) and atrophy of the skin, joints and tendons, skeletal muscles, and internal organs, and immunological disturbances. One-year survival for patients with SSc-PAH ranges from 50-81%. There is currently no cure for SSc-PAH and treatment is limited to vasodilator therapy used in all forms of PAH. In recent studies, immunotherapy was shown to be effective in treating SSc-interstitial lung disease, another serious, life-threatening manifestation of SSc. In addition, there are compelling pre-clinical data and anecdotal clinical reports that suggest modulation of the immune system may be an effective strategy for treating SSc-PAH. To test this approach, this trial will determine if rituximab, an immunotherapy, has a marked beneficial effect on clinical disease progression, with minimal toxicity, in patients with SSc-PAH when compared to placebo.

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  • A Study of RoActemra/Actemra (Tocilizumab) Versus Placebo in Patients With Systemic Sclerosis Not Recruiting

    This multicenter, randomized, double-blind, placebo-controlled, two-arm, parallel-group study will evaluate the efficacy and safety of RoActemra/Actemra (tocilizumab) in participants with systemic sclerosis. Participants will be randomized to receive either RoActemra/Actemra 162 mg subcutaneously weekly or placebo for 48 weeks. From Week 48 to Week 96, all participants will receive open-label RoActemra/Actemra 162 mg subcutaneously weekly. Anticipated time on study treatment is 96 weeks.

    Stanford is currently not accepting patients for this trial. For more information, please contact Amanda Foster, (650) 721 - 7147.

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  • A Study to Evaluate the Efficacy of an Oral Medication in the Treatment and Prevention of Digital Ulcers in Patients With Systemic Sclerosis (Scleroderma). Not Recruiting

    This is a research study of an investigational drug called ambrisentan (Letairis) in the treatment and prevention of digital ulcers in patients with systemic sclerosis.

    Stanford is currently not accepting patients for this trial.

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  • Imatinib in Systemic Sclerosis Not Recruiting

    Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs and widespread vasculopathy. Patients with SSc are classified according to the extent of cutaneous sclerosis: patients with limited SSc have skin thickening of the face, neck, and distal extremities, while those with diffuse SSc have involvement of the trunk, abdomen, and proximal extremities as well. The disease course varies depending on the subtype of SSc. However, common features that result in significant morbidity and mortality, in addition to cutaneous fibrosis, include Raynaud's phenomenon and digital ulcerations, interstitial lung disease (ILD), and pulmonary arterial hypertension (PAH). Current therapeutic options for patients with SSc and these clinical manifestations have shown limited efficacy. Imatinib antagonizes specific tyrosine kinases that mediate fibrotic pathways involved in the pathogenesis of SSc, including c-Abl, a downstream mediator of transforming growth factor (TGF)-beta, and platelet derived growth factor (PDGF) receptors. The efficacy of imatinib has also been reported in the treatment of patients with refractory idiopathic PAH through its effects on vascular remodeling. Based on the mechanism of action and preliminary patient data, we hypothesize that imatinib may be effective in the treatment of the fibrotic and vasculopathic features of patients with SSc. This is an open label pilot study to evaluate the safety and efficacy of imatinib in patients with progressive SSc refractory to other treatment(s). Validated measures of skin thickness and disease activity will be determined over 6-months of therapy and compared with baseline measures.

    Stanford is currently not accepting patients for this trial.

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  • Safety and Tolerability of Pirfenidone in Participants With Systemic Sclerosis−Related Interstitial Lung Disease (SSc-ILD) (LOTUSS) Not Recruiting

    PSSc-001 (LOTUSS) This study is a Phase 2, multinational, open-label, randomized, parallel-group, safety and tolerability study of pirfenidone in participants with systemic sclerosis−related interstitial lung disease (SSc-ILD).

    Stanford is currently not accepting patients for this trial.

    View full details

2018-19 Courses


Stanford Advisees


All Publications


  • Whole-Exome Sequencing to Identify Rare Variants and Gene Networks That Increase Susceptibility to Scleroderma in African Americans ARTHRITIS & RHEUMATOLOGY Gourh, P., Remmers, E. F., Boyden, S. E., Alexander, T., Morgan, N. D., Shah, A. A., Mayes, M. D., Doumatey, A., Bentley, A. R., Shriner, D., Domsic, R. T., Medsger, T. A., Steen, V. D., Ramos, P. S., Silver, R. M., Korman, B., Varga, J., Schiopu, E., Khanna, D., Hsu, V., Gordon, J. K., Saketkoo, L., Gladue, H., Kron, B., Criswell, L. A., Derk, C. T., Bridges, S., Shanmugam, V. K., Kolstad, K. D., Chung, L., Jan, R., Bernstein, E. J., Goldberg, A., Trojanowski, M., Kafaja, S., Maksimowicz-McKinnon, K. M., Mullikin, J. C., Adeyemo, A., Rotimi, C., Boin, F., Kastner, D. L., Wigley, F. M. 2018; 70 (10): 1654–60

    Abstract

    Whole-exome sequencing (WES) studies in systemic sclerosis (SSc) patients of European American (EA) ancestry have identified variants in the ATP8B4 gene and enrichment of variants in genes in the extracellular matrix (ECM)-related pathway that increase SSc susceptibility. This study was undertaken to evaluate the association of the ATP8B4 gene and the ECM-related pathway with SSc in a cohort of African American (AA) patients.SSc patients of AA ancestry were enrolled from 23 academic centers across the US under the Genome Research in African American Scleroderma Patients consortium. Unrelated AA individuals without serologic evidence of autoimmunity who were enrolled in the Howard University Family Study were used as unaffected controls. Functional variants in genes reported in the 2 WES studies in EA patients with SSc were selected for gene association testing using the optimized sequence kernel association test (SKAT-O) and pathway analysis by Ingenuity Pathway Analysis in 379 patients and 411 controls.Principal components analysis demonstrated that the patients and controls had similar ancestral backgrounds, with roughly equal proportions of mean European admixture. Using SKAT-O, we examined the association of individual genes that were previously reported in EA patients and none remained significant, including ATP8B4 (P = 0.98). However, we confirmed the previously reported association of the ECM-related pathway with enrichment of variants within the COL13A1, COL18A1, COL22A1, COL4A3, COL4A4, COL5A2, PROK1, and SERPINE1 genes (corrected P = 1.95 × 10-4 ).In the largest genetic study in AA patients with SSc to date, our findings corroborate the role of functional variants that aggregate in a fibrotic pathway and increase SSc susceptibility.

    View details for DOI 10.1002/art.40541

    View details for Web of Science ID 000445723200016

    View details for PubMedID 29732714

    View details for PubMedCentralID PMC6160338

  • Risk Factors for Mortality and Cardiopulmonary Hospitalization in Systemic Sclerosis Patients At Risk for Pulmonary Hypertension, in the PHAROS Registry. The Journal of rheumatology Hsu, V. M., Chung, L., Hummers, L. K., Shah, A., Simms, R., Bolster, M., Hant, F. N., Silver, R. M., Fischer, A., Hinchcliff, M. E., Varga, J., Goldberg, A. Z., Derk, C. T., Schiopu, E., Khanna, D., Shapiro, L. S., Domsic, R. T., Medsger, T., Mayes, M. D., Furst, D., Csuka, M. E., Molitor, J. A., Saketkoo, L. A., Salazar, C. R., Steen, V. D. 2018

    Abstract

    OBJECTIVE: We sought to identify predictors of mortality and cardiopulmonary hospitalizations in patients at risk for pulmonary hypertension (PH) and enrolled in PHAROS, a prospective cohort study to investigate the natural history of PH in systemic sclerosis (SSc).METHODS: The at-risk population for PH was defined by the following entry criteria: echocardiogram systolic pulmonary arterial pressure > 40 mmHg, or DLCO < 55% predicted or ratio of % forced vital capacity/%DLCO > 1.6, measured by pulmonary function testing. Baseline clinical measures were evaluated as predictors of hospitalization and death between 2005 and 2014. Cox proportional hazards models were censored at date of PH onset or latest study visit and adjusted for age, sex, race, and disease duration.RESULTS: Of the 236 at-risk subjects who were followed for a median of 4 years (range 0.4-8.5 yrs), 35 developed PH after entering PHAROS (reclassified as PH group). In the at-risk group, higher mortality was strongly associated with male sex, low %DLCO, exercise oxygen desaturation, anemia, abnormal dyspnea scores, and baseline pericardial effusion. Risks for cardiopulmonary hospitalization were associated with increased dyspnea and pericardial effusions, although PH patients with DLCO < 50% had the highest risk of cardiopulmonary hospitalizations.CONCLUSION: Risk factors for poor outcome in patients with SSc who are at risk for PH were similar to others with SSc-PH and SSc-pulmonary arterial hypertension, including male sex, DLCO < 50%, exercise oxygen desaturation, and pericardial effusions. This group should undergo right heart catheterization and receive appropriate intervention if PH is confirmed.

    View details for DOI 10.3899/jrheum.180018

    View details for PubMedID 30275260

  • The Scleroderma Patient-Centered Intervention Network Cohort: baseline clinical features and comparison with other large scleroderma cohorts RHEUMATOLOGY Dougherty, D. H., Kwakkenbos, L., Carrier, M., Salazar, G., Assassi, S., Baron, M., Bartlett, S. J., Furst, D. E., Gottesman, K., van den Hoogen, F., Malcarne, V. L., Mouthon, L., Nielson, W. R., Poiraudeau, S., Sauve, M., Boire, G., Bruns, A., Chung, L., Denton, C., Dunne, J. V., Fortin, P., Frech, T., Gill, A., Gordon, J., Herrick, A. L., Hinchcliff, M., Hudson, M., Johnson, S. R., Jones, N., Kafaja, S., Larche, M., Manning, J., Pope, J., Spiera, R., Steen, V., Sutton, E., Thorne, C., Wilcox, P., Thombs, B. D., Mayes, M. D., SPIN Investigators 2018; 57 (9): 1623–31

    Abstract

    The Scleroderma Patient-centered Intervention Network (SPIN) Cohort is a web-based cohort designed to collect patient-reported outcomes at regular intervals as a framework for conducting trials of psychosocial, educational, self-management and rehabilitation interventions for patients with SSc. The aim of this study was to present baseline demographic, medical and patient-reported outcome data of the SPIN Cohort and to compare it with other large SSc cohorts.Descriptive statistics were used to summarize SPIN Cohort characteristics; these were compared with published data of the European Scleroderma Trials and Research (EUSTAR) and Canadian Scleroderma Research Group (CSRG) cohorts.Demographic, organ involvement and antibody profile data for SPIN (N = 1125) were generally comparable with that of the EUSTAR (N = 7319) and CSRG (N = 1390) cohorts. There was a high proportion of women and White patients in all cohorts, though relative proportions differed. Scl70 antibody frequency was highest in EUSTAR, somewhat lower in SPIN, and lowest in CSRG, consistent with the higher proportion of interstitial lung disease among dcSSc patients in SPIN compared with in CSRG (48.5 vs 40.3%). RNA polymerase III antibody frequency was highest in SPIN and remarkably lower in EUSTAR (21.1 vs 2.4%), in line with the higher prevalence of SSc renal crisis (4.5 vs 2.1%) in SPIN.Although there are some differences, the SPIN Cohort is broadly comparable with other large prevalent SSc cohorts, increasing confidence that insights gained from the SPIN Cohort should be generalizable, although it should be noted that all three cohorts include primarily White participants.

    View details for DOI 10.1093/rheumatology/key139

    View details for Web of Science ID 000443544700019

    View details for PubMedID 29868924

  • Strong HLA and Novel Non-HLA Associations Identified By Auto-Antibody Subset Analysis of African Americans with Scleroderma from the Genome Research in African American Scleroderma Patients Cohort Gourh, P., Remmers, E. F., Alexander, T., Boyden, S., Morgan, N. D., Shah, A. A., Mayes, M. D., Doumatey, A., Bentley, A., Shriner, D., Domsic, R. T., Medsger, T. A., Steen, V. D., Ramos, P. S., Silver, R., Korman, B. D., Varga, J., Schiopu, E., Khanna, D., Hsu, V., Gordon, J. K., Saketkoo, L., Gladue, H., Kron, B., Criswell, L. A., Derk, C. T., Bridges, S., Shanmugam, V., Kolstad, K. D., Chung, L., Jan, R., Bernstein, E. J., Goldberg, A., Trojanowski, M., Kafaja, S., Maksimowicz-McKinnon, K., Chandrasekharappa, S. C., Adeyemo, A., Rotimi, C., Wigley, F. M., Boin, F., Kastner, D. L. WILEY. 2018
  • Abatacept Vs. Placebo in Early Diffuse Cutaneous Systemic Sclerosis-Results of a Phase 2 Investigator Initiated, Double- Blind, Placebo-Controlled, Multicenter, Randomized Controlled Trial Study Khanna, D., Spino, C., Bush, E., Johnson, S., Chung, L., Molitor, J., Steen, V. D., Lafyatis, R., Simms, R. W., Denton, C. P., Kafaja, S., Frech, T. M., Hsu, V., Domsic, R. T., Pope, J. E., Gordon, J. K., Mayes, M. D., Schiopu, E., Young, A., Sandorfi, N., Park, J., Hant, F. N., Bernstein, E. J., Chatterjee, S., Castelino, F. V., Ajam, A., Allanore, Y., Matucci-Cerinic, M., Distler, O., Singer, O., Zhong, H., Fox, D., Furst, D. E. WILEY. 2018
  • HLA Contributions to Risk and Protection for Anti-Centromere Autoantibody-Positive Scleroderma Remmers, E. F., Alexander, T., Morgan, N. D., Shah, A. A., Mayes, M. D., Adeyemo, A., Doumatey, A., Bentley, A., Shriner, D., Chandrasekharappa, S. C., Carns, M. A., Chung, L., Criswell, L. A., Derk, C. T., Domsic, R. T., Gladue, H., Goldberg, A., Gordon, J. K., Hsu, V., Jan, R., Khanna, D., Medsger, T. A., Ramos, P. S., Trojanowski, M. A., Saketkoo, L., Schiopu, E., Shanmugam, V., Korman, B. D., Kron, B., Louis Bridges, S., Kolstad, K. D., Bernstein, E. J., Kafaja, S., Maksimowicz-McKinnon, K., Silver, R., Steen, V. D., Varga, J., Rotimi, C., Boin, F., Wigley, F. M., Kastner, D. L., Gourh, P. WILEY. 2018
  • Safety and Efficacy of Lenabasum in an Open-Label Extension of a Phase 2 Study in Diffuse Cutaneous Systemic Sclerosis Subjects Spiera, R. F., Hummers, L. K., Chung, L., Frech, T. M., Domsic, R. T., Hsu, V., Furst, D. E., Gordon, J. K., Mayes, M. D., Simms, R. W., Lee, E., Constantine, S., White, B. WILEY. 2018
  • Rituximab Versus Mycophenolate Mofetil in Interstitial Lung Disease Secondary to Connective Tissue Disease Zhu, L., Li, S., Gagne, L., Jacobs, S., Morisset, J., Mooney, J., Raj, R., Chung, L. WILEY. 2018
  • Increased Mortality in Black and Asian Patients with Systemic Sclerosis in Northern California Chung, M., Dontsi, M., Postlethwaite, D., Kesh, S., Zaba, L., Chung, L. WILEY. 2018
  • Identification of Risk Factors for Gastric Antral Vascular Ectasia (GAVE) Among Systemic Sclerosis Patients Serling-Boyd, N., Li, S., Fiorentino, D., Becker, L., Fernandez-Becker, N., Clarke, J., Chung, L. WILEY. 2018
  • Multi-Organ RNA-Sequencing of Patients with Systemic Sclerosis (SSc) Finds That Intrinsic Subsets Are Conserved across Organ Systems Mehta, B. K., Franks, J., Wang, Y., Cai, G., Toledo, D. M., Wood, T. A., Archambault, K. A., Kosarek, N., Kolstad, K. D., Stark, M., Valenzuela, A., Fiorentino, D., Fernandez-Becker, N., Becker, L., Nguyen, L., Clarke, J., Boin, F., Wolters, P., Chung, L., Whitfield, M. L. WILEY. 2018
  • Calcinosis in scleroderma. Current opinion in rheumatology Valenzuela, A., Song, P., Chung, L. 2018

    Abstract

    PURPOSE OF REVIEW: To provide an update on the available literature regarding the epidemiology, pathophysiology, diagnosis, and treatment of calcinosis cutis in patients with systemic sclerosis (SSc).RECENT FINDINGS: We identified observational studies that describe the frequency of calcinosis in SSc and associated clinical features; molecular studies exploring potential pathogenic mechanisms; and case reports and case series describing new diagnostic approaches and treatments.SUMMARY: Calcinosis cutis is the deposition of insoluble calcium in the skin and subcutaneous tissues. It represents a major clinical problem in patients with SSc affecting at least one quarter of patients. It is associated with longer disease duration, digital ulcers, acro-osteolysis, positive anticentromere antibody, and positive anti-PM/Scl antibody. Although pathogenesis is unknown, there is evidence supporting local trauma, chronic inflammation, vascular hypoxia, and dysregulation of bone matrix proteins as potential mechanisms. Diagnosis can be made clinically or with plain radiography. Several pharmacologic therapies have been tried for calcinosis with variable and modest results, but surgical excision of calcium deposits remains the mainstay of treatment.

    View details for DOI 10.1097/BOR.0000000000000539

    View details for PubMedID 30124603

  • Clinical significance of autoantibodies in dermatomyositis and systemic sclerosis CLINICS IN DERMATOLOGY Tartar, D. M., Chung, L., Fiorentino, D. F. 2018; 36 (4): 508–24

    Abstract

    Autoimmune connective tissue diseases, including dermatomyositis and systemic sclerosis, have a heterogeneous clinical presentation and prognosis; moreover, their clinical features are often incomplete and overlap with other rheumatic disorders, which can make diagnosis and prognostic stratification challenging. Specific autoantibodies have been associated with certain clinical findings as well as prognostic implications, and many new associations have been made over the last decade. Although patient populations manifest considerable heterogeneity, autoantibodies can be used to help predict clinical features, prognosis, and response to therapy. In this review, the clinical and prognostic implications associated with disease-specific autoantibodies in dermatomyositis and scleroderma are summarized with an emphasis on how the clinician can use this information for patient care.

    View details for DOI 10.1016/j.clindermatol.2018.04.008

    View details for Web of Science ID 000439763200008

    View details for PubMedID 30047434

  • Long-term Outcomes in Systemic Sclerosis Associated Pulmonary Arterial Hypertension from the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma Registry (PHAROS). Chest Kolstad, K. D., Li, S., Steen, V., Chung, L., PHAROS investigators 2018

    Abstract

    BACKGROUND: Pulmonary arterial hypertension (PAH) is a leading cause of death in patients with systemic sclerosis (SSc). The purpose of this study was to assess long-term outcomes in patients with SSc-PAH.METHODS: Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma is a prospective registry of SSc patients at high risk for or with incident pulmonary hypertension based on right heart catheterization (RHC). Incident World Health Organization Group I PAH patients were analyzed. Kaplan-Meier survival curves were generated for the overall cohort and those who died of PAH. Multivariate cox regression models identified predictors of mortality.RESULTS: Survival in 160 incident SSc-PAH patients at 1, 3, 5, and 8-years was 95%, 75%, 63%, and 49%, respectively. PAH accounted for 52% of all deaths. When restricted to deaths due to PAH, respective survival rates were 97%, 83%, 76%, and 76%, with 93% of PAH-related deaths occurring within 4 years of diagnosis. Male sex (HR 3.11 95%CI 1.38-6.98), diffuse disease (HR 2.12 95%CI 1.13-3.93), systolic pulmonary artery pressure (PAP) on echocardiogram (HR 1.06 95%CI 1.01-1.11), mean PAP on RHC (HR 1.03 95%CI 1001-1.07), six-minute walk distance (HR 0.92 95%CI 0.86-0.99), and diffusing capacity for carbon monoxide (HR 0.65 95% CI 0.46-0.92) significantly impacted survival on multivariate analysis.CONCLUSION: Overall survival in PHAROS was higher than other SSc-PAH cohorts. PAH accounted for more than half of deaths and primarily within the first few years after PAH diagnosis. Optimization of treatment for those at greatest risk of early PAH-related death is crucial.

    View details for DOI 10.1016/j.chest.2018.05.002

    View details for PubMedID 29777655

  • Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study ANNALS OF THE RHEUMATIC DISEASES Herrick, A. L., Peytrignet, S., Lunt, M., Pan, X., Hesselstrand, R., Mouthon, L., Silman, A. J., Dinsdale, G., Brown, E., Czirjak, L., Distler, J. W., Distler, O., Fligelstone, K., Gregory, W. J., Ochiel, R., Vonk, M. C., Ancuta, C., Ong, V. H., Farge, D., Hudson, M., Matucci-Cerinic, M., Balbir-Gurman, A., Midtvedt, O., Jobanputra, P., Jordan, A. C., Stevens, W., Moinzadeh, P., Hall, F. C., Agard, C., Anderson, M. E., Diot, E., Madhok, R., Akil, M., Buch, M. H., Chung, L., Damjanov, N. S., Gunawardena, H., Lanyon, P., Ahmad, Y., Chakravarty, K., Jacobsen, S., MacGregor, A. J., McHugh, N., Mueller-Ladner, U., Riemekasten, G., Becker, M., Roddy, J., Carreira, P. E., Fauchais, A., Hachulla, E., Hamilton, J., Inanc, M., McLaren, J. S., van Laar, J. M., Pathare, S., Proudman, S. M., Rudin, A., Sahhar, J., Coppere, B., Serratrice, C., Sheeran, T., Veale, D. J., Grange, C., Trad, G., Denton, C. P. 2018; 77 (4): 563–70

    Abstract

    Our aim was to use the opportunity provided by the European Scleroderma Observational Study to (1) identify and describe those patients with early diffuse cutaneous systemic sclerosis (dcSSc) with progressive skin thickness, and (2) derive prediction models for progression over 12 months, to inform future randomised controlled trials (RCTs).The modified Rodnan skin score (mRSS) was recorded every 3 months in 326 patients. 'Progressors' were defined as those experiencing a 5-unit and 25% increase in mRSS score over 12 months (±3 months). Logistic models were fitted to predict progression and, using receiver operating characteristic (ROC) curves, were compared on the basis of the area under curve (AUC), accuracy and positive predictive value (PPV).66 patients (22.5%) progressed, 227 (77.5%) did not (33 could not have their status assessed due to insufficient data). Progressors had shorter disease duration (median 8.1 vs 12.6 months, P=0.001) and lower mRSS (median 19 vs 21 units, P=0.030) than non-progressors. Skin score was highest, and peaked earliest, in the anti-RNA polymerase III (Pol3+) subgroup (n=50). A first predictive model (including mRSS, duration of skin thickening and their interaction) had an accuracy of 60.9%, AUC of 0.666 and PPV of 33.8%. By adding a variable for Pol3 positivity, the model reached an accuracy of 71%, AUC of 0.711 and PPV of 41%.Two prediction models for progressive skin thickening were derived, for use both in clinical practice and for cohort enrichment in RCTs. These models will inform recruitment into the many clinical trials of dcSSc projected for the coming years.NCT02339441.

    View details for DOI 10.1136/annrheumdis-2017-211912

    View details for Web of Science ID 000429731800019

    View details for PubMedID 29306872

    View details for PubMedCentralID PMC5890636

  • An Update on Systemic Sclerosis-Associated Pulmonary Arterial Hypertension: a Review of the Current Literature CURRENT RHEUMATOLOGY REPORTS Sundaram, S. M., Chung, L. 2018; 20 (2): 10

    Abstract

    This review will summarize the most current literature on the clinical impact, epidemiology, risk factors, screening recommendations, predictors of outcomes, and treatment options in patients with pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc).PAH continues to be a major cause of morbidity and mortality in SSc. Many risk factors and predictors of outcomes have been identified in patients with SSc including clinical, hemodynamic, and laboratory parameters. Screening for PAH in SSc patients is important and screening algorithms have been developed. Despite many available treatment options for PAH, prognosis remains poor. Awareness of risk factors, early detection, and up-front combination treatment are important considerations in SSc-PAH and may lead to improved outcomes. Further research to develop better biomarkers and therapies is needed to continue to improve survival and outcomes in patients with SSc-PAH.

    View details for DOI 10.1007/s11926-018-0709-5

    View details for Web of Science ID 000427652100001

    View details for PubMedID 29488016

  • Safety and efficacy of subcutaneous tocilizumab in systemic sclerosis: results from the open-label period of a phase II randomised controlled trial (faSScinate) ANNALS OF THE RHEUMATIC DISEASES Khanna, D., Denton, C. P., Lin, C. F., van Laar, J. M., Frech, T. M., Anderson, M. E., Baron, M., Chung, L., Fierlbeck, G., Lakshminarayanan, S., Allanore, Y., Pope, J. E., Riemekasten, G., Steen, V., Mueller-Ladner, U., Spotswood, H., Burke, L., Siegel, J., Jahreis, A., Furst, D. E. 2018; 77 (2): 212–20

    Abstract

    Assess the efficacy and safety of tocilizumab in patients with systemic sclerosis (SSc) in a phase II study.Patients with SSc were treated for 48 weeks in an open-label extension phase of the faSScinate study with weekly 162 mg subcutaneous tocilizumab. Exploratory end points included modified Rodnan Skin Score (mRSS) and per cent predicted forced vital capacity (%pFVC) through week 96.Overall, 24/44 (55%) placebo-tocilizumab and 27/43 (63%) continuous-tocilizumab patients completed week 96. Observed mean (SD (95% CI)) change from baseline in mRSS was -3.1 (6.3 (-5.4 to -0.9)) for placebo and -5.6 (9.1 (-8.9 to-2.4)) for tocilizumab at week 48 and -9.4 (5.6 (-8.9 to -2.4)) for placebo-tocilizumab and -9.1 (8.7 (-12.5 to -5.6)) for continuous-tocilizumab at week 96. Of patients who completed week 96, any decline in %pFVC was observed for 10/24 (42% (95% CI 22% to 63%)) placebo-tocilizumab and 12/26 (46% (95% CI 27% to 67%)) continuous-tocilizumab patients in the open-label period; no patients had >10% absolute decline in %pFVC. Serious infection rates/100 patient-years (95% CI) were 10.9 (3.0 to 27.9) with placebo and 34.8 (18.0 to 60.8) with tocilizumab during the double-blind period by week 48 and 19.6 (7.2 to 42.7) with placebo-tocilizumab and 0.0 (0.0 to 12.2) with continuous-tocilizumab during the open-label period.Skin score improvement and FVC stabilisation in the double-blind period were observed in placebo-treated patients who transitioned to tocilizumab and were maintained in the open-label period. Safety data indicated increased serious infections in patients with SSc but no new safety signals with tocilizumab.NCT01532869; Results.

    View details for DOI 10.1136/annrheumdis-2017-211682

    View details for Web of Science ID 000423879600014

    View details for PubMedID 29066464

    View details for PubMedCentralID PMC5867414

  • Disability, fatigue, pain and their associates in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study RHEUMATOLOGY Peytrignet, S., Denton, C. P., Lunt, M., Hesselstrand, R., Mouthon, L., Silman, A., Pan, X., Brown, E., Czirjak, L., Distler, J. W., Distler, O., Fligelstone, K., Gregory, W. J., Ochiel, R., Vonk, M., Ancuta, C., Ong, V. H., Farge, D., Hudson, M., Matucci-Cerinic, M., Balbir-Gurman, A., Midtvedt, O., Jordan, A. C., Stevens, W., Moinzadeh, P., Hall, F. C., Agard, C., Anderson, M. E., Diot, E., Madhok, R., Akil, M., Buch, M. H., Chung, L., Damjanov, N., Gunawardena, H., Lanyon, P., Ahmad, Y., Chakravarty, K., Jacobsen, S., MacGregor, A. J., McHugh, N., Muller-Ladner, U., Riemekasten, G., Becker, M., Roddy, J., Carreira, P. E., Fauchais, A., Hachulla, E., Hamilton, J., Inanc, M., McLaren, J. S., van Laar, J. M., Pathare, S., Proudman, S., Rudin, A., Sahhar, J., Coppere, B., Serratrice, C., Sheeran, T., Veale, D. J., Grange, C., Trad, G., Herrick, A. L. 2018; 57 (2): 370–81

    Abstract

    Our aim was to describe the burden of early dcSSc in terms of disability, fatigue and pain in the European Scleroderma Observational Study cohort, and to explore associated clinical features.Patients completed questionnaires at study entry, 12 and 24 months, including the HAQ disability index (HAQ-DI), the Cochin Hand Function Scale (CHFS), the Functional Assessment of Chronic Illness Therapy-fatigue and the Short Form 36 (SF36). Associates examined included the modified Rodnan skin score (mRSS), current digital ulcers and internal organ involvement. Correlations between 12-month changes were also examined.The 326 patients recruited (median disease duration 11.9 months) displayed high levels of disability [mean (s.d.) HAQ-DI 1.1 (0.83)], with 'grip' and 'activity' being most affected. Of the 18 activities assessed in the CHFS, those involving fine finger movements were most affected. High HAQ-DI and CHFS scores were both associated with high mRSS (ρ = 0.34, P < 0.0001 and ρ = 0.35, P < 0.0001, respectively). HAQ-DI was higher in patients with digital ulcers (P = 0.004), pulmonary fibrosis (P = 0.005), cardiac (P = 0.005) and muscle involvement (P = 0.002). As anticipated, HAQ-DI, CHFS, the Functional Assessment of Chronic Illness Therapy and SF36 scores were all highly correlated, in particular the HAQ-DI with the CHFS (ρ = 0.84, P < 0.0001). Worsening HAQ-DI over 12 months was strongly associated with increasing mRSS (ρ = 0.40, P < 0.0001), decreasing hand function (ρ = 0.57, P < 0.0001) and increasing fatigue (ρ = -0.53, P < 0.0001).The European Scleroderma Observational Study highlights the burden of disability in early dcSSc, with high levels of disability and fatigue, associating with the degree of skin thickening (mRSS). Impaired hand function is a major contributor to overall disability.

    View details for DOI 10.1093/rheumatology/kex410

    View details for Web of Science ID 000424223400025

    View details for PubMedID 29207002

    View details for PubMedCentralID PMC5850714

  • Evidence supports blind screening for internal malignancy in dermatomyositis Data from 2 large US dermatology cohorts MEDICINE Leatham, H., Schadt, C., Chisolm, S., Fretwell, D., Chung, L., Callen, J. P., Fiorentino, D. 2018; 97 (2): e9639

    Abstract

    The association between dermatomyositis and internal malignancy is well established, but there is little consensus about the methods of cancer screening that should be utilized.We wished to analyze the prevalence and yield of selected cancer screening modalities in patients with dermatomyositis.We performed a retrospective analysis of 2 large US dermatomyositis cohorts comprising 400 patients.We measured the frequency of selected screening tests used to search for malignancy. Patients with a biopsy-confirmed malignancy were identified. Prespecified clinical and laboratory factors were tested for association with malignancy. For each malignancy we identified the screening test(s) that led to diagnosis and classified these tests as either blind (not guided by suspicious sign/symptom) or triggered (by a suspicious sign or symptom).Forty-eight patients (12.0% of total cohort) with 53 cancers were identified with dermatomyositis-associated malignancy. Twenty-one of these 53 cancers (40%) were diagnosed within 1 year of dermatomyositis symptom onset. In multivariate analysis, older age (P = .0005) was the only significant risk factor for internal malignancy. There was no significant difference in cancer incidence between classic and clinically amyopathic patients. Twenty-seven patients (6.8% of the total cohort) harbored an undiagnosed malignancy at the time of dermatomyositis diagnosis. The majority (59%) of these cancers were asymptomatic and computed tomography (CT) scans were the most common studies to reveal a cancer.This is the largest US cohort studied to examine malignancy prevalence and screening practices in dermatomyositis patients. Our results demonstrate that, while undiagnosed malignancy is present in <10% of US patients at the time of dermatomyositis onset, it is often not associated with a suspicious sign or symptom. Our data suggest that effective malignancy screening of dermatomyositis patients often requires evaluation beyond a history, physical examination, and "age-appropriate" cancer screening-these data may help to inform future guidelines for malignancy screening in this population.

    View details for DOI 10.1097/MD.0000000000009639

    View details for Web of Science ID 000424081000055

    View details for PubMedID 29480875

  • Patient acceptable symptom state in scleroderma: results from the tocilizumab compared with placebo trial in active diffuse cutaneous systemic sclerosis RHEUMATOLOGY Arnold, M. B., Khanna, D., Denton, C. P., van Laar, J. M., Frech, T. M., Anderson, M. E., Baron, M., Chung, L., Fierlbeck, G., Lakshminarayanan, S., Allanore, Y., Riemekasten, G., Steen, V., Mueller-Ladner, U., Spotswood, H., Burke, L., Siegel, J., Jahreis, A., Furst, D. E., Pope, J. E. 2018; 57 (1): 152–57

    Abstract

    Patient acceptable symptom state (PASS) as an absolute state of well-being has shown promise as an outcome measure in many rheumatologic conditions. We aimed to assess whether PASS may be effective in active diffuse cutaneous SSc differentiating active from placebo.Data from the phase 2 Safety and Efficacy of Subcutaneous Tocilizumab in Adults with Systemic Sclerosis (faSScinate) trial were used, which compared tocilizumab (TCZ) vs placebo over 48 weeks followed by an open-label TCZ period to 96 weeks. Three different types of PASS questions were evaluated at weeks 8, 24, 48 and 96, including if a current state would be acceptable over time as a yes vs no response and Likert scales about how acceptable a current state is if remaining over time. Additional outcomes assessed included modified Rodnan skin score, HAQ disability index (HAQ-DI), physician and patient global assessments on a visual analogue scale, CRP and ESR.The placebo group consisted of 44 patients and the TCZ group had 43 patients. At baseline, 33% achieved a PASS for all three PASS questions, with the proportion increasing to 69, 71 and 78%, respectively, at 96 weeks. Changes in PASS scores showed a moderately negative correlation with HAQ-DI and patient and physician global assessments visual analogue scales, which indicates expected improvements as PASS improved. The PASS question, 'Considering all of the ways your scleroderma has affected you, how acceptable would you rate your level of symptoms?' showed significant correlations with patient-reported outcomes and differentiating placebo vs TCZ at 48 weeks (P = 0.023).PASS may be used as a patient-centred outcome in SSc, especially as a 7-point Likert scale. Further validation is required to determine the utility as an outcome measure in trials and clinical practice.

    View details for DOI 10.1093/rheumatology/kex396

    View details for Web of Science ID 000419623800028

    View details for PubMedID 29077900

    View details for PubMedCentralID PMC5850780

  • EXPRESS: Non-invasive Right Ventricular Load Adaptability Indices in Patients with Scleroderma-Associated Pulmonary Arterial Hypertension. Pulmonary circulation French, S., Amsallem, M., Ouazani, N., Li, S., Kudelko, K., Zamanian, R., Haddad, F., Chung, L. 2018: 2045894018788268

    View details for DOI 10.1177/2045894018788268

    View details for PubMedID 29938590

  • Factors Associated With Clinical Remission of Skin Disease in Dermatomyositis JAMA DERMATOLOGY Wolstencroft, P. W., Chung, L., Li, S., Casciola-Rosen, L., Fiorentino, D. F. 2018; 154 (1): 44–51

    Abstract

    Cutaneous disease represents a significant burden for patients with dermatomyositis. However, quantitative estimates of the probability of skin disease remission and clinical factors associated with skin outcomes are lacking.To characterize cutaneous disease course in adult patients with dermatomyositis.Prospective cohort study conducted at a dermatology clinic at a tertiary academic referral center. All adult patients with dermatomyositis (age >18 years) seen between May 15, 2007, and October 28, 2016, were eligible. Patients were included in the current analysis if they had a baseline Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) activity score of 12 or higher, and 2 or more CDASI scores separated by 3 months or more within their first 3 years of follow-up.The percentage of patients who achieved clinical remission of their cutaneous disease as measured by the CDASI over a 3-year follow-up.A total of 74 patients met our inclusion criteria (mean [SD] age at initial CDASI scoring, 54 [13] years; 58 women [78%]), and 28 (38%) achieved clinical remission during our 3-year follow-up period. Increased age (odds ratio [OR], 1.07; 95% CI, 1.02-1.12; P = .01), a dermatomyositis-associated malignancy (OR, 14.46; 95% CI, 2.18-96.07; P = .01), and treatment with mycophenolate mofetil (OR, 6.00; 95% CI, 1.66-21.78; P = .01) were significantly associated with clinical remission of skin disease in multivariable analysis. Patients with anti-melanoma differentiation-associated protein 5 antibodies had a significantly lower probability of meeting outcome criteria in our time-to-event analysis. Baseline cutaneous disease activity, disease duration at baseline, and disease duration before first systemic therapy were not significantly associated with clinical remission of skin disease.Clinical remission was relatively uncommon in our population despite aggressive systemic therapy, and patients with anti-melanoma differentiation-associated protein 5 antibodies were even less likely to enter clinical remission during a 3-year follow-up period. Although mycophenolate mofetil compared favorably with other treatment options, our data provide evidence that a substantial population of patients with dermatomyositis have skin disease that is not adequately managed with standard-of-care therapies.

    View details for DOI 10.1001/jamadermatol.2017.3758

    View details for Web of Science ID 000419969300006

    View details for PubMedID 29114741

    View details for PubMedCentralID PMC5833585

  • Clinical and serological features of systemic sclerosis in a multicenter African American cohort: Analysis of the genome research in African American scleroderma patients clinical database MEDICINE Morgan, N. D., Shah, A. A., Mayes, M. D., Domsic, R. T., Medsger, T. A., Steen, V. D., Varga, J., Carns, M., Ramos, P. S., Silver, R. M., Schiopu, E., Khanna, D., Hsu, V., Gordon, J. K., Gladue, H., Saketkoo, L. A., Criswell, L. A., Derk, C. T., Trojanowski, M. A., Shanmugam, V. K., Chung, L., Valenzuela, A., Jan, R., Goldberg, A., Remmers, E. F., Kastner, D. L., Wigley, F. M., Gourh, P., Boin, F. 2017; 96 (51): e8980

    Abstract

    Racial differences exist in the severity of systemic sclerosis (SSc). To enhance our knowledge about SSc in African Americans, we established a comprehensive clinical database from the largest multicenter cohort of African American SSc patients assembled to date (the Genome Research in African American Scleroderma Patients (GRASP) cohort).African American SSc patients were enrolled retrospectively and prospectively over a 30-year period (1987-2016), from 18 academic centers throughout the United States. The cross-sectional prevalence of sociodemographic, clinical, and serological features was evaluated. Factors associated with clinically significant manifestations of SSc were assessed using multivariate logistic regression analyses.The study population included a total of 1009 African American SSc patients, comprised of 84% women. In total, 945 (94%) patients met the 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for SSc, with the remaining 64 (6%) meeting the 1980 ACR or CREST (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia) criteria. While 43% were actively employed, 33% required disability support. The majority (57%) had the more severe diffuse subtype and a young age at symptom onset (39.1 ± 13.7 years), in marked contrast to that reported in cohorts of predominantly European ancestry. Also, 1 in 10 patients had a severe Medsger cardiac score of 4. Pulmonary fibrosis evident on computed tomography (CT) chest was present in 43% of patients and was significantly associated with anti-topoisomerase I positivity. 38% of patients with CT evidence of pulmonary fibrosis had a severe restrictive ventilator defect, forced vital capacity (FVC) ≤50% predicted. A significant association was noted between longer disease duration and higher odds of pulmonary hypertension, telangiectasia, and calcinosis. The prevalence of potentially fatal scleroderma renal crisis was 7%, 3.5 times higher than the 2% prevalence reported in the European League Against Rheumatism Scleroderma Trials and Research (EUSTAR) cohort.Our study emphasizes the unique and severe disease burden of SSc in African Americans compared to those of European ancestry.

    View details for DOI 10.1097/MD.0000000000008980

    View details for Web of Science ID 000422992300015

    View details for PubMedID 29390428

    View details for PubMedCentralID PMC5758130

  • Pregnancy outcomes in adult patients with dermatomyositis and polymyositis. Seminars in arthritis and rheumatism Kolstad, K. D., Fiorentino, D., Li, S., Chakravarty, E. F., Chung, L. 2017

    Abstract

    OBJECTIVE: The idiopathic inflammatory myopathies dermatomyositis (DM) and polymyositis (PM) are autoimmune diseases that can affect females of childbearing potential. We assessed pregnancy outcomes in DM and PM patients compared with the general obstetric population.METHODS: The Nationwide Inpatient Sample (NIS) (1993-2007) was used to identify delivery-associated hospitalizations in women with DM or PM (DM/PM, n = 853). Controls were from the general obstetric population delivery-associated hospitalizations matched to each case by year of delivery. Pregnancy outcomes included hospital length of stay (LOS), hypertensive disorders (HTN), premature rupture of membranes (PROM), intrauterine growth restriction (IUGR), and cesarean delivery. Multivariate regression analyses were performed using maternal age, race/ethnicity, and diabetes mellitus as covariates.RESULTS: On multivariate analysis, patients with DM/PM had longer LOS compared to controls (p < 0.001). DM/PM was associated with an increased risk of hypertensive disorders compared to controls (OR = 2.90, 95% CI: 2.00-4.22). There were no differences in rates of PROM, IUGR, or cesarean section in patients with DM/PM compared with controls. Independent of a DM/PM diagnosis, African-American race, older age, and diagnosis of diabetes increased the hospital LOS (p < 0.001). African-American race and diabetes increased the risk of hypertensive disorders (OR = 1.38, 95% CI: 1.19-1.60; OR = 2.94, 95% CI: 2.04-4.23, respectively) compared to controls.CONCLUSION: These data suggest that patients with inflammatory myopathies are at increased risk of hypertensive disorders of pregnancy and longer length of hospitalization. Vigilant monitoring of blood pressure is advisable in pregnant patients with DM or PM.

    View details for DOI 10.1016/j.semarthrit.2017.11.005

    View details for PubMedID 29217291

  • Factors Associated with Clinical Remission of Skin Disease in Dermatomyositis Wolstencroft, P., Chung, L., Li, S., Casciola-Rosen, L., Fiorentino, D. WILEY. 2017
  • Safety and Efficacy of Anabasum (JBT-101) in Diffuse Cutaneous Systemic Sclerosis (dcSSc) Subjects Treated in an Open-Label Extension of Trial JBT101-SSc-001 Spiera, R. F., Hummers, L. K., Chung, L., Frech, T. M., Domsic, R. T., Hsu, V., Furst, D. E., Gordon, J. K., Mayes, M. D., Simms, R. W., Constantine, S., White, B. WILEY. 2017
  • HLA Type Imputation in the Genome Research in African American Scleroderma Patients (GRASP) Cohort Reveals Strong Associations of African Ancestry MHC Class II Types with Scleroderma and Lack of Class I HLA Type Associations Remmers, E. F., Gourh, P., Boyden, S., Morgan, N. D., Shah, A. A., Adeyemo, A., Bentley, A., Carns, M. A., Chandrasekharappa, S. C., Chung, L., Criswell, L. A., Derk, C. T., Domsic, R. T., Doumatey, A., Gladue, H., Goldberg, A., Gordon, J. K., Hsu, V. M., Jan, R., Khanna, D., Mayes, M. D., Medsger, T. A., Ramos, P. S., Trojanowski, M. A., Saketkoo, L. A., Schiopu, E., Shanmugam, V. K., Shriner, D., Silver, R. M., Steen, V. D., Valenzuela, A., Varga, J., Rotimi, C., Wigley, F. M., Boin, F., Kastner, D. L. WILEY. 2017
  • A Phase 2 Study of Safety and Efficacy of Anabasum (JBT-101), a Cannabinoid Receptor Type 2 Agonist, in Diffuse Cutaneous Systemic Sclerosis Spiera, R. F., Hummers, L. K., Chung, L., Frech, T. M., Domsic, R. T., Hsu, V., Furst, D. E., Gordon, J. K., Mayes, M. D., Simms, R. W., Constantine, S., White, B. WILEY. 2017
  • Clinical and Serological Features of Systemic Sclerosis in a Multicenter African American Cohort: Analysis of the Genome Research in African American Scleroderma Patients Clinical Database Morgan, N. D., Shah, A. A., Mayes, M. D., Domsic, R. T., Medsger, T. A., Steen, V. D., Varga, J., Carns, M. A., Ramos, P. S., Silver, R. M., Schiopu, E., Khanna, D., Hsu, V., Gordon, J. K., Gladue, H., Saketkoo, L. A., Criswell, L. A., Derk, C. T., Trojanowski, M. A., Shanmugam, V. K., Chung, L., Valenzuela, A., Jan, R., Goldberg, A., Remmers, E. F., Kastner, D. L., Wigley, F. M., Gourh, P., Boin, F. WILEY. 2017
  • Transcriptome Sequencing Reveals Genetic Polymorphisms Associated with Ssc Gene Expression Subtypes Cai, G., Mehta, B. K., Huang, M., Franks, J., Wood, T. A., Kolstad, K. D., Stark, M., Valenzuela, A., Fiorentino, D., Simms, R. W., Orzechowski, N., Chung, L., Whitfield, M. L. WILEY. 2017
  • Multi-Organ RNA-Sequencing of Patients with Systemic Sclerosis (SSc) Finds That Intrinsic Subsets Are Conserved across Organ Systems Mehta, B. K., Franks, J., Cai, G., Toledo, D., Wood, T. A., Archambault, K. A., Kosarek, N., Kolstad, K., Stark, M., Valenzuela, A., Fiorentino, D., Fernandez-Becker, N., Becker, L., Nguyen, L., Clarke, J., Boin, F., Wolters, P., Chung, L., Whitfield, M. L. WILEY. 2017
  • Identification of Biomarkers Predictive of Pulmonary Arterial Hypertension in Systemic Sclerosis Kolstad, K. D., Holmes, T., Rosenberg-Hasson, Y., Sweatt, A., Zamanian, R. T., Li, S., Steen, V. D., Utz, P. J., Chung, L. WILEY. 2017
  • Transforming Growth Factor Beta 3 (TGFB3) - a Novel Systemic Sclerosis Susceptibility Locus Involved in Fibrosis and Th17 Cell Development Identified By Genome-Wide Association Study in African Americans from the Genome Research in African American Scleroderma Patients Consortium Gourh, P., Remmers, E. F., Satpathy, A., Boyden, S., Morgan, N. D., Shah, A. A., Adeyemo, A., Bentley, A., Carns, M. A., Chandrasekharappa, S. C., Chung, L., Criswell, L. A., Derk, C. T., Domsic, R. T., Doumatey, A., Gladue, H., Goldberg, A., Gordon, J. K., Hsu, V., Jan, R., Khanna, D., Mayes, M. D., Medsger, T. A., Mumbach, M., Ramos, P. S., Trojanowski, M., Saketkoo, L., Schiopu, E., Shanmugam, V. K., Shriner, D., Silver, R. M., Steen, V. D., Valenzuela, A., Varga, J., Chang, H., Rotimi, C., Wigley, F. M., Boin, F., Kastner, D. L. WILEY. 2017
  • Preterm Birth Phenotypes in Women with Autoimmune Diseases Kolstad, K. D., Mayo, J. A., Chung, L., Chaichian, Y., Kelly, V. M., Druzin, M., Stevenson, D. K., Shaw, G. M., Simard, J. F. WILEY. 2017
  • Differential expression of hepatocyte growth factor in patients with systemic sclerosis-associated pulmonary arterial hypertension JOURNAL OF SCLERODERMA AND RELATED DISORDERS Sung, Y. K., Zamanian, R. T., Wagner, C. A., Robinson, W., Steen, V., Chung, L. 2017; 2 (3): 225–30
  • Patient Centered Approach to Disease Modification in Scleroderma: Results from the faSScinate Trial of Tocilizumab Compared to Placebo in Active Diffuse Cutaneous Systemic Sclerosis Arnold, M., Khanna, D., Denton, C., Lin, C., van Laar, J., Frech, T., Anderson, M., Baron, M., Chung, L., Fierlbeck, G., Allanore, Y., Riemekasten, G., Steen, V., Mueller-Ladner, U., Spotswood, H., Burke, L., Siegel, J., Jahreis, A., Furst, D., Pope, J. J RHEUMATOL PUBL CO. 2017: 881
  • 2016 American College of Rheumatology/European League Against Rheumatism Criteria for Minimal, Moderate, and Major Clinical Response in Adult Dermatomyositis and Polymyositis An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative ARTHRITIS & RHEUMATOLOGY Aggarwal, R., Rider, L. G., Ruperto, N., Bayat, N., Erman, B., Feldman, B. M., Oddis, C. V., Amato, A. A., Chinoy, H., Cooper, R. G., Dastmalchi, M., Fiorentino, D., Isenberg, D., Katz, J. D., Mammen, A., de Visser, M., Ytterberg, S. R., Lundberg, I. E., Chung, L., Danko, K., Garcia-De La Torre, I., Song, Y. W., Villa, L., Rinaldi, M., Rockette, H., Lachenbruch, P. A., Miller, F. W., Vencovsky, J. 2017; 69 (5): 898-910

    Abstract

    To develop response criteria for adult dermatomyositis (DM) and polymyositis (PM).Expert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement in 2 core set measures were presented. The PAPRIKA (Potentially All Pairwise Rankings of All Possible Alternatives) method determined the relative weights of core set measures and conjoint analysis definitions. The performance characteristics of the definitions were evaluated on patient profiles using expert consensus (gold standard) and were validated using data from a clinical trial. The nominal group technique was used to reach consensus.Consensus was reached for a conjoint analysis-based continuous model using absolute percent change in core set measures (physician, patient, and extramuscular global activity, muscle strength, Health Assessment Questionnaire, and muscle enzyme levels). A total improvement score (range 0-100), determined by summing scores for each core set measure, was based on improvement in and relative weight of each core set measure. Thresholds for minimal, moderate, and major improvement were ≥20, ≥40, and ≥60 points in the total improvement score. The same criteria were chosen for juvenile DM, with different improvement thresholds. Sensitivity and specificity in DM/PM patient cohorts were 85% and 92%, 90% and 96%, and 92% and 98% for minimal, moderate, and major improvement, respectively. Definitions were validated in the clinical trial analysis for differentiating the physician rating of improvement (P < 0.001).The response criteria for adult DM/PM consisted of the conjoint analysis model based on absolute percent change in 6 core set measures, with thresholds for minimal, moderate, and major improvement.

    View details for DOI 10.1002/art.40064

    View details for Web of Science ID 000400068300004

    View details for PubMedID 28382787

  • 2016 American College of Rheumatology/European League Against Rheumatism criteria for minimal, moderate, and major clinical response in adult dermatomyositis and polymyositis An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative ANNALS OF THE RHEUMATIC DISEASES Aggarwal, R., Rider, L. G., Ruperto, N., Bayat, N., Erman, B., Feldman, B. M., Oddis, C. V., Amato, A. A., Chinoy, H., Cooper, R. G., Dastmalchi, M., Fiorentino, D., Isenberg, D., Katz, J. D., Mammen, A., de Visser, M., Ytterberg, S. R., Lundberg, I. E., Chung, L., Danko, K., Garcia-De La Torre, I., Song, Y. W., Villa, L., Rinaldi, M., Rockette, H., Lachenbruch, P. A., Miller, F. W., Vencovsky, J. 2017; 76 (5)

    Abstract

    To develop response criteria for adult dermatomyositis (DM) and polymyositis (PM). Expert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement in 2 core set measures were presented. The PAPRIKA (Potentially All Pairwise Rankings of All Possible Alternatives) method determined the relative weights of core set measures and conjoint analysis definitions. The performance characteristics of the definitions were evaluated on patient profiles using expert consensus (gold standard) and were validated using data from a clinical trial. The nominal group technique was used to reach consensus. Consensus was reached for a conjoint analysis-based continuous model using absolute per cent change in core set measures (physician, patient, and extramuscular global activity, muscle strength, Health Assessment Questionnaire, and muscle enzyme levels). A total improvement score (range 0-100), determined by summing scores for each core set measure, was based on improvement in and relative weight of each core set measure. Thresholds for minimal, moderate, and major improvement were ≥20, ≥40, and ≥60 points in the total improvement score. The same criteria were chosen for juvenile DM, with different improvement thresholds. Sensitivity and specificity in DM/PM patient cohorts were 85% and 92%, 90% and 96%, and 92% and 98% for minimal, moderate, and major improvement, respectively. Definitions were validated in the clinical trial analysis for differentiating the physician rating of improvement (p<0.001). The response criteria for adult DM/PM consisted of the conjoint analysis model based on absolute per cent change in 6 core set measures, with thresholds for minimal, moderate, and major improvement.

    View details for DOI 10.1136/annrheumdis-2017-211400

    View details for Web of Science ID 000398387200006

    View details for PubMedID 28385805

  • Proteomic Analysis of Sera from Individuals with Diffuse Cutaneous Systemic Sclerosis Reveals a Multianalyte Signature Associated with Clinical Improvement during Imatinib Mesylate Treatment JOURNAL OF RHEUMATOLOGY Haddon, D. J., Wand, H. E., Jarrell, J. A., Spiera, R. F., Utz, P. J., Gordon, J. K., Chung, L. S. 2017; 44 (5): 631-638

    Abstract

    Imatinib has been investigated for the treatment of systemic sclerosis (SSc) because of its ability to inhibit the platelet-derived growth factor receptor and transforming growth factor-β signaling pathways, which have been implicated in SSc pathogenesis. In a 12-month open-label clinical trial assessing the safety and efficacy of imatinib in the treatment of diffuse cutaneous SSc (dcSSc), significant improvements in skin thickening were observed. Here, we report our analysis of sera collected during the clinical trial.We measured the levels of 46 cytokines, chemokines, and growth factors in the sera of individuals with dcSSc using Luminex and ELISA. Autoantigen microarrays were used to measure immunoglobulin G reactivity to 28 autoantigens. Elastic net regularization was used to identify a signature that was predictive of clinical improvement (reduction in the modified Rodnan skin score ≥ 5) during treatment with imatinib. The signature was also tested using sera from a clinical trial of nilotinib, a tyrosine kinase inhibitor that is structurally related to imatinib, in dcSSc.The elastic net algorithm identified a signature, based on levels of CD40 ligand, chemokine (C-X-C motif) ligand 4 (CXCL4), and anti-PM/Scl-100, that was significantly higher in individuals who experienced clinical improvement than in those who did not (p = 0.0011). The signature was validated using samples from a clinical trial of nilotinib.Identification of patients with SSc with the greatest probability of benefit from treatment with imatinib has the potential to guide individualized treatment. Validation of the signature will require testing in randomized, placebo-controlled studies. Clinicaltrials.gov NCT00555581 and NCT01166139.

    View details for DOI 10.3899/jrheum.160833

    View details for Web of Science ID 000401094300016

    View details for PubMedID 28298564

  • Insights into CCL21's roles in immunosurveillance and immunotherapy for gliomas JOURNAL OF NEUROIMMUNOLOGY Nguyen, T., Lagman, C., Chung, L. K., Chen, C. H., Poon, J., Ong, V., Voth, B. L., Yang, I. 2017; 305: 29-34

    Abstract

    Chemokine (C-C) motif ligand 21 (CCL21) is involved in immunosurveillance and has recently garnered the attention of neuro-oncologists and neuroscientists. CCL21 contains an extended C-terminus, which increases binding to lymphatic glycosaminoglycans and provides a mechanism for cell trafficking by forming a stationary chemokine concentration gradient that allows cell migration via haptotaxis. CCL21 is expressed by endothelial cells of the blood-brain barrier in physiologic and pathologic conditions. CCL21 has also been implicated in leukocyte extravasation into the central nervous system. In this review, we summarize the role of CCL21 in immunosurveillance and explore its potential as an immunotherapeutic agent for the treatment of gliomas.

    View details for DOI 10.1016/j.jneuroim.2017.01.010

    View details for Web of Science ID 000397694200006

    View details for PubMedID 28284342

  • Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS). Annals of the rheumatic diseases Herrick, A. L., Pan, X., Peytrignet, S., Lunt, M., Hesselstrand, R., Mouthon, L., Silman, A., Brown, E., Czirják, L., Distler, J. H., Distler, O., Fligelstone, K., Gregory, W. J., Ochiel, R., Vonk, M., Ancuta, C., Ong, V. H., Farge, D., Hudson, M., Matucci-Cerinic, M., Balbir-Gurman, A., Midtvedt, Ø., Jordan, A. C., Jobanputra, P., Stevens, W., Moinzadeh, P., Hall, F. C., Agard, C., Anderson, M. E., Diot, E., Madhok, R., Akil, M., Buch, M. H., Chung, L., Damjanov, N., Gunawardena, H., Lanyon, P., Ahmad, Y., Chakravarty, K., Jacobsen, S., MacGregor, A. J., McHugh, N., Müller-Ladner, U., Riemekasten, G., Becker, M., Roddy, J., Carreira, P. E., Fauchais, A. L., Hachulla, E., Hamilton, J., Inanç, M., McLaren, J. S., van Laar, J. M., Pathare, S., Proudman, S., Rudin, A., Sahhar, J., Coppere, B., Serratrice, C., Sheeran, T., Veale, D. J., Grange, C., Trad, G., Denton, C. P. 2017

    Abstract

    The rarity of early diffuse cutaneous systemic sclerosis (dcSSc) makes randomised controlled trials very difficult. We aimed to use an observational approach to compare effectiveness of currently used treatment approaches.This was a prospective, observational cohort study of early dcSSc (within three years of onset of skin thickening). Clinicians selected one of four protocols for each patient: methotrexate, mycophenolate mofetil (MMF), cyclophosphamide or 'no immunosuppressant'. Patients were assessed three-monthly for up to 24 months. The primary outcome was the change in modified Rodnan skin score (mRSS). Confounding by indication at baseline was accounted for using inverse probability of treatment (IPT) weights. As a secondary outcome, an IPT-weighted Cox model was used to test for differences in survival.Of 326 patients recruited from 50 centres, 65 were prescribed methotrexate, 118 MMF, 87 cyclophosphamide and 56 no immunosuppressant. 276 (84.7%) patients completed 12 and 234 (71.7%) 24 months follow-up (or reached last visit date). There were statistically significant reductions in mRSS at 12 months in all groups: -4.0 (-5.2 to -2.7) units for methotrexate, -4.1 (-5.3 to -2.9) for MMF, -3.3 (-4.9 to -1.7) for cyclophosphamide and -2.2 (-4.0 to -0.3) for no immunosuppressant (p value for between-group differences=0.346). There were no statistically significant differences in survival between protocols before (p=0.389) or after weighting (p=0.440), but survival was poorest in the no immunosuppressant group (84.0%) at 24 months.These findings may support using immunosuppressants for early dcSSc but suggest that overall benefit is modest over 12 months and that better treatments are needed.NCT02339441.

    View details for DOI 10.1136/annrheumdis-2016-210503

    View details for PubMedID 28188239

  • The cutaneous and systemic findings associated with nuclear matrix protein-2 antibodies in adult dermatomyositis patients. Arthritis care & research Rogers, A., Chung, L., Li, S., Casciola-Rosen, L., Fiorentino, D. F. 2017

    Abstract

    To characterize the cutaneous and systemic clinical phenotype of dermatomyositis patients with anti-NXP-2 antibodies.We conducted a retrospective cohort analysis of 178 dermatomyositis patients seen at the Stanford University Clinic. Electronic chart review employing a keyword search strategy was performed to collect clinical and laboratory data. Anti-NXP-2 antibodies were assayed by immunoprecipitation using NXP-2 produced by in vitro transcription/translation.Antibodies to NXP-2 were detected in 20 (11%) of the 178 patients. Anti-NXP-2 antibodies were associated with male gender (50% vs. 25%, p=0.02), dysphagia (74% vs. 39%, p=0.006), myalgia (89% vs. 52%, p=0.002), peripheral edema (35% vs. 11%, p=0.016), and calcinosis (37% vs. 11%, p=0.007). These patients were less likely to be clinically amyopathic (5% vs 23%, p=0.08). Five of the 20 patients with NXP-2 antibodies (25%) had an associated internal malignancy. No other cutaneous characteristics were associated with anti-NXP-2 antibodies except a decreased frequency of Gottron's sign (44% vs. 75%, p=0.012) and the fact that these patients were more likely to have mild skin disease.Dermatomyositis patients with anti-NXP2 antibodies have a distinct and often severe systemic phenotype that includes myalgia, peripheral edema and significant dysphagia despite having milder inflammatory skin disease. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/acr.23210

    View details for PubMedID 28129490

  • Association between GWAS-identified lung adenocarcinoma susceptibility loci and EGFR mutations in never-smoking Asian women, and comparison with findings from Western populations HUMAN MOLECULAR GENETICS Seow, W. J., Matsuo, K., Hsiung, C. A., Shiraishi, K., Song, M., Kim, H. N., Wong, M. P., Hong, Y., Hosgood, H. D., Wang, Z., Chang, I., Wang, J., Chatterjee, N., Tucker, M., Wei, H., Mitsudomi, T., Zheng, W., Kim, J. H., Zhou, B., Caporaso, N. E., Albanes, D., Shin, M., Chung, L. P., An, S., Wang, P., Zheng, H., Yatabe, Y., Zhang, X., Kim, Y. T., Shu, X., Kim, Y., Bassig, B. A., Chang, J., Ho, J. C., Ji, B., Kubo, M., Daigo, Y., Ito, H., Momozawa, Y., Ashikawa, K., Kamatani, Y., Honda, T., Sakamoto, H., Kunitoh, H., Tsuta, K., Watanabe, S., Nokihara, H., Miyagi, Y., Nakayama, H., Matsumoto, S., Tsuboi, M., Goto, K., Yin, Z., Shi, J., Takahashi, A., Goto, A., Minamiya, Y., Shimizu, K., Tanaka, K., Wu, T., Wei, F., Wong, J. Y., Matsuda, F., Su, J., Kim, Y. H., Oh, I., Song, F., Lee, V. H., Su, W., Chen, Y., Chang, G., Chen, K., Huang, M., Yang, P., Lin, H., Xiang, Y., Seow, A., Park, J. Y., Kweon, S., Chen, C., Li, H., Gao, Y., Wu, C., Qian, B., Lu, D., Liu, J., Jeon, H., Hsiao, C., Sung, J. S., Tsai, Y., Jung, Y. J., Guo, H., Hu, Z., Wang, W., Chung, C. C., Lawrence, C., Burdett, L., Yeager, M., Jacobs, K. B., Hutchinson, A., Berndt, S. I., He, X., Wu, W., Wang, J., Li, Y., Choi, J. E., Park, K. H., Sung, S. W., Liu, L., Kang, C. H., Hu, L., Chen, C., Yang, T., Xu, J., Guan, P., Tan, W., Wang, C., Sihoe, A. D., Chen, Y., Choi, Y. Y., Hung, J., Kim, J. S., Yoon, H., Cai, Q., Lin, C., Park, I. K., Xu, P., Dong, J., Kim, C., He, Q., Perng, R., Chen, C., Vermeulen, R., Wu, J., Lim, W., Chen, K., Chan, J. K., Chu, M., Li, Y., Li, J., Chen, H., Yu, C., Jin, L., Lo, Y., Chen, Y., Fraumeni, J. F., Liu, J., Yamaji, T., Yang, Y., Hicks, B., Wyatt, K., Li, S. A., Dai, J., Ma, H., Jin, G., Song, B., Wang, Z., Cheng, S., Li, X., Ren, Y., Cui, P., Iwasaki, M., Shimazu, T., Tsugane, S., Zhu, J., Jiang, G., Fei, K., Wu, G., Chien, L., Chen, H., Su, Y., Tsai, F., Chen, Y., Yu, J., Stevens, V. L., Laird-Offringa, I. A., Marconett, C. N., Lin, D., Chen, K., Wu, Y., Landi, M. T., Shen, H., Rothman, N., Kohno, T., Chanock, S. J., Lan, Q. 2017; 26 (2): 454-465

    View details for DOI 10.1093/hmg/ddw414

    View details for Web of Science ID 000397066400018

  • beta-Catenin overexpression causes an increase in inflammatory cytokines and NF-kappa B activation in cardiomyocytes CELLULAR AND MOLECULAR BIOLOGY Lin, J. C., Chang, R., Chen, Y., Yang, J., Baskaran, R., Chung, L., Chen, R., Day, C. H., Padma, V. V., Huang, C. 2017; 63 (1): 17-22
  • Utility of B-type natriuretic peptides in the assessment of patients with systemic sclerosis-associated pulmonary hypertension in the PHAROS registry CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Chung, L., Fairchild, R. M., Furst, D. E., Li, S., Alkassab, F., Bolster, M. B., Csuka, M. E., Derk, C. T., Domsic, R. T., Fischer, A., Frech, T. M., Gomberg-Maitland, M., Gordon, J. K., Hinchcliff, M., Hsu, V., Hummers, L. K., Khanna, D., Medsger, T. A., Molitor, J. A., Preston, I. R., Schiopu, E., Shapiro, L., Hant, F., Silver, R., Simms, R., Varga, J., Steen, V. D., Zamanian, R. T. 2017; 35 (4): S106–S113
  • Integrated, multicohort analysis of systemic sclerosis identifies robust transcriptional signature of disease severity. JCI insight Lofgren, S., Hinchcliff, M., Carns, M., Wood, T., Aren, K., Arroyo, E., Cheung, P., Kuo, A., Valenzuela, A., Haemel, A., Wolters, P. J., Gordon, J., Spiera, R., Assassi, S., Boin, F., Chung, L., Fiorentino, D., Utz, P. J., Whitfield, M. L., Khatri, P. 2016; 1 (21)

    Abstract

    Systemic sclerosis (SSc) is a rare autoimmune disease with the highest case-fatality rate of all connective tissue diseases. Current efforts to determine patient response to a given treatment using the modified Rodnan skin score (mRSS) are complicated by interclinician variability, confounding, and the time required between sequential mRSS measurements to observe meaningful change. There is an unmet critical need for an objective metric of SSc disease severity. Here, we performed an integrated, multicohort analysis of SSc transcriptome data across 7 datasets from 6 centers composed of 515 samples. Using 158 skin samples from SSc patients and healthy controls recruited at 2 centers as a discovery cohort, we identified a 415-gene expression signature specific for SSc, and validated its ability to distinguish SSc patients from healthy controls in an additional 357 skin samples from 5 independent cohorts. Next, we defined the SSc skin severity score (4S). In every SSc cohort of skin biopsy samples analyzed in our study, 4S correlated significantly with mRSS, allowing objective quantification of SSc disease severity. Using transcriptome data from the largest longitudinal trial of SSc patients to date, we showed that 4S allowed us to objectively monitor individual SSc patients over time, as (a) the change in 4S of a patient is significantly correlated with change in the mRSS, and (b) the change in 4S at 12 months of treatment could predict the change in mRSS at 24 months. Our results suggest that 4S could be used to distinguish treatment responders from nonresponders prior to mRSS change. Our results demonstrate the potential clinical utility of a novel robust molecular signature and a computational approach to SSc disease severity quantification.

    View details for DOI 10.1172/jci.insight.89073

    View details for PubMedID 28018971

    View details for PubMedCentralID PMC5161207

  • Keratin 13 expression reprograms bone and brain metastases of human prostate cancer cells ONCOTARGET Li, Q., Yin, L., Jones, L. W., Chu, G. C., Wu, J. B., Huang, J., Li, Q., You, S., Kim, J., Lu, Y., Mrdenovic, S., Wang, R., Freeman, M. R., Garraway, I., Lewis, M. S., Chung, L. W., Zhau, H. E. 2016; 7 (51): 84645-84657

    Abstract

    Lethal progression of prostate cancer metastasis can be improved by developing animal models that recapitulate the clinical conditions. We report here that cytokeratin 13 (KRT13), an intermediate filament protein, plays a directive role in prostate cancer bone, brain, and soft tissue metastases. KRT13 expression was elevated in bone, brain, and soft tissue metastatic prostate cancer cell lines and in primary and metastatic clinical prostate, lung, and breast cancer specimens. When KRT13 expression was determined at a single cell level in primary tumor tissues of 44 prostate cancer cases, KRT13 level predicted bone metastasis and the overall survival of prostate cancer patients. Genetically enforced KRT13 expression in human prostate cancer cell lines drove metastases toward mouse bone, brain and soft tissues through a RANKL-independent mechanism, as KRT13 altered the expression of genes associated with EMT, stemness, neuroendocrine/neuromimicry, osteomimicry, development, and extracellular matrices, but not receptor activator NF-κB ligand (RANKL) signaling networks in prostate cancer cells. Our results suggest new inhibitors targeting RANKL-independent pathways should be developed for the treatment of prostate cancer bone and soft tissue metastases.

    View details for DOI 10.18632/oncotarget.13175

    View details for Web of Science ID 000391353200069

    View details for PubMedID 27835867

  • Calcinosis is associated with digital ulcers and osteoporosis in patients with systemic sclerosis: A Scleroderma Clinical Trials Consortium study SEMINARS IN ARTHRITIS AND RHEUMATISM Valenzuela, A., Baron, M., Herrick, A. L., Proudman, S., Stevens, W., Rodriguez-Reyna, T. S., Vacca, A., Medsger, T. A., Hinchcliff, M., Hsu, V., Wu, J. Y., Fiorentino, D., Chung, L. 2016; 46 (3): 344-349

    Abstract

    We sought to identify the clinical factors associated with calcinosis in an international multicenter collaborative effort with the Scleroderma Clinical Trials Consortium (SCTC).This is a retrospective cohort study of 5218 patients with systemic sclerosis (SSc). Logistic regression was used to obtain odds ratios (OR) relating calcinosis to various clinical features in multivariate analyses.A total of 1290 patients (24.7%) had calcinosis. In univariate analyses, patients with calcinosis were older than patients without calcinosis, more likely to be female, and had longer disease duration from the first non-Raynaud phenomenon symptom. Patients with calcinosis were more likely to have digital ulcers, telangiectasias, acro-osteolysis, cardiac disease, pulmonary hypertension, gastrointestinal involvement, arthritis, and osteoporosis, but less likely to have muscle disease. Anti-Scl-70, RNA-polymerase-III, and U1-RNP autoantibodies were significantly less common in patients with calcinosis, while anticentromere (ACA), anti-PM/Scl, and anticardiolipin antibodies were more frequent. In multivariate analysis, the strongest associations with calcinosis were digital ulcers (OR = 3.9; 95% CI: 2.7-5.5; p < 0.0001) and osteoporosis (OR = 4.2; 95% CI: 2.3-7.9; p < 0.0001).One quarter of patients with SSc have calcinosis at some time during their illness. Our data confirm a strong association of calcinosis with digital ulcers, and support a novel association with osteoporosis.

    View details for DOI 10.1016/j.semarthrit.2016.05.008

    View details for Web of Science ID 000390979200012

    View details for PubMedID 27371996

  • Utility of B-type natriuretic peptides in the assessment of patients with systemic sclerosis-associated pulmonary hypertension in the PHAROS registry. Clinical and experimental rheumatology Chung, L., Fairchild, R. M., Furst, D. E., Li, S., Alkassab, F., Bolster, M. B., Csuka, M. E., Derk, C. T., Domsic, R. T., Fischer, A., Frech, T., Gomberg-Maitland, M., Gordon, J. K., Hinchcliff, M., Hsu, V., Hummers, L. K., Khanna, D., Medsger, T. A., Molitor, J. A., Preston, I. R., Schiopu, E., Shapiro, L., Hant, F., Silver, R., Simms, R., Varga, J., Steen, V. D., Zamanian, R. T. 2016: -?

    Abstract

    To assess the utility of B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) in detecting and monitoring pulmonary hypertension (PH) in systemic sclerosis (SSc).PHAROS is a multicenter prospective cohort of SSc patients at high risk for developing pulmonary arterial hypertension (SSc-AR-PAH) or with a definitive diagnosis of SSc-PH. We evaluated 1) the sensitivity and specificity of BNP≥64 and NT-proBNP≥210 pg/mL for the detection of SSc-PAH and/ or SSc-PH in the SSc-AR-PAH population; 2) baseline and longitudinal BNP and NT-proBNP levels as predictors of progression to SSc-PAH and/or SSc-PH; 3) baseline BNP≥180, NT-proBNP≥553 pg/mL, and longitudinal changes in BNP and NT-proBNP as predictors of mortality in SSc-PH diagnosed patients.172 SSc-PH and 157 SSc-AR- PAH patients had natriuretic peptide levels available. Median BNP and NT-proBNP were significantly higher in the SSc-PH versus SSc-AR-PAH group. The sensitivity and specificity for SSc-PAH detection using baseline BNP≥64 pg/mL was 71% and 59%; and for NT-proBNP≥210 pg/mL, 73% and 78%. NT-proBNP showed stronger correlations with haemodynamic indicators of right ventricular dysfunction than BNP. Baseline creatinine, RVSP > 40 mmHg, and FVC%:DLco% ratio ≥1.8 were associated with progression from SSc-AR-PAH to SSc-PH but no association with individual or combined baseline BNP and NT-proBNP levels was observed. Baseline and follow-up BNP or NT-proBNP levels were not predictive of death, however, a composite BNP/NT-proBNP group predicted mortality (HR 3.81 (2.08-6.99), p<.0001).NT-proBNP may be more useful than BNP in the detection and monitoring of PAH in SSc patients, but additional studies are necessary.

    View details for PubMedID 27908301

  • Multi-Organ RNA-Sequencing of Systemic Sclerosis (SSc) Patients Shows Reproducible Gene Expression Profiles Across Organ Systems Mehta, B. K., Johnson, M. E., Archambault, K. A., Wood, T. A., Valenzuela, A., Crawford, A., Fiorentino, D., Fernandez-Becker, N., Becker, L., Nguyen, L., Boin, F., Wolters, P., Chung, L., Whitfield, M. WILEY. 2016
  • Right Ventricular Load-Adaptability and Response to Therapy in Scleroderma Versus Idiopathic Pulmonary Arterial Hypertension French, S., Ouazani, N., Amsallem, M., Li, S., Zamanian, R. T., Chung, L., Haddad, F. WILEY. 2016
  • Dermatomyositis and Pregnancy: Assessment of Disease Activity and Pregnancy Outcomes Complicated By Maternal Dermatomyositis Miller, G., Moore, E., Valenzuela, A., Chung, L., Werth, V. P. WILEY. 2016
  • Immunosignature Technology Differentiates Patients with Systemic Sclerosis and Internal Organ Involvement Chung, L., Fiorentino, D., Gerwien, R., Jia, K., Legutki, J., Vergara, A., Zhu, L., Tarasow, T. M., Sykes, K. WILEY. 2016
  • Combined cell surface carbonic anhydrase 9 and CD147 antigens enable high-efficiency capture of circulating tumor cells in clear cell renal cell carcinoma patients ONCOTARGET Liu, S., Tian, Z., Zhang, L., Hou, S., Hu, S., Wu, J., Jing, Y., Sun, H., Yu, F., Zhao, L., Wang, R., Tseng, H., Zhau, H. E., Chung, L. W., Wu, K., Wang, H., Wu, J. B., Nie, Y., Shao, C. 2016; 7 (37): 59877-59891

    Abstract

    Circulating tumor cells (CTCs) have emerged as promising tools for noninvasive cancer detection and prognosis. Most conventional approaches for capturing CTCs use an EpCAM-based enrichment strategy, which does not work well in cancers that show low or no expression of EpCAM, such as renal cell carcinoma (RCC). In this study, we developed a new set of cell surface markers including CA9 and CD147 as alternative CTC-capture antigens specifically designed for RCC patients. We showed that the expression of both CA9 and CD147 was prevalent in a RCC patient cohort (n=70) by immunohistochemical analysis, with both molecules in combination covering 97.1% of cases. The NanoVelcro platform combined with CA9-/CD147-capture antibodies demonstrated significantly higher efficiency for capturing both CTC-mimicking renal cancer cells and RCC CTCs in peripheral blood, compared to the conventional EpCAM-based method. Using immunofluorescence cytological validation at the single-cell level, we were able to identify bona fide CTCs in RCC patient blood following the well-accepted criteria in our CTC-capture system. We further demonstrated a significant association of CTC numbers as well as the CTC expression status of Vimentin, a mesenchymal marker, with disease progression, including pathologic features and clinical staging. These results provide new insights into developing novel, effective targets/approaches for capturing CTCs, making CTCs a valuable tool for improved cancer detection, prognosis and treatment in RCC.

    View details for DOI 10.18632/oncotarget.10979

    View details for Web of Science ID 000387153900087

    View details for PubMedID 27494883

  • An Open-label, Phase II Study of the Safety and Tolerability of Pirfenidone in Patients with Scleroderma-associated Interstitial Lung Disease: the LOTUSS Trial. journal of rheumatology Khanna, D., Albera, C., Fischer, A., Khalidi, N., Raghu, G., Chung, L., Chen, D., Schiopu, E., Tagliaferri, M., Seibold, J. R., Gorina, E. 2016; 43 (9): 1672-1679

    Abstract

    Systemic sclerosis-associated interstitial lung disease (SSc-ILD) shares a number of clinical features and pathogenic mechanisms with idiopathic pulmonary fibrosis (IPF). This study was designed to evaluate the tolerability of the IPF treatment pirfenidone in SSc-ILD. The known gastrointestinal, skin, and liver adverse events (AE) of pirfenidone are of importance given the involvement of these organs in SSc.All patients received pirfenidone and were randomized 1:1 to either a 2- or 4-week titration starting at 801 mg/day and finishing at a maintenance dose of 2403 mg/day. Patients received pirfenidone for 16 weeks in total. Assessments included treatment-emergent AE (TEAE) and exploratory disease outcomes.Sixty-three patients were randomized; 96.8% experienced a TEAE and more patients reported TEAE during the titration versus the maintenance period. The most commonly reported TEAE were consistent with those observed for pirfenidone in IPF (nausea, headache, fatigue) and were similar regardless of titration schedule. More patients discontinued treatment because of TEAE in the 2- versus 4-week titration group (5 vs 1, respectively); all discontinuation events occurred > 3 weeks after reaching the full dose of pirfenidone. Mycophenolate mofetil (MMF), taken by 63.5% of patients in addition to pirfenidone, did not appear to affect tolerability. Exploratory disease outcomes remained largely unchanged.Pirfenidone showed an acceptable tolerability profile in SSc-ILD, although a longer titration may be associated with better tolerability. Tolerability was not affected by concomitant MMF. The present findings support further investigation of pirfenidone in future clinical trials in patients with SSc-ILD.ClinicalTrials.gov; www.clinicaltrials.gov NCT01933334.

    View details for DOI 10.3899/jrheum.151322

    View details for PubMedID 27370878

  • Secondhand Smoke Exposure Enhances Cardiac Fibrosis Effects on the Aging Rat Hearts ACTA CARDIOLOGICA SINICA Wu, J., Chang-Lee, S. N., Day, C. H., Ho, T., Viswanadha, V. P., Chung, L., Hwang, J., Jong, G., Kuo, W., Huang, C. 2016; 32 (5): 594-603

    Abstract

    Examining aging rats exposed to secondhand smoke (SHS) engenders changes in left ventricular remodeling due to age- or disease-dependent alterations.Rats were placed in whole-body exposure chambers and exposed to 10 cigarettes. Filtered air was introduced into the chamber at a low rate. Rats were exposed to SHS for 30 min, twice a day, 5 days per week for 1 month. After 4 weeks SHS exposure, rats were sacrificed for morphological study with trichome staining and left ventricular remodeling related protein analysis using western blot.Characteristic fibrotic morphology in the left ventricle increased significantly with aging and exposure to SHS. Exposure to SHS elevated TGFβ1/p-Smad2/3/CTGF and MMP2/MMP9 protein expression levels (p < 0.05). No significant differences in FGF-2 and UPA protein expression were noted as a result of SHS exposure. However, TIMP-1, TIMP-2, TIMP-3 and TIMP-4 protein expression were suppressed by SHS exposure. We also observed increased TGFβ1/p-Smad2/3/CTGF (p < 0.01), FGF-2/UPA (p < 0.05) and decreased TIMPs protein expression levels. Corresponding MMP2 and MMP9 upregulation occurred with aging and exposure to SHS. TGFβ1/p-Smad2/3/CTGF and FGF-2/UPA protein expression from SHS exposure were higher than that from aging. In contrast, MMP2 and MMP9 were increased in aging rats compared with SHS exposed rats (p < 0.05); however, TIMP-1 (p < 0.01), TIMP-2 (p < 0.01) and TIMP-3 (p < 0.05) were decreased. TIMP-4 protein expression levels were decreased compared with SHS exposed rats (p < 0.01).Aging and SHS exposure in rats will produce elevated fibrosis. Exposure to SHS will accelerate aging and left ventricular fibrosis.

    View details for DOI 10.6515/ACS20150824C

    View details for Web of Science ID 000384516400010

    View details for PubMedID 27713609

  • Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial LANCET Khanna, D., Denton, C. P., Jahreis, A., van Laar, J. M., Frech, T. M., Anderson, M. E., Baron, M., Chung, L., Fierlbeck, G., Lakshminarayanan, S., Allanore, Y., Pope, J. E., Riemekasten, G., Steen, V., Mueller-Ladner, U., Lafyatis, R., Stifano, G., Spotswood, H., Chen-Harris, H., Dziadek, S., Morimoto, A., Sornasse, T., Siegel, J., Furst, D. E. 2016; 387 (10038): 2630-2640

    Abstract

    Systemic sclerosis is a rare disabling autoimmune disease with few treatment options. The efficacy and safety of tocilizumab, an interleukin 6 receptor-α inhibitor, was assessed in the faSScinate phase 2 trial in patients with systemic sclerosis.We did this double-blind, placebo-controlled study at 35 hospitals in Canada, France, Germany, the UK, and the USA. We enrolled adults with progressive systemic sclerosis of 5 or fewer years' duration from first non-Raynaud's sign or symptom. Patients were randomly assigned (1:1) to weekly subcutaneous tocilizumab 162 mg or placebo. The primary endpoint was the difference in mean change from baseline in modified Rodnan skin score at 24 weeks. This study is registered with ClinicalTrials.gov, number NCT01532869.We enrolled 87 patients: 43 assigned to tocilizumab and 44 assigned to placebo. The least squares mean change in modified Rodnan skin score at 24 weeks was -3·92 in the tocilizumab group and -1·22 in the placebo group (difference -2·70, 95% CI -5·85 to 0·45; p=0·0915). The least squares mean change at 48 weeks was -6·33 in the tocilizumab group and -2·77 in the placebo group (treatment difference -3·55, 95% CI -7·23 to 0·12; p=0·0579). In one of several exploratory analyses, fewer patients in the tocilizumab group than in the placebo group had a decline in percent predicted forced vital capacity at 48 weeks (p=0·0373). However, we detected no significant difference in disability, fatigue, itching, or patient or clinician global disease severity. 42 (98%) of 43 patients in the tocilizumab group versus 40 (91%) of 44 in the placebo group had adverse events. 14 (33%) versus 15 (34%) had serious adverse events. Serious infections were more common in the tocilizumab group (seven [16%] of 43 patients) than in the placebo group (two [5%] of 44). One patient died in relation to tocilizumab treatment.Tocilizumab was not associated with a significant reduction in skin thickening. However, the difference was greater in the tocilizumab group than in the placebo group and we found some evidence of less decline in forced vital capacity. The efficacy and safety of tocilizumab should be investigated in a phase 3 trial before definitive conclusions can be made about its risks and benefits.F Hoffmann-La Roche, Genentech.

    View details for DOI 10.1016/S0140-6736(16)00232-4

    View details for Web of Science ID 000378390500031

    View details for PubMedID 27156934

  • Intestinal pseudo-obstruction in patients with systemic sclerosis: an analysis of the Nationwide Inpatient Sample. Rheumatology Valenzuela, A., Li, S., Becker, L., Fernandez-Becker, N., Khanna, D., Nguyen, L., Chung, L. 2016; 55 (4): 654-658

    Abstract

    Intestinal pseudo-obstruction is a rare gastrointestinal complication in patients with SSc without large studies examining its prevalence or outcomes. We aimed to compare outcomes in SSc patients with intestinal pseudo-obstruction to patients with intestinal pseudo-obstruction secondary to other causes, and SSc patients without intestinal pseudo-obstruction.This is a case-control study using the Healthcare Cost and Utilization Project Nationwide Inpatient Sample for the period 2002-2011. We included patients with the previously validated International Classification of Diseases-Clinical Modification-9 code 710.1 for SSc in combination with codes for intestinal pseudo-obstruction, and determined length of hospitalization and the risks for surgical procedures, use of total parenteral nutrition (TPN) and in-hospital mortality.A total of 193 610 SSc hospitalizations occurred in the USA between 2002 and 2011, of which 5.4% (n = 10 386) were associated with a concurrent intestinal pseudo-obstruction diagnosis (cases). In-hospital mortality was 7.3%. In multivariate analyses, cases were more likely to die during the inpatient stay and to receive TPN than patients with idiopathic intestinal pseudo-obstruction (control group 1), patients with intestinal pseudo-obstruction and diabetes (control group 2), and SSc patients without intestinal pseudo-obstruction (control group 3). Cases had longer in-hospital stay than control groups 2 and 3, and were less likely to undergo surgical procedures than control groups 1 and 2.Intestinal pseudo-obstruction is a rare cause of hospitalization in patients with SSc, but is associated with high in-hospital mortality in comparison with other SSc patients and those with intestinal pseudo-obstruction secondary to other causes.

    View details for DOI 10.1093/rheumatology/kev393

    View details for PubMedID 26615031

  • SREBP-2 promotes stem cell-like properties and metastasis by transcriptional activation of c-Myc in prostate cancer ONCOTARGET Li, X., Wu, J. B., Li, Q., Shigemura, K., Chung, L. W., Huang, W. 2016; 7 (11): 12869-12884

    Abstract

    Sterol regulatory element-binding protein-2 (SREBP-2) transcription factor mainly controls cholesterol biosynthesis and homeostasis in normal cells. The role of SREBP-2 in lethal prostate cancer (PCa) progression remains to be elucidated. Here, we showed that expression of SREBP-2 was elevated in advanced pathologic grade and metastatic PCa and significantly associated with poor clinical outcomes. Biofunctional analyses demonstrated that SREBP-2 induced PCa cell proliferation, invasion and migration. Furthermore, overexpression of SREBP-2 increased the PCa stem cell population, prostasphere-forming ability and tumor-initiating capability, whereas genetic silencing of SREBP-2 inhibited PCa cell growth, stemness, and xenograft tumor growth and metastasis. Clinical and mechanistic data showed that SREBP-2 was positively correlated with c-Myc and induced c-Myc activation by directly interacting with an SREBP-2-binding element in the 5'-flanking c-Myc promoter region to drive stemness and metastasis. Collectively, these clinical and experimental results reveal a novel role of SREBP-2 in the induction of a stem cell-like phenotype and PCa metastasis, which sheds light on translational potential by targeting SREBP-2 as a promising therapeutic approach in PCa.

    View details for Web of Science ID 000375679600084

    View details for PubMedID 26883200

  • Corticosteroids in Myositis and Scleroderma. Rheumatic diseases clinics of North America Postolova, A., Chen, J. K., Chung, L. 2016; 42 (1): 103-118

    Abstract

    Idiopathic inflammatory myopathies (IIMs) involve inflammation of the muscles and are classified by the patterns of presentation and immunohistopathologic features on skin and muscle biopsy into 4 categories: dermatomyositis, polymyositis, inclusion body myositis, and immune-mediated necrotizing myopathy. Systemic corticosteroid (CS) treatment is the standard of care for IIM with muscle and organ involvement. The extracutaneous features of systemic sclerosis are frequently treated with CS; however, high doses have been associated with scleroderma renal crisis in high-risk patients. Although CS can be effective first-line agents, their significant side effect profile encourages concomitant treatment with other immunosuppressive medications to enable timely tapering.

    View details for DOI 10.1016/j.rdc.2015.08.011

    View details for PubMedID 26611554

  • Corticosteroids in Myositis and Scleroderma. Rheumatic diseases clinics of North America Postolova, A., Chen, J. K., Chung, L. 2016; 42 (1): 103-118

    Abstract

    Idiopathic inflammatory myopathies (IIMs) involve inflammation of the muscles and are classified by the patterns of presentation and immunohistopathologic features on skin and muscle biopsy into 4 categories: dermatomyositis, polymyositis, inclusion body myositis, and immune-mediated necrotizing myopathy. Systemic corticosteroid (CS) treatment is the standard of care for IIM with muscle and organ involvement. The extracutaneous features of systemic sclerosis are frequently treated with CS; however, high doses have been associated with scleroderma renal crisis in high-risk patients. Although CS can be effective first-line agents, their significant side effect profile encourages concomitant treatment with other immunosuppressive medications to enable timely tapering.

    View details for DOI 10.1016/j.rdc.2015.08.011

    View details for PubMedID 26611554

  • Digital Sympathectomy in Patients With Scleroderma: An Overview of the Practice and Referral Patterns and Perceptions of Rheumatologists. Annals of plastic surgery Chiou, G., Crowe, C., Suarez, P., Chung, L., Curtin, C., Chang, J. 2015; 75 (6): 637-643

    Abstract

    Periarterial sympathectomy is a treatment option for patients with systemic sclerosis (SSc) suffering from digital vasculopathy. Despite potential benefits of ulcer healing, pain improvement, and amputation prevention, this operation appears to be infrequently performed. The aims of our study are as follows: (1) to assess national digital sympathectomy rates in patients with SSc and (2) to improve our understanding of referring physicians' perceptions of operative management and access to hand surgeons. Our hypothesis is that rheumatologists' practices largely influence their referral patterns for digital sympathectomy.To determine the rates and demographics of hospitalized patients with SSc who had undergone digital sympathectomy, we queried the Nationwide Inpatient Sample from 2006 to 2010. Additionally, we mailed a self-administered survey to a national sample of 500 board-certified rheumatologists to elicit their practice patterns and perceptions of digital sympathectomy. Using logistic regression, we analyzed potential predictor variables associated with rheumatologists performing the following: (1) routinely counseling patients about digital sympathectomy and (2) expressing the desire to refer these patients for operative evaluation.Of 348,539 hospitalizations associated with a diagnosis of SSc, only 0.2% were for digital sympathectomy. Our questionnaire revealed that only 50% of rheumatologists routinely counseled, whereas 67% expressed the desire to refer. Factors associated with increased rheumatologists' interest in surgical management for patients with SSc included positive perception of the operation's efficacy, comfort with postoperative management, and interdisciplinary relationship with a hand surgeon.Critical components to increasing appropriate utilization of digital sympathectomy include enhancing rheumatologists' understanding of the operation, comfort with postoperative management, and promoting strong, interdisciplinary relationships with hand surgeons. Increasing education and awareness, as well as establishing a solid referral network of hand surgeons may thereby improve patient access to digital sympathectomy.

    View details for DOI 10.1097/SAP.0000000000000614

    View details for PubMedID 26418780

  • Anti-cancer efficacy of SREBP inhibitor, alone or in combination with docetaxel, in prostate cancer harboring p53 mutations ONCOTARGET Li, X., Wu, J. B., Chung, L. W., Huang, W. 2015; 6 (38): 41018-41032

    Abstract

    Mutant p53 proteins (mutant p53s) have oncogenic gain-of-function properties correlated with tumor grade, castration resistance, and prostate cancer (PCa) tumor recurrence. Docetaxel is a standard first-line treatment for metastatic castration-resistant PCa (mCRPC) after the failure of hormone therapy. However, most mCRPC patients who receive docetaxel experience only transient benefits and rapidly develop incurable drug resistance, which is closely correlated with the p53 mutation status. Mutant p53s were recently reported to regulate the metabolic pathways via sterol regulatory element-binding proteins (SREBPs). Therefore, targeting the SREBP metabolic pathways with docetaxel as a combination therapy may offer a potential strategy to improve anti-tumor efficacy and delay cellular drug resistance in mCRPC harboring mutant p53s. Our previous data showed that fatostatin, a new SREBP inhibitor, inhibited cell proliferation and induced apoptosis in androgen receptor (AR)-positive PCa cell lines and xenograft mouse models. In this study, we demonstrated that mutant p53s activate the SREBP-mediated metabolic pathways in metastatic AR-negative PCa cells carrying mutant p53s. By blocking the SREBP pathways, fatostatin inhibited cell growth and induced apoptosis in metastatic AR-negative PCa cells harboring mutant p53s. Furthermore, the combination of fatostatin and docetaxel resulted in greater proliferation inhibition and apoptosis induction compared with single agent treatment in PCa cells in vitro and in vivo, especially those with mutant p53s. These data suggest for the first time that fatostatin alone or in combination with docetaxel could be exploited as a novel and promising therapy for metastatic PCa harboring p53 mutations.

    View details for Web of Science ID 000366115500048

    View details for PubMedID 26512780

  • Survival in systemic sclerosis-pulmonary arterial hypertension by serum autoantibody status in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) Registry SEMINARS IN ARTHRITIS AND RHEUMATISM Hinchcliff, M., Khanna, S., Hsu, V. M., Lee, J., Almagor, O., Chang, R. W., Steen, V., Chung, L. 2015; 45 (3): 309-314

    Abstract

    To determine the association between serum autoantibodies and survival in patients with incident systemic sclerosis (SSc)-pulmonary arterial hypertension (PAH) enrolled in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) Registry.Patients with definite PAH diagnosed by right heart catheterization within 6 months of registry enrollment were studied. Serum autoantibodies were assayed at each participating institution's clinical laboratory. Mortality data were collected from electronic medical records and/or the Social Security Death Index. Kaplan-Meier survival estimates were reported for five autoantibody groups (anticentromere/AC, nucleolar ANA/NUC, anti-topoisomerase/Scl-70, overlapping or non-specific autoantibodies/other, and a combined group with similar survival consisting of RNA polymerase III, U1RNP, and autoantibody-negative patients). Cox proportional hazards models permitted examination of the association between autoantibody groups and overall survival, controlling for age, sex, race, and SSc disease duration.In all, 162 subjects had PAH, and serum autoantibody and survival information; 60 (37%) had AC, 39 (24%) NUC, 11 (7%) Scl-70, 28 (17%) had other, 9 (6%) RNA pol, 8 (5%) U1RNP autoantibodies, and 7 (4%) had negative antibodies; 32 (20%) subjects died over a median follow-up time of 2.1 years (range: 0.01-6.8); 1- and 3-year survival estimates were, respectively, 94% and 78% for AC, 94% and 72% for NUC, 89% and 63% for Scl-70, 92% and 79% for the other group, and 100% and 93% for the combined group. Unadjusted and adjusted hazard ratios revealed no statistically significant association between risk of death and autoantibodies.Anticentromere and NUC autoantibodies are prevalent in SSc-PAH patients. An association between serum autoantibodies and survival in patients with SSc-PAH was not identified in the PHAROS cohort.

    View details for DOI 10.1016/j.semarthrit.2015.06.011

    View details for Web of Science ID 000369773800008

    View details for PubMedID 26210782

    View details for PubMedCentralID PMC4656087

  • Leukotriene B-4 Activates Pulmonary Artery Adventitial Fibroblasts in Pulmonary Hypertension HYPERTENSION Qian, J., Tian, W., Jiang, X., Tamosiuniene, R., Sung, Y. K., Shuffle, E. M., Tu, A. B., Valenzuela, A., Jiang, S., Zamanian, R. T., Fiorentino, D. F., Voelkel, N. F., Peters-Golden, M., Stenmark, K. R., Chung, L., Rabinovitch, M., Nicolls, M. R. 2015; 66 (6): 1227-1239

    Abstract

    A recent study demonstrated a significant role for leukotriene B4 (LTB4) causing pulmonary vascular remodeling in pulmonary arterial hypertension. LTB4 was found to directly injure luminal endothelial cells and promote growth of the smooth muscle cell layer of pulmonary arterioles. The purpose of this study was to determine the effects of LTB4 on the pulmonary adventitial layer, largely composed of fibroblasts. Here, we demonstrate that LTB4 enhanced human pulmonary artery adventitial fibroblast proliferation, migration, and differentiation in a dose-dependent manner through its cognate G-protein-coupled receptor, BLT1. LTB4 activated human pulmonary artery adventitial fibroblast by upregulating p38 mitogen-activated protein kinase as well as Nox4-signaling pathways. In an autoimmune model of pulmonary hypertension, inhibition of these pathways blocked perivascular inflammation, decreased Nox4 expression, reduced reactive oxygen species production, reversed arteriolar adventitial fibroblast activation, and attenuated pulmonary hypertension development. This study uncovers a novel mechanism by which LTB4 further promotes pulmonary arterial hypertension pathogenesis, beyond its established effects on endothelial and smooth muscle cells, by activating adventitial fibroblasts.

    View details for DOI 10.1161/HYPERTENSIONAHA.115.06370

    View details for Web of Science ID 000364481400021

    View details for PubMedID 26558820

    View details for PubMedCentralID PMC4646718

  • Calcinosis: pathophysiology and management. Current opinion in rheumatology Valenzuela, A., Chung, L. 2015; 27 (6): 542-548

    Abstract

    This article reviews the most updated literature regarding the epidemiology, pathophysiology, diagnosis, and treatment of calcinosis cutis in patients with systemic sclerosis (SSc).Our review identified observational studies that describe the frequency of calcinosis in SSc and associated clinical features, genetic studies in animal models of heritable disorders leading to calcium deposition, and case series and case reports describing new diagnostic approaches and therapeutic interventions.Calcinosis cutis is the deposition of calcium in the skin and subcutaneous tissues. It affects almost one quarter of patients with SSc, and is associated with longer disease duration, digital ulcers, acroosteolysis, positive anticentromere antibody, and positive anti-PM/Scl antibody. Local trauma, chronic inflammation, and vascular hypoxia have been proposed as potential pathomechanisms. The development of mouse models that mimic heritable ectopic mineralization disorders are contributing to the understanding of the process of calcification. Diagnosis can be made clinically or with plain radiography. Experimental diagnostic studies include ultrasonography, multidetector computed tomography, and dual-energy computed tomography. Several pharmacologic therapies have been tried for calcinosis with variable results, but surgical excision of calcium deposits remains the mainstay of treatment.

    View details for DOI 10.1097/BOR.0000000000000220

    View details for PubMedID 26352733

  • Validation of the Cutaneous Dermatomyositis Disease Area and Severity Index: characterizing disease severity and assessing responsiveness to clinical change BRITISH JOURNAL OF DERMATOLOGY Anyanwu, C. O., Fiorentino, D. F., Chung, L., Dzuong, C., Wang, Y., Okawa, J., Carr, K., PROPERT, K. J., Werth, V. P. 2015; 173 (4): 969-974

    Abstract

    The Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) was developed for use in clinical trials and longitudinal patient assessment.To characterize disease severity using the CDASI and assess the responsiveness of this instrument to clinically meaningful changes in disease activity.Patients with cutaneous dermatomyositis at the University of Pennsylvania (UPenn, n = 93) and Stanford University (Stanford, n = 106) were prospectively evaluated using the CDASI, physician global assessment (PGA) Likert scales and a visual analogue scale (VAS). Data was analysed using logistic regression models and receiver operating characteristic curves to select cut-offs.Baseline CDASI activity scores for the patients evaluated at UPenn ranged from 0 to 47 (median 17), and baseline PGA VAS scores ranged from 0 to 9·6 (median 1·1). At UPenn a CDASI activity score of 19 differentiated mild from moderate and severe disease. At Stanford baseline CDASI scores ranged from 0 to 48 (median 21), baseline PGA VAS scores ranged from 0 to 9·7 (median 4·2) and CDASI activity scores of 14 or less characterized mild disease. When a 2-cm change in the PGA VAS was regarded as a clinically significant improvement, a 4-point (UPenn) or 5-point (Stanford) change in CDASI reflected a minimal clinically significant response.The CDASI is a valid and responsive measure that can be used to characterize cutaneous dermatomyositis severity and detect improvement in disease activity. Variations in cut-offs may be due to differences in disease severity between the two populations or inter-rater variations in the use of the external gold measures.

    View details for DOI 10.1111/bjd.13915

    View details for Web of Science ID 000363896800020

    View details for PubMedID 25994337

    View details for PubMedCentralID PMC4878996

  • Near-infrared fluorescence heptamethine carbocyanine dyes mediate imaging and targeted drug delivery for human brain tumor BIOMATERIALS Wu, J. B., Shi, C., Chu, G. C., Xu, Q., Zhang, Y., Li, Q., Yu, J. S., Zhau, H. E., Chung, L. W. 2015; 67: 1-10

    Abstract

    Brain tumors and brain metastases are among the deadliest malignancies of all human cancers, largely due to the cellular blood-brain and blood-tumor barriers that limit the delivery of imaging and therapeutic agents from the systemic circulation to tumors. Thus, improved strategies for brain tumor visualization and targeted treatment are critically needed. Here we identified and synthesized a group of near-infrared fluorescence (NIRF) heptamethine carbocyanine dyes and derivative NIRF dye-drug conjugates for effective imaging and therapeutic targeting of brain tumors of either primary or metastatic origin in mice, which is mechanistically mediated by tumor hypoxia and organic anion-transporting polypeptide genes. We also demonstrate that these dyes, when conjugated to chemotherapeutic agents such as gemcitabine, significantly restricted the growth of both intracranial glioma xenografts and prostate tumor brain metastases and prolonged survival in mice. These results show promise in the application of NIRF dyes as novel theranostic agents for the detection and treatment of brain tumors.

    View details for DOI 10.1016/j.biomaterials.2015.07.028

    View details for Web of Science ID 000361078600001

    View details for PubMedID 26197410

  • There Is a Need for New Systemic Sclerosis Subset Criteria: A Content Analytic Approach Johnson, S., Soowamber, M., Fransen, J., Khanna, D., van den Hoogen, F. J., Baron, M., Cerinic, M., Denton, C. P., Medsger, T. A., Carreira, P. E., Riemekasten, G., Distler, J. W., Gabrielli, A., Steen, V. D., Chung, L., Silver, R., Varga, J., Mueller-Ladner, U., Vonk, M. C., Walker, U. A., Wollheim, F., Herrick, A. L., Furst, D. E., Czirjak, L., Kowal-Bielecka, O., Del Galdo, F., Cutolo, M., Hunzelmann, N., Murray, C., Foeldvari, I., Mouthon, L., Damjanov, N., Kahaleh, B., Frech, T. M., Assassi, S., Saketkoo, L., Pope, J. E. WILEY-BLACKWELL. 2015
  • Safety and Tolerability of Pirfenidone in Patients with Systemic Sclerosis Interstitial Lung Disease Khanna, D., Albera, C., Fischer, A., Seibold, J. R., Khalidi, N. A., Raghu, G., Chung, L., Schiopu, E., Chen, D., Gorina, E. WILEY-BLACKWELL. 2015
  • Surgical treatment of systemic sclerosis-is it justified to offer peripheral sympathectomy earlier in the disease process? Microsurgery Momeni, A., Sorice, S. C., Valenzuela, A., Fiorentino, D. F., Chung, L., Chang, J. 2015; 35 (6): 441-446

    Abstract

    Systemic sclerosis (SSc) is a rare connective tissue disease associated with significant digital vasculopathy. Peripheral sympathectomy is frequently offered late in the disease process after severe digital ischemia has already occurred with patients being symptomatic for numerous years. The purpose of the present study was to analyze the results of peripheral sympathectomy in patients with a confirmed diagnosis of SSc.A retrospective analysis of 17 patients (26 hands) who underwent peripheral sympathectomy between January 2003 and September 2013 was performed. Data regarding patient demographics, clinical features, and postoperative outcomes were retrieved. Of note, preoperative pain was present in all patients with a mean duration of 9.6 years prior to peripheral sympathectomy.Pain improvement/resolution was seen in 24 hands (92.3%). Digital ulcers healed in all patients with only two patients (two hands; 7.7%) requiring surgical intervention for ulcer recurrence 6 months and 4.5 years later. Minor complications were seen in seven hands (26.9%); including infection, wound opening, and stitch abscess, but none required surgical intervention. Seven of eight patients queried would have preferred surgical treatment at an earlier point in the disease process.Peripheral sympathectomy is a well-tolerated procedure in patients with SSc and is associated with predictable pain relief and ulcer healing in the majority of patients. In light of these findings it seems prudent to offer surgical treatment not as a last resort but rather earlier in the disease process to decrease the duration that patients suffer pain. © 2015 Wiley Periodicals, Inc. Microsurgery, 2015.

    View details for DOI 10.1002/micr.22379

    View details for PubMedID 25585522

  • Monitoring and Diagnostic Approaches for Pulmonary Arterial Hypertension in Patients with Systemic Sclerosis. Rheumatic diseases clinics of North America Valenzuela, A., Nandagopal, S., Steen, V. D., Chung, L. 2015; 41 (3): 489-506

    Abstract

    Pulmonary arterial hypertension (PAH) is one of the leading causes of death in patients with systemic sclerosis (SSc). Given the high prevalence and poor survival of SSc-PAH, and that aggressive management of mild disease may be associated with better outcomes, screening is critical. Right heart catheterization (RHC) is the gold standard for the definitive diagnosis of PAH, and should be performed in those patients in whom this diagnosis is suspected. Once a diagnosis of PAH is confirmed by RHC, treatment with PAH-specific therapies should be initiated as soon as possible.

    View details for DOI 10.1016/j.rdc.2015.04.009

    View details for PubMedID 26210131

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

    Abstract

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

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

    View details for Web of Science ID 000357069900001

    View details for PubMedID 26071192

    View details for PubMedCentralID PMC4487200

  • Validation of the ICD-9-CM code for systemic sclerosis using updated ACR/EULAR classification criteria SCANDINAVIAN JOURNAL OF RHEUMATOLOGY VALENZUELA, A., Yaqub, A., Fiorentino, D., Krishnan, E., Chung, L. 2015; 44 (3): 253-255
  • Connective Tissue Disease-Associated Pulmonary Arterial Hypertension RHEUMATIC DISEASE CLINICS OF NORTH AMERICA Sung, Y. K., Chung, L. 2015; 41 (2): 295-?

    Abstract

    Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling of pulmonary arterioles that leads to increased pulmonary vascular resistance, right heart failure, and death. It is associated with connective tissue diseases, including systemic sclerosis, systemic lupus erythematosus, and mixed connective tissue disease. PAH is characterized by dyspnea on exertion and fatigue. Syncopal events suggest severe disease. Patients may present with signs of right heart failure. One- and 3-year survival rates are approximately 81% and 52%, respectively. Given the high prevalence and mortality, algorithms for screening are currently under investigation and will hopefully lead to earlier diagnosis and improved survival.

    View details for DOI 10.1016/j.rdc.2015.01.003

    View details for Web of Science ID 000353435900011

  • Cutaneous ulceration in dermatomyositis: association with anti-melanoma differentiation-associated gene 5 antibodies and interstitial lung disease. Arthritis care & research Narang, N. S., Casciola-Rosen, L., Li, S., Chung, L., Fiorentino, D. F. 2015; 67 (5): 667-672

    Abstract

    To identify clinical and serologic correlates of cutaneous ulcers in dermatomyositis (DM).We retrospectively examined a cohort of 152 DM patients. We compared the features of patients with ulcers to those without ulcers using chi-square or Fisher's exact tests and used univariate and multivariate logistic regression models to assess the association between ulcers and clinical features such as malignancy, interstitial lung disease (ILD), and amyopathic disease.Forty-three patients (28%) had cutaneous ulcers. Nearly half the patients had ulcers present in more than 1 location: 24 (56%) had ulcers over the extensor surfaces of joints, 18 (42%) at the digital pulp or periungual areas, and 25 (58%) had ulcers located elsewhere. In univariate analysis ulcers were associated with Asian race, but not with other clinical and demographic features, including malignancy or ILD. In multivariate analysis ulcers were significantly associated with anti-melanoma differentiation gene 5 (anti-MDA5) antibodies (odds ratio 10.14, 95% confidence interval 1.95-52.78; P = 0.0059) and this was greatest for ulcers located at the digital pulp. In patients with cutaneous ulcers, ILD risk was specifically increased only in patients with anti-MDA5-positive antibodies.We confirmed the strong association between anti-MDA5 antibodies and cutaneous ulcers, with the novel finding that the association of cutaneous ulcers with ILD depends upon the presence of anti-MDA5 antibodies. DM patients who display this cutaneous phenotype should undergo appropriate evaluation for ILD.

    View details for DOI 10.1002/acr.22498

    View details for PubMedID 25331610

    View details for PubMedCentralID PMC4404195

  • Connective tissue disease-associated pulmonary arterial hypertension. Rheumatic diseases clinics of North America Sung, Y. K., Chung, L. 2015; 41 (2): 295-313

    Abstract

    Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling of pulmonary arterioles that leads to increased pulmonary vascular resistance, right heart failure, and death. It is associated with connective tissue diseases, including systemic sclerosis, systemic lupus erythematosus, and mixed connective tissue disease. PAH is characterized by dyspnea on exertion and fatigue. Syncopal events suggest severe disease. Patients may present with signs of right heart failure. One- and 3-year survival rates are approximately 81% and 52%, respectively. Given the high prevalence and mortality, algorithms for screening are currently under investigation and will hopefully lead to earlier diagnosis and improved survival.

    View details for DOI 10.1016/j.rdc.2015.01.003

    View details for PubMedID 25836644

  • Distinctive cutaneous and systemic features associated with antitranscriptional intermediary factor-1? antibodies in adults with dermatomyositis. Journal of the American Academy of Dermatology Fiorentino, D. F., Kuo, K., Chung, L., Zaba, L., Li, S., Casciola-Rosen, L. 2015; 72 (3): 449-455

    Abstract

    Antibodies against transcriptional intermediary factor (TIF)-1γ are associated with malignancy in dermatomyositis (DM). Identification of clinical findings associated with anti-TIF-1γ antibodies in DM is a high priority for both patient diagnosis and risk assessment.We sought to define the clinical phenotype of patients with anti-TIF-1γ DM.Using a novel, sensitive, and specific assay for anti-TIF-1γ antibodies, we retrospectively tested plasma from 134 adult patients with DM and examined associations between anti-TIF-1γ antibodies and particular clinical and laboratory features.In all, 55 (41%) patients had autoantibodies to TIF-1γ. Anti-TIF-1γ positive patients were less likely to have systemic features including interstitial lung disease, Raynaud phenomenon, and arthritis/arthralgia. Patients with TIF-1γ autoantibodies had more extensive skin involvement, and some patients manifested characteristic findings including palmar hyperkeratotic papules, psoriasis-like lesions and a novel finding of hypopigmented and telangiectatic ("red on white") patches.This was a retrospective study from a single tertiary referral center.TIF-1γ is the most commonly targeted DM-specific autoantigen in adults in a large US cohort. Although these patients tend to have less systemic involvement, their skin disease is often extensive and characteristic. Recognition of cutaneous findings in anti-TIF-1γ positive patients may allow more accurate and timely diagnosis and effective treatment of patients with DM.

    View details for DOI 10.1016/j.jaad.2014.12.009

    View details for PubMedID 25595720

    View details for PubMedCentralID PMC4351728

  • Validation of a Novel Radiographic Scoring System for Calcinosis Affecting the Hands of Patients With Systemic Sclerosis ARTHRITIS CARE & RESEARCH Chung, L., Valenzuela, A., Fiorentino, D., Stevens, K., Li, S., Harris, J., Hutchinson, C., Assassi, S., Beretta, L., Lakshminarayanan, S., Rodriguez-Reyna, T. S., Denton, C. P., Taillefer, R. G., Herrick, A. L., Baron, M. 2015; 67 (3): 425-430

    Abstract

    Objective: There are currently no validated outcome measures to assess calcinosis severity in systemic sclerosis (SSc). We sought to develop and validate a novel radiographic scoring system for calcinosis affecting the hands of SSc patients for potential use in future clinical trials. Methods: Following a 1-hour teleconference training session, 12 investigators (8 rheumatologists, 1 dermatologist, 3 radiologists) scored 12 hand radiographs in random order using two scoring systems (termed "simple" and "complex"), and re-scored 2 randomly assigned radiographs after a minimum of 24 hours. Inter-rater and intra-rater reliability were assessed using a weighted kappa coefficient for the simple system, and intraclass correlation coefficient (ICC) for the complex system (ICC < 0.4 poor, 0.4-0.7 moderate, > 0.7 excellent). Results: Mean time to complete the complex scoring system was significantly longer than the simple scoring system (4.0 vs. 0.4 minutes, p<.0001). Overall inter-rater reliability for the simple scoring system was poor (kappa=0.39, 95% CI 0.1-0.52), but improved if dichotomized as mild/moderate vs. severe (kappa=0.51, 95% CI 0.26-0.7). Inter-rater reliability was excellent for the complex scoring system (ICC=0.89, 95% CI 0.86-0.92). Intra-rater reliability was moderate for the simple scoring system (kappa=0.67, 95% CI 0.37-0.96), but almost perfect for the complex scoring system (ICC=0.93, 95%CI 0.89-0.97). Conclusion: We developed a novel radiographic scoring system that accounts for the area coverage, density, and anatomic location of calcinosis affecting the hands in patients with SSc. This scoring system is feasible with excellent reliability and should undergo further validation testing for use in clinical trials. © 2014 American College of Rheumatology.

    View details for DOI 10.1002/acr.22434

    View details for Web of Science ID 000350295500015

    View details for PubMedID 25155948

  • Monoamine Oxidase A Inhibitor-Near-Infrared Dye Conjugate Reduces Prostate Tumor Growth JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Wu, J. B., Lin, T., Gallagher, J. D., Kushal, S., Chung, L. W., Zhau, H. E., Oenyuk, B. Z., Shih, J. C. 2015; 137 (6): 2366-2374

    Abstract

    Development of anti-cancer agents with high tumor-targeting specificity and efficacy is critical for modern multidisciplinary cancer research. Monoamine oxidase A (MAOA), a mitochondria-bound enzyme, degrades monoamine neurotransmitters and dietary monoamines. Recent evidence suggests a correlation between increased MAOA expression and prostate cancer (PCa) progression with poor outcomes for patients. MAOA induces epithelial-mesenchymal transition (EMT) and augments hypoxic effects by producing excess reactive oxygen species. Thus, development of MAOA inhibitors which selectively target tumors becomes an important goal in cancer pharmacology. Here we describe the design, synthesis, and in vitro and in vivo evaluation of NMI, a conjugate that combines a near-infrared dye for tumor targeting with the moiety derived from the MAOA inhibitor clorgyline. NMI inhibits MAOA with low micromolar IC50, suppresses PCa cell proliferation and colony formation, and reduces migration and invasion. In mouse PCa xenografts, NMI targets tumors with no detectable accumulation in normal tissues, providing effective reduction of the tumor burden. Analysis of tumor specimens shows reduction in Ki-67(+) and CD31(+) cells, suggesting a decrease of cell proliferation and angiogenesis and an increase in M30(+) cells, indicating increased apoptosis. Gene expression profiles of tumors treated with NMI demonstrate reduced expression of oncogenes FOS, JUN, NFKB, and MYC and cell cycle regulators CCND1, CCNE1, and CDK4/6, along with increases in the levels of tumor suppressor gene TP53, cell cycle inhibitors CDKN1A and CDKN2A, and MAOA-downstream genes that promote EMT, tumor hypoxia, cancer cell migration, and invasion. These data suggest that NMI exerts its effect through tumor-targeted delivery of a MAOA-inactivating group, making NMI a valuable anti-tumor agent.

    View details for DOI 10.1021/ja512613j

    View details for Web of Science ID 000349807000039

    View details for PubMedID 25585152

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

    Abstract

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

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

    View details for PubMedID 26071192

  • Management of digital ischemia Raynaud's Phenomenon: A Guide to Pathogenesis and Treatment Chung, L., Valenzuela, A., Adeduntan, R. Heidelberg, Dordrecht, London, Springer. 2015; 1: 339–360
  • Unique predictors of mortality in patients with pulmonary arterial hypertension associated with systemic sclerosis in the REVEAL registry. Chest Chung, L., Farber, H. W., Benza, R., Miller, D. P., Parsons, L., Hassoun, P. M., McGoon, M., Nicolls, M. R., Zamanian, R. T. 2014; 146 (6): 1494-1504

    Abstract

    Background:Patients with pulmonary arterial hypertension associated with systemic sclerosis (SSc-APAH) experience higher mortality rates than patients with idiopathic disease and those with other connective tissue diseases (CTD-APAH). We sought to identify unique predictors of mortality associated with SSc-APAH in the CTD-APAH population. Methods:The Registry to Evaluate Early and Long-Term PAH Management (REVEAL) is a multicenter, prospective US-based registry of patients with previously and newly diagnosed (enrollment within 90 days of diagnostic right heart catheterization) PAH. Cox regression models evaluated all previously identified candidate predictors of mortality in the overall REVEAL population to identify significant predictors of mortality in the SSc-APAH (n=500) versus non-SSc-CTD-APAH (n=304) populations. Results:Three-year survival in the previously diagnosed and newly diagnosed SSc-APAH group was 61.4±2.7% and 51.2±4.0%, respectively, compared with 80.9±2.7% and 76.4±4.6%, respectively, in the non-SSc-CTD-APAH group (P<.001). In multivariate analyses, males aged >60 years, systolic blood pressure (SBP) ≤110 mmHg, 6-minute walk distance (6MWD) <165 m, mean right atrial pressure (mRAP) >20 mmHg within 1 year, and pulmonary vascular resistance (PVR) >32 WU remained unique predictors of mortality in the SSc-APAH group; 6MWD ≥440 m was protective in the non-SSc-CTD-APAH group, but not the SSc-APAH group. Conclusions:Patients with SSc-APAH have higher mortality rates than non-SSc-CTD-APAH patients. Identifying SSc-APAH patients who are at particularly high risk of death, including elderly males and patients with low baseline SBP or 6MWD, or markedly elevated mRAP or PVR, will enable clinicians to identify patients who may benefit from closer monitoring and more aggressive treatment. Registered at:www.clinicaltrials.gov #NCT00370214.Patients with pulmonary arterial hypertension associated with systemic sclerosis (SSc-APAH) experience higher mortality rates than patients with idiopathic disease and those with other connective tissue diseases (CTD-APAH). We sought to identify unique predictors of mortality associated with SSc-APAH in the CTD-APAH population.The Registry to Evaluate Early and Long-Term PAH Management (REVEAL) is a multicenter, prospective US-based registry of patients with previously and newly diagnosed (enrollment within 90 days of diagnostic right heart catheterization) PAH. Cox regression models evaluated all previously identified candidate predictors of mortality in the overall REVEAL population to identify significant predictors of mortality in the SSc-APAH (n=500) versus non-SSc-CTD-APAH (n=304) populations.Three-year survival in the previously diagnosed and newly diagnosed SSc-APAH group was 61.4±2.7% and 51.2±4.0%, respectively, compared with 80.9±2.7% and 76.4±4.6%, respectively, in the non-SSc-CTD-APAH group (P<.001). In multivariate analyses, males aged >60 years, systolic blood pressure (SBP) ≤110 mmHg, 6-minute walk distance (6MWD) <165 m, mean right atrial pressure (mRAP) >20 mmHg within 1 year, and pulmonary vascular resistance (PVR) >32 WU remained unique predictors of mortality in the SSc-APAH group; 6MWD ≥440 m was protective in the non-SSc-CTD-APAH group, but not the SSc-APAH group.Patients with SSc-APAH have higher mortality rates than non-SSc-CTD-APAH patients. Identifying SSc-APAH patients who are at particularly high risk of death, including elderly males and patients with low baseline SBP or 6MWD, or markedly elevated mRAP or PVR, will enable clinicians to identify patients who may benefit from closer monitoring and more aggressive treatment.www.clinicaltrials.gov #NCT00370214.

    View details for DOI 10.1378/chest.13-3014

    View details for PubMedID 24992469

  • Pulmonary hypertension and interstitial lung disease within PHAROS: impact of extent of fibrosis and pulmonary physiology on cardiac haemodynamic parameters CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Fischer, A., Swigris, J. J., Bolster, M. B., Chung, L., Csuka, M. E., Domsic, R. T., Frech, T., Hinchcliff, M., Hsu, V., Hummers, L. K., Gomberg-Maitland, M., Mathai, S. C., Simms, R., Steen, V. D. 2014; 32 (6): S109-S114
  • Pulmonary hypertension and interstitial lung disease within PHAROS: impact of extent of fibrosis and pulmonary physiology on cardiac haemodynamic parameters. Clinical and experimental rheumatology Fischer, A., Swigris, J. J., Bolster, M. B., Chung, L., Csuka, M. E., Domsic, R., Frech, T., Hinchcliff, M., Hsu, V., Hummers, L. K., Gomberg-Maitland, M., Mathai, S. C., Simms, R., Steen, V. D. 2014; 32 (6): S-109 14

    Abstract

    We sought to examine the relationship between measures of ILD severity and PH in patients with SSc.We identified 55 subjects from 12 PHAROS sites with RHC-proven PH and HRCT evidence of ILD. Subjects with PH due to left heart disease were excluded. Baseline HRCT scans were scored by a standardised system that graded severity of ILD. Summary statistics were generated for baseline characteristics. Spearman correlation and linear regression were used to examine relationships between ILD and PH severity variables.The majority of subjects were white women; nearly half had limited cutaneous SSc. Most subjects were New York Heart Association functional class II or III. Pulmonary function testing revealed moderate restriction (mean FVC 64.3 ± 17.2% predicted) with severe reduction in diffusing capacity (mean DLco 34.2 ± 13.3% predicted). RHC demonstrated mild to moderate PH (mean PAP 35 ± 9 mmHg, mean PVR 5.1 ± 3.7 WU). There was no correlation between severity of ILD (by either HRCT or PFT) and cardiac haemodynamic parameters of PH.No association between severity of ILD and cardiac haemodynamic profiles were identified in this cohort. We believe this underscores the complex nature of PH and ILD in individuals with SSc. We do suspect that some individuals with SSc-ILD will also have concomitant pulmonary vascular disease but simple assessments to grade severity of ILD - by PFT or HRCT estimates of ILD extent - are likely not enough to reliably distinguish between PAH versus PH-ILD. Further research into how to distinguish and manage these subsets is warranted.

    View details for PubMedID 25372796

  • Heptamethine carbocyanine dye-mediated near-infrared imaging of canine and human cancers through the HIF-1 alpha/OATPs signaling axis ONCOTARGET Shi, C., Wu, J. B., Chu, G. C., Li, Q., Wang, R., Zhang, C., Zhang, Y., Kim, H. L., Wang, J., Zhau, H. E., Pan, D., Chung, L. W. 2014; 5 (20): 10114-10126

    Abstract

    Near-infrared (NIR) fluorescence imaging agents are promising tools for noninvasive cancer imaging. This study explored the specific uptake and retention of a NIR heptamethine carbocyanine MHI-148 dye by canine cancer cells and tissues and human prostate cancer (PCa) specimens and also the dye uptake mechanisms. The accumulation of MHI-148 was detected specifically in canine cancer cells and tissues and freshly harvested human PCa tissues xenografted in mice by NIR fluorescence microscopy and whole-body NIR optical imaging. Specific dye uptake in canine spontaneous tumors was further confirmed by PET imaging. Higher hypoxia-inducible factor-1α (HIF-1α) and organic anion-transporting polypeptide (OATP) protein and mRNA expression was demonstrated by multiplex quantum dots labeling and qPCR in tumors over that of normal tissues. Treating cancer cells with HIF-1α stabilizers activated HIF-1α downstream target genes, induced OATP superfamily gene expression and enhanced cellular uptake and retention of NIR dyes. Moreover, silencing HIF-1α by siRNA significantly decreased OATP mRNA expression and blocked NIR dye uptake in cancer cells. Together, these results demonstrated the preferential uptake of NIR dyes by canine and human cancer cells and tissues via the HIF-1α/OATPs signaling axis, which provides insights into future application of these dyes for cancer detection and treatment.

    View details for Web of Science ID 000348036500046

    View details for PubMedID 25361418

  • Muscle Disease in Systemic Sclerosis Is Associated with an Increased Risk for Cardiac Involvement Hong, J., Valenzuela, A., Fiorentino, D., Chung, L. WILEY-BLACKWELL. 2014: S314–S315
  • Intestinal Pseudo-Obstruction in Patients with Systemic Sclerosis: An Analysis of the Nationwide Inpatient Sample. Valenzuela, A., Li, S., Becker, L., Fernandez-Becker, N., Khanna, D., Linda Nguyen, Chung, L. WILEY-BLACKWELL. 2014: S1310
  • Survival in Systemic Sclerosis-Pulmonary Arterial Hypertension By Serum Autoantibody Status Hinchcliff, M., Khanna, S., Lee, J., Almagor, O., Chang, R. W., Steen, V. D., Chung, L. WILEY-BLACKWELL. 2014: S1180
  • Connective tissue disease-associated pulmonary arterial hypertension: "Beijing style" EUROPEAN RESPIRATORY JOURNAL Chung, L., Kawut, S. M. 2014; 44 (4): 839–41

    View details for DOI 10.1183/09031936.00090814

    View details for Web of Science ID 000342543700005

    View details for PubMedID 25271223

  • Lower Socioeconomic Status, Male Gender and Diffuse Scleroderma Are Associated with Worse Survival in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma Cohort Gordon, J. K., Zhang, W., Chung, L., Ma, Y., Steen, V. D., PHAROS Investigators WILEY-BLACKWELL. 2014: S321–S322
  • Near-infrared fluorescence imaging of cancer mediated by tumor hypoxia and HIFI alpha/OATPs signaling axis BIOMATERIALS Wu, J. B., Shao, C., Li, X., Shi, C., Li, Q., Hu, P., Chen, Y., Dou, X., Sahu, D., Li, W., Harada, H., Zhang, Y., Wang, R., Zhau, H. E., Chung, L. W. 2014; 35 (28): 8175-8185

    Abstract

    Near-infrared fluorescence (NIRF) imaging agents are promising tools for noninvasive cancer imaging. Here, we explored the mechanistic properties of a specific group of NIR heptamethine carbocyanines including MHI-148 dye we identified and synthesized, and demonstrated these dyes to achieve cancer-specific imaging and targeting via a hypoxia-mediated mechanism. We found that cancer cells and tumor xenografts exhibited hypoxia-dependent MHI-148 dye uptake in vitro and in vivo, which was directly mediated by hypoxia-inducible factor 1α (HIF1α). Microarray analysis and dye uptake assay further revealed a group of hypoxia-inducible organic anion-transporting polypeptides (OATPs) responsible for dye uptake, and the correlation between OATPs and HIF1α was manifested in progressive clinical cancer specimens. Finally, we demonstrated increased uptake of MHI-148 dye in situ in perfused clinical tumor samples with activated HIF1α/OATPs signaling. Our results establish these NIRF dyes as potential tumor hypoxia-dependent cancer-targeting agents and provide a mechanistic rationale for continued development of NIRF imaging agents for improved cancer detection, prognosis and therapy.

    View details for DOI 10.1016/j.biomaterials.2014.05.073

    View details for Web of Science ID 000339774700012

    View details for PubMedID 24957295

  • Effect of the endothelin type A-selective endothelin receptor antagonist ambrisentan on digital ulcers in patients with systemic sclerosis: Results of a prospective pilot study. Journal of the American Academy of Dermatology Chung, L., Ball, K., Yaqub, A., Lingala, B., Fiorentino, D. 2014; 71 (2): 400-401

    View details for DOI 10.1016/j.jaad.2014.04.028

    View details for PubMedID 25037794

  • Pharmacologic Therapy for Pulmonary Arterial Hypertension in Adults CHEST Guideline and Expert Panel Report CHEST Taichman, D. B., Ornelas, J., Chung, L., Klinger, J. R., Lewis, S., Mandel, J., Palevsky, H. I., Rich, S., Sood, N., Rosenzweig, E. B., Trow, T. K., Yung, R., Elliott, C. G., Badesch, D. B. 2014; 146 (2): 449-475

    Abstract

    Choices of pharmacologic therapies for pulmonary arterial hypertension (PAH) are ideally guided by high-level evidence. The objective of this guideline is to provide clinicians advice regarding pharmacologic therapy for adult patients with PAH as informed by available evidence.This guideline was based on systematic reviews of English language evidence published between 1990 and November 2013, identified using the MEDLINE and Cochrane Library databases. The strength of available evidence was graded using the Grades of Recommendations, Assessment, Development, and Evaluation methodology. Guideline recommendations, or consensus statements when available evidence was insufficient to support recommendations, were developed using a modified Delphi technique to achieve consensus.Available evidence is limited in its ability to support high-level recommendations. Therefore, we drafted consensus statements to address many clinical questions regarding pharmacotherapy for patients with PAH. A total of 79 recommendations or consensus statements were adopted and graded.Clinical decisions regarding pharmacotherapy for PAH should be guided by high-level recommendations when sufficient evidence is available. Absent higher level evidence, consensus statements based upon available information must be used. Further studies are needed to address the gaps in available knowledge regarding optimal pharmacotherapy for PAH.

    View details for DOI 10.1378/chest.14-0793

    View details for Web of Science ID 000340482400052

    View details for PubMedID 24937180

    View details for PubMedCentralID PMC4137591

  • Development of pulmonary hypertension in a high-risk population with systemic sclerosis in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS) cohort study. Seminars in arthritis and rheumatism Hsu, V. M., Chung, L., Hummers, L. K., Wigley, F., Simms, R., Bolster, M., Silver, R., Fischer, A., Hinchcliff, M. E., Varga, J., Goldberg, A. Z., Derk, C. T., Schiopu, E., Khanna, D., Shapiro, L. S., Domsic, R. T., Medsger, T., Mayes, M. D., Furst, D., Csuka, M. E., Molitor, J. A., Alkassab, F., Steen, V. D. 2014; 44 (1): 55-62

    Abstract

    PHAROS registry is a prospective longitudinal cohort study to understand the natural history of pulmonary hypertension (PH) in systemic sclerosis (SSc)."At-risk" pulmonary arterial hypertension (PAH) is defined by these entry criteria: echocardiogram (echo) systolic pulmonary arterial pressure (sPAP) >40mmHg, diffusion lung capacity of carbon monoxide (DLco) <55% predicted, or ratio of percentage forced vital capacity (FVC)/percentage DLco >1.6, as measured by pulmonary function testing (PFT). Patients were followed up annually and right heart catheterization (RHC) performed if PH was suspected. We used descriptive statistics and Kaplan-Meier estimate of time to PH diagnosis.A total of 251 "at-risk" subjects were enrolled between 2005 and 2012 and followed up for mean of 2.5 ± 1.2 years. The mean age at entry was 56.7 ± 11.0 and disease duration was 9.9 ± 8.7 years. Overall, 82 patients had RHC, and 35 were confirmed to have new PH. There were no differences in age, gender, SSc subtypes, antibodies, and disease duration between the "at-risk" and new PH groups. Using Kaplan-Meier survival, the time to PH was 10% at 2 years, 13% at 3 years, and 25% at 5 years. Most new PH patients at entry met the PFT criteria (76%), had significantly higher sPAP (p = 0.013), had shorter 6-min walk distance, and had exercise-induced hypoxia (p = 0.003) than "at-risk" PAH group.A low DLco, high FVC/DLco, exercise-induced hypoxia and entry echo sPAP > 40 were strongly associated with future PH, though RHC was necessary to confirm PH. This ongoing prospective study confirms that these high-risk factors do predict future PH.

    View details for DOI 10.1016/j.semarthrit.2014.03.002

    View details for PubMedID 24709277

  • Identification of clinical features and autoantibodies associated with calcinosis in dermatomyositis. JAMA dermatology Valenzuela, A., Chung, L., Casciola-Rosen, L., Fiorentino, D. 2014; 150 (7): 724-729

    Abstract

    Prior studies have estimated that up to 20% of adults with dermatomyositis (DM) have calcinosis, which can lead to significant morbidity. Identification of risk factors may provide a better understanding of the pathogenesis and ultimately therapy for this difficult clinical problem. Risk factors for calcinosis in adults with DM have not been extensively studied.To determine the prevalence of calcinosis and to identify associated clinical features in a cohort of extensively phenotyped adults with DM.A cross-sectional study of 126 patients diagnosed as having DM from January 1, 2006, through January 1, 2013, was performed. Patients were adults (≥18 years of age) attending the Stanford University Medical Center clinic.Calcinosis, defined as the presence of calcium deposition in the skin and subcutaneous tissues on physical examination.Fourteen patients (11.1%) had calcinosis, with the extremities most commonly involved. Patients with vs those without calcinosis had a longer disease duration (median, 6.9 years; range, 2.4-18.1; vs median, 3.9 years; range, 0.2-19.2 years; P = .003) and more fingertip ulcers (50.0% vs 9.3%, P < .001). An association between calcinosis and both interstitial lung disease and anti-MDA-5 autoantibodies was identified, but this association did not persist in multivariate models that adjusted for fingertip ulcers. Fingertip ulcers and disease duration were strongly associated with calcinosis in all multivariate models, independent of the underlying autoantibody present. Autoantibodies to NXP-2 were associated with calcinosis (odds ratio, 15.52; 95% CI, 2.01-119.90), whereas anti-transcriptional intermediary factor 1-γ antibodies were protective (odds ratio, 0.2; 95% CI, 0.01-0.99) in multivariate analyses that adjusted for fingertip ulcers and other covariates.Calcinosis was a relatively uncommon clinical feature in our cohort of adults with DM. Our data suggest that calcinosis is positively associated with longer disease duration, fingertip ulcers, and NXP-2 autoantibodies and negatively associated with transcriptional intermediary factor 1-γ antibodies. A common vascular mechanism may underlie the development of both calcinosis and fingertip ulcers in patients with DM.

    View details for DOI 10.1001/jamadermatol.2013.10416

    View details for PubMedID 24869801

  • Monoamine oxidase A mediates prostate tumorigenesis and cancer metastasis JOURNAL OF CLINICAL INVESTIGATION Wu, J. B., Shao, C., Li, X., Li, Q., Hu, P., Shi, C., Li, Y., Chen, Y., Yin, F., Liao, C., Stiles, B. L., Zhau, H. E., Shih, J. C., Chung, L. W. 2014; 124 (7): 2891-2908

    Abstract

    Tumors from patients with high-grade aggressive prostate cancer (PCa) exhibit increased expression of monoamine oxidase A (MAOA), a mitochondrial enzyme that degrades monoamine neurotransmitters and dietary amines. Despite the association between MAOA and aggressive PCa, it is unclear how MAOA promotes PCa progression. Here, we found that MAOA functions to induce epithelial-to-mesenchymal transition (EMT) and stabilize the transcription factor HIF1α, which mediates hypoxia through an elevation of ROS, thus enhancing growth, invasiveness, and metastasis of PCa cells. Knockdown and overexpression of MAOA in human PCa cell lines indicated that MAOA induces EMT through activation of VEGF and its coreceptor neuropilin-1. MAOA-dependent activation of neuropilin-1 promoted AKT/FOXO1/TWIST1 signaling, allowing FOXO1 binding at the TWIST1 promoter. Importantly, the MAOA-dependent HIF1α/VEGF-A/FOXO1/TWIST1 pathway was activated in high-grade PCa specimens, and knockdown of MAOA reduced or even eliminated prostate tumor growth and metastasis in PCa xenograft mouse models. Pharmacological inhibition of MAOA activity also reduced PCa xenograft growth in mice. Moreover, high MAOA expression in PCa tissues correlated with worse clinical outcomes in PCa patients. These findings collectively characterize the contribution of MAOA in PCa pathogenesis and suggest that MAOA has potential as a therapeutic target in PCa.

    View details for DOI 10.1172/JCI070982

    View details for Web of Science ID 000338688400017

    View details for PubMedID 24865426

  • Cardiac arrhythmias and conduction defects in systemic sclerosis. Rheumatology Vacca, A., Meune, C., Gordon, J., Chung, L., Proudman, S., Assassi, S., Nikpour, M., Rodriguez-Reyna, T. S., Khanna, D., Lafyatis, R., Matucci-Cerinic, M., Distler, O., Allanore, Y. 2014; 53 (7): 1172-1177

    Abstract

    Signs and symptoms of arrhythmias or conduction defects are frequently reported in patients with SSc. These rhythm disorders may have several origins (i.e., related to primary heart involvement, pericardial disease, valvular regurgitation or pulmonary arterial hypertension) and may negatively affect the overall prognosis of these patients. It is therefore important to identify patients at high risk for cardiac arrhythmias with a complete cardiological evaluation and to identify the underlying heart disease, including SSc-related myocardial involvement. In addition, some therapeutic options in SSc patients may differ from those recommended in other populations.

    View details for DOI 10.1093/rheumatology/ket377

    View details for PubMedID 24241036

  • Cardiac arrhythmias and conduction defects in systemic sclerosis RHEUMATOLOGY Vacca, A., Meune, C., Gordon, J., Chung, L., Proudman, S., Assassi, S., Nikpour, M., Rodriguez-Reyna, T. S., Khanna, D., Lafyatis, R., Matucci-Cerinic, M., Distler, O., Allanore, Y. 2014; 53 (7): 1172-1177

    Abstract

    Signs and symptoms of arrhythmias or conduction defects are frequently reported in patients with SSc. These rhythm disorders may have several origins (i.e., related to primary heart involvement, pericardial disease, valvular regurgitation or pulmonary arterial hypertension) and may negatively affect the overall prognosis of these patients. It is therefore important to identify patients at high risk for cardiac arrhythmias with a complete cardiological evaluation and to identify the underlying heart disease, including SSc-related myocardial involvement. In addition, some therapeutic options in SSc patients may differ from those recommended in other populations.

    View details for DOI 10.1093/rheumatology/ket377

    View details for Web of Science ID 000338647000004

    View details for PubMedCentralID PMC4065005

  • Identification of clinical features and autoantibodies associated with calcinosis in dermatomyositis. JAMA dermatology Valenzuela, A., Chung, L., Casciola-Rosen, L., Fiorentino, D. 2014; 150 (7): 724-729

    Abstract

    Prior studies have estimated that up to 20% of adults with dermatomyositis (DM) have calcinosis, which can lead to significant morbidity. Identification of risk factors may provide a better understanding of the pathogenesis and ultimately therapy for this difficult clinical problem. Risk factors for calcinosis in adults with DM have not been extensively studied.To determine the prevalence of calcinosis and to identify associated clinical features in a cohort of extensively phenotyped adults with DM.A cross-sectional study of 126 patients diagnosed as having DM from January 1, 2006, through January 1, 2013, was performed. Patients were adults (≥18 years of age) attending the Stanford University Medical Center clinic.Calcinosis, defined as the presence of calcium deposition in the skin and subcutaneous tissues on physical examination.Fourteen patients (11.1%) had calcinosis, with the extremities most commonly involved. Patients with vs those without calcinosis had a longer disease duration (median, 6.9 years; range, 2.4-18.1; vs median, 3.9 years; range, 0.2-19.2 years; P = .003) and more fingertip ulcers (50.0% vs 9.3%, P < .001). An association between calcinosis and both interstitial lung disease and anti-MDA-5 autoantibodies was identified, but this association did not persist in multivariate models that adjusted for fingertip ulcers. Fingertip ulcers and disease duration were strongly associated with calcinosis in all multivariate models, independent of the underlying autoantibody present. Autoantibodies to NXP-2 were associated with calcinosis (odds ratio, 15.52; 95% CI, 2.01-119.90), whereas anti-transcriptional intermediary factor 1-γ antibodies were protective (odds ratio, 0.2; 95% CI, 0.01-0.99) in multivariate analyses that adjusted for fingertip ulcers and other covariates.Calcinosis was a relatively uncommon clinical feature in our cohort of adults with DM. Our data suggest that calcinosis is positively associated with longer disease duration, fingertip ulcers, and NXP-2 autoantibodies and negatively associated with transcriptional intermediary factor 1-γ antibodies. A common vascular mechanism may underlie the development of both calcinosis and fingertip ulcers in patients with DM.

    View details for DOI 10.1001/jamadermatol.2013.10416

    View details for PubMedID 24869801

  • Multicriteria decision analysis methods with 1000Minds for developing systemic sclerosis classification criteria JOURNAL OF CLINICAL EPIDEMIOLOGY Johnson, S. R., Naden, R. P., Fransen, J., van den Hoogen, F., Pope, J. E., Baron, M., Tyndall, A., Matucci-Cerinic, M., Denton, C. P., Distler, O., Gabrielli, A., van Laar, J. M., Mayes, M., Steen, V., Seibold, J. R., clements, P., Medsger, T. A., Carreira, P. E., Riemekasten, G., Chung, L., Fessler, B. J., Merkel, P. A., Silver, R., Varga, J., Allanore, Y., Mueller-Ladner, U., Vonk, M. C., Walker, U. A., Cappelli, S., Khanna, D. 2014; 67 (6): 706-714

    Abstract

    Classification criteria for systemic sclerosis (SSc) are being developed. The objectives were to develop an instrument for collating case data and evaluate its sensibility; use forced-choice methods to reduce and weight criteria; and explore agreement among experts on the probability that cases were classified as SSc.A standardized instrument was tested for sensibility. The instrument was applied to 20 cases covering a range of probabilities that each had SSc. Experts rank ordered cases from highest to lowest probability; reduced and weighted the criteria using forced-choice methods; and reranked the cases. Consistency in rankings was evaluated using intraclass correlation coefficients (ICCs).Experts endorsed clarity (83%), comprehensibility (100%), face and content validity (100%). Criteria were weighted (points): finger skin thickening (14-22), fingertip lesions (9-21), friction rubs (21), finger flexion contractures (16), pulmonary fibrosis (14), SSc-related antibodies (15), Raynaud phenomenon (13), calcinosis (12), pulmonary hypertension (11), renal crisis (11), telangiectasia (10), abnormal nailfold capillaries (10), esophageal dilation (7), and puffy fingers (5). The ICC across experts was 0.73 [95% confidence interval (CI): 0.58, 0.86] and improved to 0.80 (95% CI: 0.68, 0.90).Using a sensible instrument and forced-choice methods, the number of criteria were reduced by 39% (range, 23-14) and weighted. Our methods reflect the rigors of measurement science and serve as a template for developing classification criteria.

    View details for DOI 10.1016/j.jclinepi.2013.12.009

    View details for Web of Science ID 000335610000015

    View details for PubMedID 24721558

  • Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for use in clinical trials THORAX Saketkoo, L. A., Mittoo, S., Huscher, D., Khanna, D., Dellaripa, P. F., Distler, O., Flaherty, K. R., Frankel, S., Oddis, C. V., Denton, C. P., Fischer, A., Kowal-Bielecka, O. M., LeSage, D., Merkel, P. A., Phillips, K., Pittrow, D., Swigris, J., Antoniou, K., Baughman, R. P., Castelino, F. V., Christmann, R. B., Christopher-Stine, L., Collard, H. R., Cottin, V., Danoff, S., Highland, K. B., Hummers, L., Shah, A. A., Kim, D. S., Lynch, D. A., Miller, F. W., Proudman, S. M., Richeldi, L., Ryu, J. H., Sandorfi, N., Sarver, C., Wells, A. U., Strand, V., Matteson, E. L., Brown, K. K., Seibold, J. R. 2014; 69 (5): 428-436

    Abstract

    Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities.The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology-a non-profit international organisation dedicated to consensus methodology in identification of outcome measures-conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF).A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed.Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field.

    View details for DOI 10.1136/thoraxjnl-2013-204202

    View details for Web of Science ID 000347648600009

    View details for PubMedID 24368713

    View details for PubMedCentralID PMC3995282

  • Abstract 46: surgical treatment of systemic sclerosis: re-thinking the role and timing of peripheral sympathectomy. Plastic and reconstructive surgery Momeni, A., Sorice, S. C., Valenzuela, A., Fiorentino, D. F., Chung, L., Chang, J. 2014; 133 (4): 1010-?

    View details for DOI 10.1097/01.prs.0000445829.40020.04

    View details for PubMedID 24675339

  • Reconciling Healthcare Professional and Patient Perspectives in the Development of Disease Activity and Response Criteria in Connective Tissue Disease-related Interstitial Lung Diseases JOURNAL OF RHEUMATOLOGY Saketkoo, L. A., Mittoo, S., Frankel, S., LeSage, D., Sarver, C., Phillips, K., Strand, V., Matteson, E. L. 2014; 41 (4): 792-798

    Abstract

    Interstitial lung diseases (ILD), including those related to connective tissue disease (CTD), and idiopathic pulmonary fibrosis (IPF) carry high morbidity and mortality. Great efforts are under way to develop and investigate meaningful treatments in the context of clinical trials. However, efforts have been challenged by a lack of validated outcome measures and by inconsistent use of measures in clinical trials. Lack of consensus has fragmented effective use of strategies in CTD-ILD and IPF, with a history of resultant difficulties in obtaining agency approval of treatment interventions. Until recently, the patient perspective to determine domains and outcome measures in CTD-ILD and IPF had never been applied. Efforts described here demonstrate unequivocally the value and influence of patient involvement on core set development. Regarding CTD-ILD, this is the first OMERACT working group to directly address a manifestation/comorbidity of a rheumatic disease (ILD) as well as a disease not considered rheumatic (IPF). The OMERACT 11 proceedings of the CTD-ILD Working Group describe the forward and lateral process to include both the medical and patient perspectives in the urgently needed identification of a core set of preliminary domains and outcome measures in CTD-ILD and IPF.

    View details for DOI 10.3899/jrheum.131251

    View details for Web of Science ID 000333906400024

    View details for PubMedID 24488412

    View details for PubMedCentralID PMC4369780

  • Survival and Predictors of Mortality in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension: Outcomes From the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma Registry ARTHRITIS CARE & RESEARCH Chung, L., Domsic, R. T., Lingala, B., Alkassab, F., Bolster, M., Csuka, M. E., Derk, C., Fischer, A., Frech, T., Furst, D. E., Gomberg-Maitland, M., Hinchcliff, M., Hsu, V., Hummers, L. K., Khanna, D., Medsger, T. A., Molitor, J. A., Preston, I. R., Schiopu, E., Shapiro, L., Silver, R., Simms, R., Varga, J., Gordon, J. K., Steen, V. D. 2014; 66 (3): 489-495

    Abstract

    To assess cumulative survival rates and identify independent predictors of mortality in patients with incident systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) who had undergone routine screening for PAH at SSc centers in the US.The Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma registry is a prospective registry of SSc patients at high risk for PAH or with definite pulmonary hypertension diagnosed by right-sided heart catheterization within 6 months of enrollment. Only patients with World Health Organization group I PAH (mean pulmonary artery pressure >25 mm Hg and pulmonary capillary wedge pressure <15 mm Hg without significant interstitial lung disease) were included in these analyses.In total, 131 SSc patients with incident PAH were followed for a mean ± SD of 2.0 ± 1.4 years. The 1-, 2-, and 3-year cumulative survival rates were 93%, 88%, and 75%, respectively. On multivariate analysis, age >60 years (hazard ratio [HR] 3.0, 95% confidence interval [95% CI] 1.1- 8.4), male sex (HR 3.9, 95% CI 1.1-13.9), functional class (FC) IV status (HR 6.5, 95% CI 1.8 -22.8), and diffusing capacity for carbon monoxide (DLCO) <39% predicted (HR 4.2, 95% CI 1.3-13.8) were significant predictors of mortality.This is the largest study describing survival in patients with incident SSc-associated PAH followed up at multiple SSc centers in the US who had undergone routine screening for PAH. The survival rates were better than those reported in other recently described SSc-associated PAH cohorts. Severely reduced DLCO and FC IV status at the time of PAH diagnosis portended a poor prognosis in these patients.

    View details for DOI 10.1002/acr.22121

    View details for Web of Science ID 000331684800019

  • Survival and predictors of mortality in systemic sclerosis-associated pulmonary arterial hypertension: outcomes from the pulmonary hypertension assessment and recognition of outcomes in scleroderma registry. Arthritis care & research Chung, L., Domsic, R. T., Lingala, B., Alkassab, F., Bolster, M., Csuka, M. E., Derk, C., Fischer, A., Frech, T., Furst, D. E., Gomberg-Maitland, M., Hinchcliff, M., Hsu, V., Hummers, L. K., Khanna, D., Medsger, T. A., Molitor, J. A., Preston, I. R., Schiopu, E., Shapiro, L., Silver, R., Simms, R., Varga, J., Gordon, J. K., Steen, V. D. 2014; 66 (3): 489-495

    Abstract

    To assess cumulative survival rates and identify independent predictors of mortality in patients with incident systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) who had undergone routine screening for PAH at SSc centers in the US.The Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma registry is a prospective registry of SSc patients at high risk for PAH or with definite pulmonary hypertension diagnosed by right-sided heart catheterization within 6 months of enrollment. Only patients with World Health Organization group I PAH (mean pulmonary artery pressure >25 mm Hg and pulmonary capillary wedge pressure <15 mm Hg without significant interstitial lung disease) were included in these analyses.In total, 131 SSc patients with incident PAH were followed for a mean ± SD of 2.0 ± 1.4 years. The 1-, 2-, and 3-year cumulative survival rates were 93%, 88%, and 75%, respectively. On multivariate analysis, age >60 years (hazard ratio [HR] 3.0, 95% confidence interval [95% CI] 1.1- 8.4), male sex (HR 3.9, 95% CI 1.1-13.9), functional class (FC) IV status (HR 6.5, 95% CI 1.8 -22.8), and diffusing capacity for carbon monoxide (DLCO) <39% predicted (HR 4.2, 95% CI 1.3-13.8) were significant predictors of mortality.This is the largest study describing survival in patients with incident SSc-associated PAH followed up at multiple SSc centers in the US who had undergone routine screening for PAH. The survival rates were better than those reported in other recently described SSc-associated PAH cohorts. Severely reduced DLCO and FC IV status at the time of PAH diagnosis portended a poor prognosis in these patients.

    View details for DOI 10.1002/acr.22121

    View details for PubMedID 23983198

  • International consensus criteria for the diagnosis of Raynaud's phenomenon. Journal of autoimmunity Maverakis, E., Patel, F., Kronenberg, D. G., Chung, L., Fiorentino, D., Allanore, Y., Guiducci, S., Hesselstrand, R., Hummers, L. K., Duong, C., Kahaleh, B., MacGregor, A., Matucci-Cerinic, M., Wollheim, F. A., Mayes, M. D., Gershwin, M. E. 2014; 48-49: 60-65

    Abstract

    Vasoconstriction accompanied by changes in skin color is a normal physiologic response to cold. The distinction between this normal physiology and Raynaud's phenomenon (RP) has yet to be well characterized. In anticipation of the 9th International Congress on Autoimmunity, a panel of 12 RP experts from 9 different institutes and four different countries were assembled for a Delphi exercise to establish new diagnostic criteria for RP. Relevant investigators with highly cited manuscripts in Raynaud's-related research were identified using the Web of Science and invited to participate. Surveys at each stage were administered to participants via the on-line SurveyMonkey software tool. The participants evaluated the level of appropriateness of statements using a scale of 1 (extremely inappropriate) through 9 (extremely appropriate). In the second stage, panel participants were asked to rank rewritten items from the first round that were scored as "uncertain" for the diagnosis of RP, items with significant disagreement (Disagreement Index > 1), and new items suggested by the panel. Results were analyzed using the Interpercentile Range Adjusted for Symmetry (IPRAS) method. A 3-Step Approach to diagnose RP was then developed using items the panelists "agreed" were "appropriate" diagnostic criteria. In the final stage, the panel was presented with the newly developed diagnostic criteria and asked to rate them against previous models. Following the first two iterations of the Delphi exercise, the panel of 12 experts agreed that 36 of the items were "appropriate", 12 items had "uncertain" appropriateness, and 13 items were "inappropriate" to use in the diagnostic criteria of RP. Using an expert committee, we developed a 3-Step Approach for the diagnosis of RP and 5 additional criteria for the diagnosis of primary RP. The committee came to an agreement that the proposed criteria were "appropriate and accurate" for use by physicians to diagnose patients with RP.

    View details for DOI 10.1016/j.jaut.2014.01.020

    View details for PubMedID 24491823

  • Consensus opinion of a North American Working Group regarding the classification of digital ulcers in systemic sclerosis CLINICAL RHEUMATOLOGY Baron, M., Chung, L., Gyger, G., Hummers, L., Khanna, D., Mayes, M. D., Pope, J. E., Shah, A. A., Steen, V. D., Steele, R., Tatibouet, S., Herrick, A., Mueller-Ladner, U., Hudson, M. 2014; 33 (2): 207-214

    Abstract

    The objectives of this study were to develop a standard classification of digital ulcers (DUs) in systemic sclerosis (SSc) for use in observational or therapeutic studies and to assess the reliability of these definitions as well as of the measurement of ulcer area. Ten North American rheumatologists with expertise in SSc reviewed multiple photos of DUs, examined four SSc subjects with DUs, and came to a consensus on the definitions for digital, active, healed, and indeterminate ulcers. These ten raters then examined the right hand of ten SSc subjects twice and the left hand once to classify ulcers and to measure ulcer area. Weighted and Fleiss kappa were used to calculate intra- and interrater agreement on classification of ulcers, and intraclass correlation coefficient (ICC) was used to assess agreement on ulcer area. Because the traditional ICC calculations relied on a small number of ulcers, ICCs were recalculated using the results of linear mixed models to evaluate the variance components of observations on all the data. Intrarater kappa for classifying DU as not an ulcer/healed ulcer versus active/indeterminate ulcer was substantial (0.76), and interrater kappa was moderate (0.53). The ICC for ulcer area using the linear mixed models was moderate both for intrarater (0.57) and interrater (0.48) measurements. A consensus for the classification of DUs in SSc was developed, and after a training session, rheumatologists with expertise in SSc are able to reliably classify DUs and to measure ulcer area.

    View details for DOI 10.1007/s10067-013-2460-7

    View details for Web of Science ID 000330780600006

    View details for PubMedID 24357325

  • Atherosclerotic Cardiovascular Disease in Hospitalized Patients With Systemic Sclerosis: Higher Mortality Than Patients With Lupus and Rheumatoid Arthritis ARTHRITIS CARE & RESEARCH Dave, A. J., Fiorentino, D., Lingala, B., Krishnan, E., Chung, L. 2014; 66 (2): 323-327

    Abstract

    Systemic sclerosis (SSc; scleroderma) patients have an increased risk for atherosclerotic cardiovascular disease (ASCVD), possibly mediated through inflammatory and fibrotic mechanisms affecting the macrovasculature and microvasculature. We utilized the US Nationwide Inpatient Sample to assess the frequency of and mortality risk associated with ASCVD among hospitalized SSc patients.We examined the frequency and mortality associated with primary diagnoses and procedures related to ASCVD among adult SSc patients using data from 1993 to 2007. Using multivariate logistic regression (controlling for age, sex, nonelective admission, and modified Charlson Comorbidity Index), we compared the odds of death among hospitalized SSc patients with ASCVD to those with systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA), as well as to a control group that excluded patients with connective tissue diseases.A total of 308,452 hospitalizations of SSc patients were included, of which 5.4% were associated with a primary ASCVD diagnosis or procedure. ASCVD-related SSc hospitalizations were more likely to result in death compared with non-ASCVD SSc hospitalizations (odds ratio [OR] 1.3, 95% confidence interval [95% CI] 1.1-1.4). Multivariate analyses showed that ASCVD-related SSc hospitalizations were more likely to result in death than similar hospitalizations of SLE (OR 1.5, 95% CI 1.2-1.8), RA (OR 2.3, 95% CI 1.9-2.8), and control patients (OR 1.4, 95% CI 1.2-1.8) with ASCVD.SSc patients with ASCVD have higher in-hospital mortality than comparable groups of SLE and RA patients with ASCVD. Further research to elucidate the specific mechanisms underlying ASCVD in SSc is necessary.

    View details for DOI 10.1002/acr.22152

    View details for Web of Science ID 000330266100020

    View details for PubMedID 24022876

  • Recommendations for Screening and Detection of Connective Tissue Disease-Associated Pulmonary Arterial Hypertension ARTHRITIS AND RHEUMATISM Khanna, D., Gladue, H., Channick, R., Chung, L., Distler, O., Furst, D. E., Hachulla, E., Humbert, M., Langleben, D., Mathai, S. C., Saggar, R., Visovatti, S., Altorok, N., Townsend, W., Fitzgerald, J., McLaughlin, V. V. 2013; 65 (12): 3194-3201

    Abstract

    Pulmonary arterial hypertension (PAH) affects up to 15% of patients with connective tissue diseases (CTDs). Previous recommendations developed as part of larger efforts in PAH did not include detailed recommendations for patients with CTD-associated PAH. Therefore, we sought to develop recommendations for screening and early detection of CTD-associated PAH.We performed a systematic review of the literature on the screening and diagnosis of PAH in CTD. Using the RAND/University of California, Los Angeles consensus methodology, we developed case scenarios followed by 2 stages of voting. First, international experts from a variety of specialties voted anonymously on the appropriateness of each case scenario. The experts then met face-to-face to discuss and resolve discrepant votes to arrive at consensus recommendations.The key recommendation stated that all patients with systemic sclerosis (SSc) should be screened for PAH. In addition, patients with mixed connective tissue disease or other CTDs with scleroderma features (scleroderma spectrum disorders) should be screened for PAH. It was recommended that screening pulmonary function tests (PFTs) with single-breath diffusing capacity for carbon monoxide, transthoracic echocardiogram, and measurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) be performed in all patients with SSc and scleroderma spectrum disorders. In patients with SSc and scleroderma spectrum disorders, transthoracic echocardiogram and PFTs should be performed annually. The full screening panel (transthoracic echocardiogram, PFTs, and measurement of NT-proBNP) should be performed as soon as any new signs or symptoms are present.We provide consensus-based, evidence-driven recommendations for screening and early detection of CTD-associated PAH. It is our hope that these recommendations will lead to earlier detection of CTD-associated PAH and ultimately improve patient outcomes.

    View details for DOI 10.1002/art.38172

    View details for Web of Science ID 000327692600022

    View details for PubMedID 24022584

    View details for PubMedCentralID PMC3883571

  • Most patients with cancer-associated dermatomyositis have antibodies to nuclear matrix protein NXP-2 or transcription intermediary factor 1?. Arthritis and rheumatism Fiorentino, D. F., Chung, L. S., Christopher-Stine, L., Zaba, L., Li, S., Mammen, A. L., Rosen, A., Casciola-Rosen, L. 2013; 65 (11): 2954-2962

    Abstract

    Since dermatomyositis (DM) is associated with an increased risk of malignancy, accurate identification of patients likely to harbor cancers is important. Using immunoprecipitations from radiolabeled cell lysates, several groups recently showed that anti-transcription intermediary factor 1γ (anti-TIF-1γ) antibodies are associated with malignancy in DM. We undertook this study to develop sensitive, specific assays to detect antibodies against TIF-1γ and nuclear matrix protein NXP-2 and to evaluate their association with malignancy in DM.To detect anti-TIF-1γ antibodies, immunoprecipitations were performed using lysates made from HeLa cells overexpressing TIF-1γ, with detection by immunoblotting. Anti-NXP-2 antibodies were assayed by immunoprecipitation using (35) S-methionine-labeled NXP-2 generated by in vitro transcription/translation. We analyzed patient sera from DM cohorts seen at the Stanford University Dermatology Clinic (n = 111) and the Johns Hopkins Myositis Center (n = 102).A total of 17% and 38% of patients had antibodies against NXP-2 and TIF-1γ, respectively. Reactivity against either NXP-2 or TIF-1γ identified 83% of patients with cancer-associated DM. In addition to older age and male sex, cancer was associated with antibodies to NXP-2 or TIF-1γ on multivariate analysis (odds ratio 3.78 [95% confidence interval 1.33-10.8]). Stratification by sex revealed that anti-NXP-2 was specifically associated with cancer in males (odds ratio 5.78 [95% confidence interval 1.35-24.7]).These studies demonstrate that anti-NXP-2 and anti-TIF-1γ antibodies are frequent DM specificities (found in 55% of patients) and are present in most patients with cancer-associated DM.

    View details for DOI 10.1002/art.38093

    View details for PubMedID 24037894

  • Most Patients With Cancer-Associated Dermatomyositis Have Antibodies to Nuclear Matrix Protein NXP-2 or Transcription Intermediary Factor 1?. Arthritis and rheumatism Fiorentino, D. F., Chung, L. S., Christopher-Stine, L., Zaba, L., Li, S., Mammen, A. L., Rosen, A., Casciola-Rosen, L. 2013; 65 (11): 2954-2962

    Abstract

    Since dermatomyositis (DM) is associated with an increased risk of malignancy, accurate identification of patients likely to harbor cancers is important. Using immunoprecipitations from radiolabeled cell lysates, several groups recently showed that anti-transcription intermediary factor 1γ (anti-TIF-1γ) antibodies are associated with malignancy in DM. We undertook this study to develop sensitive, specific assays to detect antibodies against TIF-1γ and nuclear matrix protein NXP-2 and to evaluate their association with malignancy in DM.To detect anti-TIF-1γ antibodies, immunoprecipitations were performed using lysates made from HeLa cells overexpressing TIF-1γ, with detection by immunoblotting. Anti-NXP-2 antibodies were assayed by immunoprecipitation using (35) S-methionine-labeled NXP-2 generated by in vitro transcription/translation. We analyzed patient sera from DM cohorts seen at the Stanford University Dermatology Clinic (n = 111) and the Johns Hopkins Myositis Center (n = 102).A total of 17% and 38% of patients had antibodies against NXP-2 and TIF-1γ, respectively. Reactivity against either NXP-2 or TIF-1γ identified 83% of patients with cancer-associated DM. In addition to older age and male sex, cancer was associated with antibodies to NXP-2 or TIF-1γ on multivariate analysis (odds ratio 3.78 [95% confidence interval 1.33-10.8]). Stratification by sex revealed that anti-NXP-2 was specifically associated with cancer in males (odds ratio 5.78 [95% confidence interval 1.35-24.7]).These studies demonstrate that anti-NXP-2 and anti-TIF-1γ antibodies are frequent DM specificities (found in 55% of patients) and are present in most patients with cancer-associated DM.

    View details for DOI 10.1002/art.38093

    View details for PubMedID 24037894

  • 2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative ANNALS OF THE RHEUMATIC DISEASES van den Hoogen, F., Khanna, D., Fransen, J., Johnson, S. R., Baron, M., Tyndall, A., Matucci-Cerinic, M., Naden, R. P., Medsger, T. A., Carreira, P. E., Riemekasten, G., Clements, P. J., Denton, C. P., Distler, O., Allanore, Y., Furst, D. E., Gabrielli, A., Mayes, M. D., van Laar, J. M., Seibold, J. R., Czirjak, L., Steen, V. D., Inanc, M., Kowal-Bielecka, O., Mueller-Ladner, U., Valentini, G., Veale, D. J., Vonk, M. C., Walker, U. A., Chung, L., Collier, D. H., Csuka, M. E., Fessler, B. J., Guiducci, S., Herrick, A., Hsu, V. M., Jimenez, S., Kahaleh, B., Merkel, P. A., Sierakowski, S., Silver, R. M., Simms, R. W., Varga, J., Pope, J. E. 2013; 72 (11): 1747-1755

    Abstract

    The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc.Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by (1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and (2) validating against the combined view of a group of experts on a set of cases with or without SSc.It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, seven additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc.The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

    View details for DOI 10.1136/annrheumdis-2013-204424

    View details for Web of Science ID 000325532200006

  • 2013 Classification Criteria for Systemic Sclerosis An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative ARTHRITIS AND RHEUMATISM van den Hoogen, F., Khanna, D., Fransen, J., Johnson, S. R., Baron, M., Tyndall, A., Matucci-Cerinic, M., Naden, R. P., Medsger, T. A., Carreira, P. E., Riemekasten, G., Clements, P. J., Denton, C. P., Distler, O., Allanore, Y., Furst, D. E., Gabrielli, A., Mayes, M. D., van Laar, J. M., Seibold, J. R., Czirjak, L., Steen, V. D., Inanc, M., Kowal-Bielecka, O., Mueller-Ladner, U., Valentini, G., Veale, D. J., Vonk, M. C., Walker, U. A., Chung, L., Collier, D. H., Csuka, M. E., Fessler, B. J., Guiducci, S., Herrick, A., Hsu, V. M., Jimenez, S., Kahaleh, B., Merkel, P. A., Sierakowski, S., Silver, R. M., Simms, R. W., Varga, J., Pope, J. E. 2013; 65 (11): 2737-2747

    Abstract

    The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc.Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by 1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and 2) validating against the combined view of a group of experts on a set of cases with or without SSc.It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, 7 additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynaud's phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc.The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

    View details for DOI 10.1002/art.38098

    View details for Web of Science ID 000326138200001

    View details for PubMedID 24122180

  • Recommendations For Screening and Detection Of Connective-Tissue Disease Associated Pulmonary Arterial Hypertension Khanna, D., Gladue, H., Fitzgerald, J. D., Channick, R. N., Chung, L., Distler, O., Furst, D., Hachulla, E., Humbert, M., Langleben, D., Mathai, S. C., Saggar, R., Visovatti, S. H., McLaughlin, V. WILEY-BLACKWELL. 2013: S1100–S1101
  • Near-infrared fluorescence and nuclear imaging and targeting of prostate cancer. Translational andrology and urology Wu, J., Pan, D., Chung, L. W. 2013; 2 (3): 254-264

    Abstract

    Despite advances in the treatment of castration-resistant and bone metastatic prostate cancer (PCa), there is still no clear demonstration that PCa growth and metastases can be unambiguously detected. We review recent advances including our own development of near-infrared fluorescence (NIRF) and near-infrared nuclear (NIRN) imaging approaches. We validated our results in experimental models of PCa bone and soft tissue metastases including PCa colonization at metastatic sites by injecting PCa cells either intratibially or intracardiacally. We describe our experience using noninvasive imaging and targeting modalities to probe PCa tumors grown at metastatic sites, molecular studies to understand the multiple molecular and cellular processes within tumor cells and their interactions with the tumor microenvironment, and targeting tumor growth at metastatic bone site. In this review, current knowledge and emerging technologies based on NIRF and NIRN disciplines will be summarized. Additionally the mechanisms of differential uptake of these agents by normal and cancerous cells will be described.

    View details for PubMedID 25285271

  • Functional Class Improvement and 3-Year Survival Outcomes in Patients With Pulmonary Arterial Hypertension in the REVEAL Registry CHEST Barst, R. J., Chung, L., Zamanian, R. T., Turner, M., Mcgoon, M. D. 2013; 144 (1): 160-168

    Abstract

    ABSTRACT OBJECTIVE: New York Heart Association/World Health Organization functional class (FC) is associated with outcomes in pulmonary arterial hypertension (PAH). We assessed whether patients with PAH who improve from FC III to FC I/II have improved survival versus patients who remain at FC III or worsen to FC IV. METHODS: Patients aged ≥19 years with FC III PAH from the REVEAL Registry (N=982) were categorized as improved, unchanged, or worsened according to their change in FC from enrollment to first follow-up assessment within 1 year of enrollment. Kaplan-Meier estimates of 3-year survival from first follow-up and changes in 6-minute walk distance (6MWD) from enrollment to first follow-up were determined. Subgroup analyses were conducted by etiology (ie, idiopathic/familial, connective tissue disease [CTD], congenital heart disease) and time of diagnosis (ie, newly and previously diagnosed [diagnostic right heart catheterization within or ≥3 months of enrollment, respectively]). RESULTS: Overall, 27% of patients improved FC. Survival was better in patients whose FC improved (84%±2%; n=263) versus those who remained unchanged (66%±2%; n=645) or worsened (29%±6%; n=74) (all P<.001). Survival was also better in patient subgroups whose FC improved versus those who remained unchanged (idiopathic/familial [P<.001], CTD-associated PAH [P=.009], whether newly [P=.004] or previously diagnosed [P<.001]. 6MWD improvements were greater in patients whose FC improved versus those who remained unchanged in the overall (P<.001) and CTD (P=.028) cohorts. CONCLUSION: Patients with PAH who improve from FC III to I/II, whether newly or previously diagnosed and regardless of PAH etiology, have better survival versus patients who remain FC III.ClinicalTrials.gov Registration Number: NCT00370214.

    View details for DOI 10.1378/chest.12-2417

    View details for Web of Science ID 000321605500026

    View details for PubMedID 23429998

  • Management of the hand in systemic sclerosis. journal of hand surgery Fox, P., Chung, L., Chang, J. 2013; 38 (5): 1012-1016

    View details for DOI 10.1016/j.jhsa.2013.02.012

    View details for PubMedID 23561724

  • Localized cutaneous fibrosing disorders. Rheumatic diseases clinics of North America Yaqub, A., Chung, L., Rieger, K. E., Fiorentino, D. F. 2013; 39 (2): 347-364

    View details for DOI 10.1016/j.rdc.2013.02.013

    View details for PubMedID 23597968

  • Localized cutaneous fibrosing disorders. Rheumatic diseases clinics of North America Yaqub, A., Chung, L., Rieger, K. E., Fiorentino, D. F. 2013; 39 (2): 347-364

    Abstract

    This article acquaints the reader with disorders of the skin that might mimic systemic sclerosis but whose pathology is localized to the skin and/or has extracutaneous manifestations that are different than systemic sclerosis. These disorders include localized scleroderma (morphea), eosinophilic fasciitis, scleredema, scleromyxedema, nephrogenic systemic fibrosis, and chronic graft-versus-host disease. Particular emphasis is placed on clinical and histopathologic features that help the clinician differentiate between these disorders. Treatment options are briefly reviewed.

    View details for DOI 10.1016/j.rdc.2013.02.013

    View details for PubMedID 23597968

  • Dyspnea Assessment and Pulmonary Hypertension in Patients With Systemic Sclerosis: Utility of the University of California, San Diego, Shortness of Breath Questionnaire ARTHRITIS CARE & RESEARCH Chung, L., Chen, H., Khanna, D., Steen, V. D. 2013; 65 (3): 454-463

    Abstract

    The University of California in San Diego Shortness of Breath Questionnaire (UCSD SOBQ) has been used to assess dyspnea-related activity limitation in patients with airway and parenchymal lung disease. We sought to assess the construct validity and responsiveness of the UCSD SOBQ in systemic sclerosis (SSc; scleroderma) patients with incident pulmonary hypertension (PH) and those at high risk of developing PH.We used data from 179 patients enrolled in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma Registry with pre-PH (defined by criteria on pulmonary function tests and/or echocardiogram) or definite PH with mean pulmonary artery pressure ≥25 mm Hg by right-sided heart catheterization within 6 months of enrollment. For this analysis, we included those subjects with complete data for self-reported measures at baseline and at 12 months.At baseline, the UCSD SOBQ had strong correlations in the expected direction with the disability index (DI) of the Health Assessment Questionnaire (HAQ) (r = 0.71, P < 0.0001), dyspnea assessment by visual analog scale (r = 0.71, P < 0.0001), and the Short Form 36 (SF-36) health survey physical component summary (PCS) score (r = -0.77, P < 0.0001), as well as a moderate correlation with the 6-minute walk test distance (r = -0.33, P < 0.0001), Borg dyspnea score (r = 0.47, P < 0.0001), and diffusing capacity of carbon monoxide (r = -0.33, P < 0.0001). Change in the UCSD SOBQ at 12 months correlated in the expected direction with change in the HAQ DI (r = 0.54, P < 0.0001) and change in the SF-36 PCS (r = -0.44, P < 0.0001). Multivariate analysis adjusting for age, sex, and race identified male sex as a significant predictor of death (odds ratio [OR] 7.00, 95% confidence interval [95% CI] 1.55-31.76), while the UCSD SOBQ showed a strong trend toward significance (OR 1.82, 95% CI 0.97-3.41).The UCSD SOBQ demonstrates good construct validity and responsiveness to change in SSc patients with pulmonary vascular disease.

    View details for DOI 10.1002/acr.21827

    View details for Web of Science ID 000316907700015

    View details for PubMedID 23042670

  • Epidemiology and risk factors for pulmonary hypertension in systemic sclerosis. Current rheumatology reports Yaqub, A., Chung, L. 2013; 15 (1): 302-?

    Abstract

    Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by vasculopathy and excessive collagen production leading to fibrosis of the skin and internal organs. SSc patients are at risk of developing pulmonary hypertension (PH), a debilitating, progressive condition of the pulmonary vasculature that leads to right heart failure and death. This review is an updated summary of the epidemiology and risk factors for PH in SSc. We describe the current literature examining the incidence, prevalence, and demographic and clinical risk factors associated with PH in SSc. We also discuss classical and novel autoantibodies and potential biomarkers that may be helpful in the assessment of risk and prognosis of PH in SSc patients. The ultimate objective in understanding the risk of developing PH in SSc is early diagnosis and early initiation of appropriate therapy with the hope for improved outcomes for patients with SSc-PH.

    View details for DOI 10.1007/s11926-012-0302-2

    View details for PubMedID 23292818

  • Atherosclerotic cardiovascular disease and dermatomyositis: an analysis of the Nationwide Inpatient Sample survey ARTHRITIS RESEARCH & THERAPY Linos, E., Fiorentino, D., Lingala, B., Krishnan, E., Chung, L. 2013; 15 (1)

    Abstract

    ABSTRACT: INTRODUCTION: Increased rates of cardiovascular disease are implicated in several rheumatologic diseases. Our aim was to characterize dermatomyositis hospitalizations and evaluate cardiovascular-associated mortality in this patient population. METHODS: We examined the frequency and mortality rates of several atherosclerotic cardiovascular diagnoses and procedures among hospitalized adult patients with dermatomyositis using data from the US Nationwide Inpatient Sample (NIS) from 1993 to 2007. We compared the odds of death among hospitalized dermatomyositis patients with each cardiovascular diagnosis or procedure to those without, as well as to controls with cardiovascular diagnoses, using logistic regression. RESULTS: A total of 50,322 hospitalizations of dermatomyositis patients occurred between 1993 and 2007 (mean age 58 years, and 73% female). Of all dermatomyositis hospitalizations, 20% were associated with a concurrent atherosclerotic cardiovascular diagnosis or procedure. The overall in-hospital mortality was 5.7%. Dermatomyositis patients with any associated atherosclerotic cardiovascular diagnosis or procedure were twice as likely to die during the inpatient stay compared to dermatomyositis patients who did not have atherosclerotic cardiovascular disease (OR = 2.0 95% CI 1.7-2.5, p < 0.0001). The odds ratio for death in patients with both dermatomyositis and cardiovascular disease compared to controls with cardiovascular disease alone was 1.98 (95% CI 1.57-2.48) in multivariate adjusted models. CONCLUSIONS: Approximately one fifth of dermatomyositis hospitalizations in the US were associated with an atherosclerotic cardiovascular diagnosis or procedure. These patients have double the risk of in-hospital death in comparison with controls and dermatomyositis patients without a cardiovascular diagnosis, making identification of these groups important for both prognostic purposes and clinical care.

    View details for DOI 10.1186/ar4135

    View details for Web of Science ID 000317932600021

  • Immune Responses to NXP-2 and TIF-g Are Associated with Distinct Clinical Phenotypes and Prognosis for Skin Disease in Dermatomyositis Patients. Annual Scientific Meeting of the American-College-of-Rheumatology (ACR) and Association-of-Rheumatology-Health-Professionals (ARHP) Fiorentino, D., Chung, L., Zaba, L., Lingala, B., Rosen, A., Casciola-Rosen, L. WILEY-BLACKWELL. 2012: S828–S828
  • World Health Organization Classification of Pulmonary Hypertension and Survival in Systemic Sclerosis Patients in the Pharos Cohort Gordon, J. K., Chung, L., Domsic, R. T., Huang, W., Lyman, S. L., Horn, E. M., Steen, V. D., PHAROS Investigators WILEY-BLACKWELL. 2012: S629
  • Survival, Hospitalization or Need for Combination Therapy At One Year in Patients with Scleroderma-Associated Pulmonary Arterial Hypertension Domsic, R. T., Chung, L., Gordon, J. K., Cloonan, Y., Steen, V. D., PHAROS Investigators WILEY-BLACKWELL. 2012: S310–S311
  • Pulmonary Hypertension and Interstitial Lung Disease within Pharos: Impact of Extent of Fibrosis and Pulmonary Physiology On Cardiac Hemodynamic Parameters Fischer, A., Mathai, S. C., Bolster, M. B., Chung, L., Csuka, M., Domsic, R. T., Frech, T. M., Hinchcliff, M. E., Hsu, V. M., Hummers, L. K., Kolfenbach, J. R., Gomberg-Maitland, M., Manu, A., Simms, R. W., Steen, V. D. WILEY-BLACKWELL. 2012: S628
  • Differential Expression of Hepatocyte Growth Factor (HGF) in Patients with Systemic Sclerosis-Associated Pulmonary Arterial Hypertension Chung, L., Cramb, C., Robinson, W. H., Steen, V. D., Zamanian, R. T. WILEY-BLACKWELL. 2012: S632
  • Clinical presentation and evaluation of dermatomyositis. Indian journal of dermatology Marvi, U., Chung, L., Fiorentino, D. F. 2012; 57 (5): 375-381

    Abstract

    Dermatomyositis (DM) is a chronic inflammatory disorder of the skin and muscles. Evidence supports that DM is an immune-mediated disease and 50-70% of patients have circulating myositis-specific auto-antibodies. Gene expression microarrays have demonstrated upregulation of interferon signaling in the muscle, blood, and skin of DM patients. Patients with classic DM typically present with symmetric, proximal muscle weakness, and skin lesions that demonstrate interface dermatitis on histopathology. Evaluation for muscle inflammation can include muscle enzymes, electromyogram, magnetic resonance imaging, and/or muscle biopsy. Classic skin manifestations of DM include the heliotrope rash, Gottron's papules, Gottron's sign, the V-sign, and shawl sign. Additional cutaneous lesions frequently observed in DM patients include periungual telangiectasias, cuticular overgrowth, "mechanic's hands", palmar papules overlying joint creases, poikiloderma, and calcinosis. Clinically amyopathic DM is a term used to describe patients who have classic cutaneous manifestations for more than 6 months, but no muscle weakness or elevation in muscle enzymes. Interstitial lung disease can affect 35-40% of patients with inflammatory myopathies and is often associated with the presence of an antisynthetase antibody. Other clinical manifestations that can occur in patients with DM include dysphagia, dysphonia, myalgias, Raynaud phenomenon, fevers, weight loss, fatigue, and a nonerosive inflammatory polyarthritis. Patients with DM have a three to eight times increased risk for developing an associated malignancy compared with the general population, and therefore all patients with DM should be evaluated at the time of diagnosis for the presence of an associated malignancy. This review summarizes the immunopathogenesis, clinical manifestations, and evaluation of patients with DM.

    View details for DOI 10.4103/0019-5154.100486

    View details for PubMedID 23112358

    View details for PubMedCentralID PMC3482801

  • Baseline characteristics and follow-up in patients with normal haemodynamics versus borderline mean pulmonary arterial pressure in systemic sclerosis: results from the PHAROS registry ANNALS OF THE RHEUMATIC DISEASES Bae, S., Saggar, R., Bolster, M. B., Chung, L., Csuka, M. E., Derk, C., Domsic, R., Fischer, A., Frech, T., Goldberg, A., Hinchcliff, M., Hsu, V., Hummers, L., Schiopu, E., Mayes, M. D., McLaughlin, V., Molitor, J., Naz, N., Furst, D. E., Maranian, P., Steen, V., Khanna, D. 2012; 71 (8): 1335-1342

    Abstract

    Patients with normal (mean pulmonary arterial pressure (mPAP) ≤20 mm Hg) and borderline mean pulmonary pressures (21-24 mm Hg) are "at risk" of developing pulmonary hypertension (PH). The objectives of this analysis were to examine the baseline characteristics in systemic sclerosis (SSc) with normal and borderline mPAP and to explore long-term outcomes in SSc patients with borderline mPAP versus normal haemodynamics.PHAROS is a multicentre prospective longitudinal cohort of patients with SSc "at risk" or recently diagnosed with resting PH on right heart catheterisation (RHC). Baseline clinical characteristics, pulmonary function tests, high-resolution CT, 2-dimensional echocardiogram and RHC results were analysed in normal and borderline mPAP groups.206 patients underwent RHC (results showed 35 normal, 28 borderline mPAP, 143 resting PH). There were no differences in the baseline demographics. Patients in the borderline mPAP group were more likely to have restrictive lung disease (67% vs 30%), fibrosis on high-resolution CT and a higher estimated right ventricular systolic pressure on echocardiogram (46.3 vs 36.2 mm Hg; p<0.05) than patients with normal haemodynamics. RHC revealed higher pulmonary vascular resistance and more elevated mPAP on exercise (≥30; 88% vs 56%) in the borderline mPAP group (p<0.05 for both). Patients were followed for a mean of 25.7 months and 24 patients had a repeat RHC during this period. During follow-up, 55% of the borderline mPAP group and 32% of the normal group developed resting PH (p=NS).Patients with borderline mPAP have a greater prevalence of abnormal lung physiology, pulmonary fibrosis and the presence of exercise mPAP ≥30 mm Hg.

    View details for DOI 10.1136/annrheumdis-2011-200546

    View details for Web of Science ID 000306407700012

    View details for PubMedID 22307943

    View details for PubMedCentralID PMC3398226

  • Hyperuricemia in Young Adults and Risk of Insulin Resistance, Prediabetes, and Diabetes: A 15-Year Follow-up Study AMERICAN JOURNAL OF EPIDEMIOLOGY Krishnan, E., Pandya, B. J., Chung, L., Hariri, A., Dabbous, O. 2012; 176 (2): 108-116

    Abstract

    The objective of this study was to assess the utility of hyperuricemia as a marker for diabetes and prediabetes (impaired fasting glucose) and insulin resistance in young adults. Using Cox proportional hazards regression models, the authors analyzed 15-year follow-up data on 5,012 persons in 4 US cities who were aged 18-30 years and diabetes-free at the time of enrollment. At baseline (1986), 88% of participants had a body mass index (weight (kg)/height (m)(2)) less than 30. During the follow-up period (through 2001), the incidence rates of diabetes and prediabetes (insulin resistance and impaired fasting glucose) were higher among persons with greater serum urate concentrations. In multivariable Cox regression analyses that adjusted for age, gender, race, body mass index, family history of diabetes, diastolic blood pressure, total cholesterol, smoking, and alcohol use, the hazard ratios for diabetes, insulin resistance, and prediabetes among persons with hyperuricemia (serum urate level >7 mg/dL vs. ≤7.0 mg/dL) were 1.87 (95% confidence interval (CI): 1.33, 2.62), 1.36 (95% CI: 1.23, 1.51), and 1.25 (95% CI: 1.04, 1.52), respectively. This observation was generally consistent across subgroups. The authors conclude that hyperuricemia in the midtwenties is an independent marker for predicting diabetes and prediabetes among young adults in the subsequent 15 years.

    View details for DOI 10.1093/aje/kws002

    View details for Web of Science ID 000306406500005

    View details for PubMedID 22753829

  • Clinical trial design in scleroderma: where are we and where do we go next? CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Chung, L., Denton, C. P., Distler, O., Furst, D. E., Khanna, D., Merkel, P. A. 2012; 30 (2): S97-S102

    Abstract

    Drug development for SSc has been hindered by the relative paucity of validated outcome measures and biomarkers for use in clinical trials. The Scleroderma Clinical Trials Consortium (SCTC) conducted an interactive session at the Scleroderma International Workshop in Cambridge, UK in July 2011 to discuss clinical trial design in SSc. The following issues were discussed: 1) primary outcome for trials of SSc - skin vs. lung vs. composite; 2) ischaemic digital ulcers in SSc - healing vs. repair vs. composite; 3) pulmonary arterial hypertension in SSc; and 4) neglected aspects of SSc - opportunities for study or of lower priority and feasibility. Randomised controlled trials with collection of biospecimens are necessary to assess efficacy of therapeutic agents, validate novel outcome measures, and discover and validate potential biomarkers for each of these areas. Although SSc is a rare, heterogeneous disease, collaborative efforts led by the SCTC and other international networks will ultimately improve the design of clinical trials of promising therapies for SSc.

    View details for Web of Science ID 000304976600016

    View details for PubMedID 22691217

  • Items for developing revised classification criteria in systemic sclerosis: Results of a consensus exercise ARTHRITIS CARE & RESEARCH Fransen, J., Johnson, S. R., van den Hoogen, F., Baron, M., Allanore, Y., Carreira, P. E., Czirjak, L., Denton, C. P., Distler, O., Furst, D. E., Gabrielli, A., Herrick, A., Inanc, M., Kahaleh, B., Kowal-Bielecka, O., Medsger, T. A., Mueller-Ladner, U., Riemekasten, G., Sierakowski, S., Valentini, G., Veale, D., Vonk, M. C., Walker, U., Chung, L., Clements, P. J., Collier, D. H., Csuka, M. E., Jimenez, S., Merkel, P. A., Seibold, J. R., Silver, R., Steen, V., Tyndall, A., Matucci-Cerinic, M., Pope, J. E., Khanna, D. 2012; 64 (3): 351-357

    Abstract

    Classification criteria for systemic sclerosis (SSc; scleroderma) are being updated. Our objective was to select a set of items potentially useful for the classification of SSc using consensus procedures, including the Delphi and nominal group techniques (NGT).Items were identified through 2 independent consensus exercises performed by the Scleroderma Clinical Trials Consortium and the European League Against Rheumatism Scleroderma Trials and Research Group. The first-round items from both exercises were collated and redundancies were removed, leaving 168 items. A 3-round Delphi exercise was performed using a 1-9 scale (where 1 = completely inappropriate and 9 = completely appropriate) and a consensus meeting using NGT was conducted. During the last Delphi round, the items were ranked on a 1-10 scale.In round 1, 106 experts rated the 168 items. Those with a median score of <4 were removed, resulting in a list of 102 items. In round 2, the items were again rated for appropriateness and subjected to a consensus meeting using NGT by European and North American SSc experts (n = 16), resulting in 23 items. In round 3, SSc experts (n = 26) then individually scored each of the 23 items in a last Delphi round using an appropriateness score (1-9) and ranking their 10 most appropriate items for the classification of SSc. Presence of skin thickening, SSc-specific autoantibodies, abnormal nailfold capillary pattern, and Raynaud's phenomenon ranked highest in the final list that also included items indicating internal organ involvement.The Delphi exercise and NGT resulted in a set of 23 items for the classification of SSc that will be assessed for their discriminative properties in a prospective study.

    View details for DOI 10.1002/acr.20679

    View details for Web of Science ID 000300831500006

    View details for PubMedID 22052558

    View details for PubMedCentralID PMC3288452

  • Classification and Diagnosis of Systemic Slerosis: Towards Early Recognition of the Disease Scleroderma: From Pathogenesis to Comprehensive Management Chung, L., Fransen, J., van den Hoogen, F. Dordrecht, Heidelberg, London, Springer. 2012; 1: 53–69
  • Evolving Concepts of Diagnosis and Classification SCLERODERMA: FROM PATHOGENESIS TO COMPREHENSIVE MANAGEMENT Chung, L., Fransen, J., Van den Hoogen, F. J., Varga, J., Denton, C. P., Wigley, F. M. 2012: 53–69
  • A Pilot Study of Abatacept for the Treatment of Patients with Diffuse Cutaneous Systemic Sclerosis. 75th Annual Scientific Meeting of the American-College-of-Rheumatology/46th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals (ARHP) Chakravarty, E. F., Fiorentino, D., Bennett, M., Chung, L. WILEY-BLACKWELL. 2011: S274–S275
  • Better Survival in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension Patients Enrolled in the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma Registry Chung, L., Domsic, R. T., Lingala, B., Steen, V. D., PHAROS Investigators WILEY-BLACKWELL. 2011: S673
  • Functional Class Change in Patients with Connective Tissue Disease-Associated Pulmonary Arterial Hypertension: Associations with Survival and Exercise Capacity Chung, L., Parsons, L. S., Hassoun, P. M., McGoon, M. D., Badesch, D. B., Miller, D. P., Nicolls, M. R., Zamanian, R. T. WILEY-BLACKWELL. 2011: S575
  • Digital Ischemic Ulcers in Scleroderma Treated with Oral Treprostinil Diethanolamine: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Study Seibold, J. R., Wigley, F. M., Schiopu, E., Denton, C. D., Silver, R. M., Steen, V. D., Medsger, T. A., Mayes, M. D., Chatterjee, S., Chung, L., Csuka, M., Khanna, D., Frech, T. M., Molitor, J. A., Rothfield, N. F., Herrick, A. L., Simms, R. W., Pope, J. E., Rollins, K. D., Arneson, C., Wade, M., DISTOL Investigators WILEY-BLACKWELL. 2011: S968–S969
  • Tyrosine kinases in inflammatory dermatologic disease JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Paniagua, R. T., Fiorentino, D. F., Chung, L., Robinson, W. H. 2011; 65 (2): 389-403

    Abstract

    Tyrosine kinases (TKs) are enzymes that catalyze the phosphorylation of tyrosine residues on protein substrates. They are key components of signaling pathways that drive an array of cellular responses including proliferation, differentiation, migration, and survival. Specific TKs have recently been identified as critical to the pathogenesis of several autoimmune and inflammatory diseases. Small-molecule inhibitors of TKs are emerging as a novel class of therapy that may provide benefit in certain patient subsets. In this review, we highlight TK signaling implicated in inflammatory dermatologic diseases, evaluate strategies aimed at inhibiting these aberrant signaling pathways, and discuss prospects for future drug development.

    View details for DOI 10.1016/j.jaad.2010.04.026

    View details for Web of Science ID 000293311200017

    View details for PubMedID 20584561

    View details for PubMedCentralID PMC2948077

  • The mucocutaneous and systemic phenotype of dermatomyositis patients with antibodies to MDA5 (CADM-140): A retrospective study JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Fiorentino, D., Chung, L., Zwerner, J., Rosen, A., Casciola-Rosen, L. 2011; 65 (1): 25-34

    Abstract

    Dermatomyositis (DM) is a multisystem autoimmune disease, in which serologic evidence of immune responses to disease-specific antigenic targets is found in approximately 50% to 70% of patients. Recently, melanoma differentiation-associated gene 5 (MDA5) has been identified as a DM-specific autoantigen that appears to be targeted in patients with DM and mild or absent muscle inflammation and with an increased risk of interstitial lung disease.We wished to understand the role of MDA5 in DM skin inflammation by testing it to determine if a specific cutaneous phenotype is associated with MDA5 reactivity.We retrospectively screened plasma from 77 patients with DM in the outpatient clinics at the Stanford University Department of Dermatology in California.We found that 10 (13%) patients had circulating anti-MDA5 antibodies, and had a characteristic cutaneous phenotype consisting of skin ulceration, tender palmar papules, or both. Typical areas of skin ulceration included the lateral nailfolds, Gottron papules, and elbows. Biopsy specimens of the palmar papules showed a vasculopathy characterized by vascular fibrin deposition with variable perivascular inflammation. Patients with anti-MDA5 antibodies also had an increased risk of oral pain and/or ulceration, hand swelling, arthritis/arthralgia, and diffuse hair loss. Consistent with previous reports, these patients had little or no myositis and had increased risk of interstitial lung disease.This study was conducted at a tertiary referral center. Multiple associations with MDA5 antibodies were tested retrospectively on a relatively small cohort of 10 anti-MDA5-positive patients.We suggest that MDA5 reactivity in DM characterizes a patient population with severe vasculopathy.

    View details for DOI 10.1016/j.jaad.2010.09.016

    View details for Web of Science ID 000292222200003

    View details for PubMedID 21531040

    View details for PubMedCentralID PMC3167687

  • Pathogenesis of dermatomyositis: role of cytokines and interferon. Current rheumatology reports Kao, L., Chung, L., Fiorentino, D. F. 2011; 13 (3): 225-232

    Abstract

    Dermatomyositis is a systemic autoimmune disease that primarily affects skeletal muscle, skin, and the lungs. Dermatomyositis is characterized by autoantibodies, tissue inflammation, parenchymal cell damage and death, and vasculopathy. This review focuses on recent advances regarding the role of cytokines and interferon in the pathogenesis of the disease. Evidence for the role of a particular cytokine is based on data showing dysregulated levels in tissue and/or blood; correlation with histopathologic or clinical markers of disease activity; and, rarely, clinical efficacy of targeted cytokine inhibitors. Many of the recent advances pertain to elucidation of the role of interferons in both muscle and skin disease in dermatomyositis. Although a great deal of progress has been made regarding the role of interferon in the disease, many critical questions remain unanswered.

    View details for DOI 10.1007/s11926-011-0166-x

    View details for PubMedID 21318338

  • Pathogenesis of Dermatomyositis: Role of Cytokines and Interferon CURRENT RHEUMATOLOGY REPORTS Kao, L., Chung, L., Fiorentino, D. F. 2011; 13 (3): 225-232

    Abstract

    Dermatomyositis is a systemic autoimmune disease that primarily affects skeletal muscle, skin, and the lungs. Dermatomyositis is characterized by autoantibodies, tissue inflammation, parenchymal cell damage and death, and vasculopathy. This review focuses on recent advances regarding the role of cytokines and interferon in the pathogenesis of the disease. Evidence for the role of a particular cytokine is based on data showing dysregulated levels in tissue and/or blood; correlation with histopathologic or clinical markers of disease activity; and, rarely, clinical efficacy of targeted cytokine inhibitors. Many of the recent advances pertain to elucidation of the role of interferons in both muscle and skin disease in dermatomyositis. Although a great deal of progress has been made regarding the role of interferon in the disease, many critical questions remain unanswered.

    View details for DOI 10.1007/s11926-011-0166-x

    View details for Web of Science ID 000208771200007

  • Survival in Pulmonary Hypertension Registries The Importance of Incident Cases Response CHEST Chung, L., Liu, J., Parsons, L. S., Hassoun, P. M., McGoon, M. D., Badesch, D. B., Miller, D. P., Nicolls, M. R., Zamanian, R. T. 2011; 139 (6): 1548-1549
  • An Analysis of Connective Tissue Disease-associated Interstitial Lung Disease at a US Tertiary Care Center: Better Survival in Patients with Systemic Sclerosis JOURNAL OF RHEUMATOLOGY Su, R., Bennett, M., Jacobs, S., Hunter, T., Bailey, C., Krishnan, E., Rosen, G., Chung, L. 2011; 38 (4): 693-701

    Abstract

    To compare survival of patients with connective tissue disease-associated interstitial lung disease (CTD-ILD) versus idiopathic pulmonary fibrosis (IPF) and patients with systemic sclerosis-associated ILD (SSc-ILD) versus other CTD-ILD followed at our center.We used the Stanford ILD database, which contains prospectively collected information on patients with ILD evaluated at our tertiary care center from 2002 to 2009. Survival at last followup from time of ILD diagnosis was calculated using the Kaplan-Meier estimator. Prognostic factors for survival in the overall cohort (IPF and CTD-ILD) and in the CTD-ILD group were identified with univariate and multivariate Cox regression models.Of 427 patients with ILD, 148 (35%) had IPF and 76 (18%) had CTD-ILD at the baseline visit. The cumulative incidence of CTD was 4%. After a median followup of 4 years, 67 patients (36.4%) had died and 4 (2.2%) were lost to followup. Patients with IPF (n = 122) and CTD-ILD (n = 62) experienced similar survival rates (5-year survival about 50%). Patients with SSc-ILD (n = 24) experienced better survival than those with other CTD-ILD (n = 38), with 1-year, 3-year, and 5-year survival rates of 100%, 90%, and 77%, respectively, versus 78%, 42%, and 38% (p = 0.01). The presence of SSc in patients with CTD-ILD decreased the risk of death by > 80% even after correcting for age at ILD diagnosis, sex, and ethnicity (HR = 0.17, 95% CI 0.04-0.83).Survival in patients with SSc-ILD was better than in patients with other CTD-ILD, potentially related to routine screening for and early detection of ILD in patients with SSc at our center.

    View details for DOI 10.3899/jrheum.100675

    View details for Web of Science ID 000289333800018

    View details for PubMedID 21285162

  • Colonic ulceration as an unusual manifestation of vasculopathy in systemic sclerosis RHEUMATOLOGY Kao, L., Myer, P., Nguyen, L., Zamanian, R. T., Chung, L. 2011; 50 (3): 626-628

    View details for DOI 10.1093/rheumatology/keq276

    View details for Web of Science ID 000287745600030

    View details for PubMedID 21172924

  • Endothelin Receptor Antagonists for the Treatment of Raynaud's Phenomenon and Digital Ulcers in Systemic Sclerosis. International journal of rheumatology Arefiev, K., Fiorentino, D. F., Chung, L. 2011; 2011: 201787-?

    Abstract

    Systemic sclerosis is a connective tissue disease characterized by fibrosis of the skin, internal organs, and widespread vasculopathy. Raynaud's phenomenon and digital ulcers are vascular manifestations of this disease and cause significant morbidity. Current treatments are only moderately effective in reducing the severity of Raynaud's in a portion of patients and typically do not lead to substantial benefit in terms of the healing or prevention of digital ulcers. Several studies have evaluated the efficacy of targeting the vasoconstrictor endothelin-1 for the treatment of systemic sclerosis-associated vascular disease. The purpose of this paper is to summarize the published studies and case reports evaluating the efficacy of endothelin receptor antagonists in the treatment of Raynaud's phenomenon and digital ulcers associated with systemic sclerosis.

    View details for DOI 10.1155/2011/201787

    View details for PubMedID 22121371

    View details for PubMedCentralID PMC3205679

  • Systemic sclerosis 2011. International journal of rheumatology Chung, L., Distler, O., Hummers, L., Krishnan, E., Steen, V. 2011; 2011: 308231-?

    View details for DOI 10.1155/2011/308231

    View details for PubMedID 22577388

    View details for PubMedCentralID PMC3332200

  • Emerging therapies in systemic sclerosis International Joural of Rheumatology Chung, L., Distler, O., Hummers, L., Krishnan, E., Steen, V. 2011
  • Hyperuricemia and the risk for subclinical coronary atherosclerosis - data from a prospective observational cohort study ARTHRITIS RESEARCH & THERAPY Krishnan, E., Pandya, B. J., Chung, L., Dabbous, O. 2011; 13 (2)

    Abstract

    Our purpose was to test the hypothesis that hyperuricemia is associated with coronary artery calcification (CAC) among a relatively healthy population, and that the extent of calcification is directly proportional to the serum uric acid (sUA) concentration.Data from 2,498 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study were analyzed using logistic regression models. Subjects were free of clinical heart disease, diabetes, and renal impairment. The main measure was the presence of any CAC by computerized tomography (Agatston score >0).Forty-eight percent of the study participants were male and 45% were African-American. Mean (± SD) age was 40 ± 4 years, body mass index 28 ± 6 kg/m2, Framingham risk score -0.7 ± 5%, blood pressure 113 ± 14/75 ± 11 mmHg, alcohol consumption 12 ± 27 ml/day, and sUA 297 ± 89 μmol/L (5.0 ± 1.5 mg/dL). Prevalence of CAC increased with sUA concentration among both men and women. Adjusted for age, gender, race, lipoproteins, triglycerides, smoking, blood pressure, presence of metabolic syndrome, C-reactive protein, waist circumference, alcohol use, creatinine, and serum albumin, the highest quartile of sUA (>393 μmol/L [6.6 mg/dL] for men and >274 μmol/L [4.6 mg/dL] for women) was associated with an odds ratio of 1.87 (1.19-2.93) compared to the lowest quartile (<291 μmol/L [4.9 mg/dL] for men and <196 μmol/L [3.3 mg/dL] for women). Among those with any CAC, each unit increase in sUA was associated with a 22% increase in Agatston score (P = 0.008) after adjusting for the above covariates.Hyperuricemia is an independent risk factor for subclinical atherosclerosis in young adults.

    View details for DOI 10.1186/ar3322

    View details for Web of Science ID 000292449700031

    View details for PubMedID 21501486

    View details for PubMedCentralID PMC3132061

  • Characterization of Connective Tissue Disease-Associated Pulmonary Arterial Hypertension From REVEAL Identifying Systemic Sclerosis as a Unique Phenotype CHEST Chung, L., Liu, J., Parsons, L., Hassoun, P. M., McGoon, M., Badesch, D. B., Miller, D. P., Nicolls, M. R., Zamanian, R. T. 2010; 138 (6): 1383-1394

    Abstract

    REVEAL (the Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management) is the largest US cohort of patients with pulmonary arterial hypertension (PAH) confirmed by right-sided heart catheterization (RHC), providing a more comprehensive subgroup characterization than previously possible. We used REVEAL to analyze the clinical features of patients with connective tissue disease-associated PAH (CTD-APAH).All newly and previously diagnosed patients with World Health Organization (WHO) group 1 PAH meeting RHC criteria at 54 US centers were consecutively enrolled. Cross-sectional and 1-year mortality and hospitalization analyses from time of enrollment compared CTD-APAH to idiopathic disease and systemic sclerosis (SSc) to systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), and rheumatoid arthritis (RA).Compared with patients with idiopathic disease (n = 1,251), patients with CTD-APAH (n = 641) had better hemodynamics and favorable right ventricular echocardiographic findings but a higher prevalence of pericardial effusions, lower 6-min walk distance (300.5 ± 118.0 vs 329.4 ± 134.7 m, P = .01), higher B-type natriuretic peptide (BNP) levels (432.8 ± 789.1 vs 245.6 ± 427.2 pg/mL, P < .0001), and lower diffusing capacity of carbon monoxide (Dlco) (44.9% ± 18.0% vs 63.6% ± 22.1% predicted, P < .0001). One-year survival and freedom from hospitalization were lower in the CTD-APAH group (86% vs 93%, P < .0001; 67% vs 73%, P = .03). Compared with patients with SSc-APAH (n = 399), those with other CTDs (SLE, n = 110; MCTD, n = 52; RA, n = 28) had similar hemodynamics; however, patients with SSc-APAH had the highest BNP levels (552.2 ± 977.8 pg/mL), lowest Dlco (41.2% ± 16.3% predicted), and poorest 1-year survival (82% vs 94% in SLE-APAH, 88% in MCTD-APAH, and 96% in RA-APAH).Patients with SSc-APAH demonstrate a unique phenotype with the highest BNP levels, lowest Dlco, and poorest survival of all CTD-APAH subgroups.ClinicalTrials.gov; No.: NCT00370214; URL: clinicaltrials.gov.

    View details for DOI 10.1378/chest.10-0260

    View details for Web of Science ID 000285494000017

    View details for PubMedID 20507945

    View details for PubMedCentralID PMC3621419

  • A 39-Year-Old Woman With Lupus, Myositis, and a Recalcitrant Vasculopathy ARTHRITIS CARE & RESEARCH Sokolove, J., Copland, A., Shirvani, S., Brown, J., Posley, K., Chung, L. 2010; 62 (9): 1351-1356

    View details for DOI 10.1002/acr.20236

    View details for Web of Science ID 000281913400022

    View details for PubMedID 20506174

  • Dyspnea in pcleroderma patients from the PHAROS Registry: a major contributor to disability Chung, L., Chen, H., Steen, V., PHAROS Investigators CLINICAL & EXPER RHEUMATOLOGY. 2010: S62
  • Evaluation of an imatinib response gene signature in patients with systemic sclerosis Chung, L., Ruiz, P., Wood, T., Shoor, S., Robinson, W., Whitfield, M., Chang, H., Fiorentino, D. CLINICAL & EXPER RHEUMATOLOGY. 2010: S62–S62
  • Digital ischemic loss in systemic sclerosis. International journal of rheumatology Marvi, U., Chung, L. 2010; 2010

    Abstract

    Digital ischemic loss is a cause of significant morbidity in patients with systemic sclerosis (SSc). Microvascular disease with intimal proliferation and luminal narrowing of small digital arteries, as well as macrovascular disease with narrowing or occlusion of larger digital arteries, contribute to the perfusion defects involved in digital ischemic loss. Immediate clinical evaluation and treatment are mandatory at the onset of critical digital ischemia to prevent digital loss. Hospitalization for medical therapies including intravenous prostacyclin therapy should be considered for all SSc patients who present with critical digital ischemia. Surgical interventions are typically reserved for patients who fail medical therapies and for those with late stage, necrotic tissue. This paper summarizes the current knowledge regarding the risk factors, pathogenesis, evaluation, and treatment of digital ischemic loss in SSc.

    View details for DOI 10.1155/2010/130717

    View details for PubMedID 20871838

    View details for PubMedCentralID PMC2943156

  • Vascular disease in systemic sclerosis. International journal of rheumatology Chung, L., Distler, O., Hummers, L., Krishnan, E., Steen, V. 2010; 2010: 714172-?

    View details for DOI 10.1155/2010/714172

    View details for PubMedID 21048994

    View details for PubMedCentralID PMC2964904

  • Prevalence of pulmonary arterial hypertension in an Australian scleroderma population: screening allows for earlier diagnosis INTERNAL MEDICINE JOURNAL Phung, S., Strange, G., Chung, L. P., Leong, J., Dalton, B., RODDY, J., Deague, J., Playford, D., Musk, M., Gabbay, E. 2009; 39 (10): 682-691

    Abstract

    We sought to determine the prevalence of pulmonary complications and especially pulmonary arterial hypertension (PAH) in an Australian scleroderma population.Between July 2005 and June 2007, physicians in Western Australia were asked to refer patients with scleroderma specifically for pulmonary hypertension screening. All patients were assessed for PAH and other respiratory conditions using echocardiography, lung function testing and clinical assessments. Right heart catheterization was carried out in patients with evidence of increased right ventricular systolic pressure.Of the 184 patients analysed, 44 had possible PAH on echocardiography. Right heart catheterization confirmed the diagnosis in 24 (13%). Diffuse interstitial lung disease was found in 32 patients representing a point prevalence of 17.4%. The severity of PAH at diagnosis varied according to whether the patients were referred for screening (group A) or for diagnostic (group B) purposes. The 6-min-walk test distance and median pulmonary vascular resistance were significantly worse in group B versus group A (324 vs 402 m; P= 0.02 and 884 dynes/s per cm(-5) vs 486 dynes/s per cm(-5); P < 0.01, respectively).Screening may result in earlier diagnosis of PAH with, in general more mild disease. This is important, given that early treatment for PAH while patients are less symptomatic is associated with improved exercise tolerance and pulmonary haemodynamics: indices indicative of disease progression and clinical worsening.

    View details for DOI 10.1111/j.1445-5994.2008.01823.x

    View details for Web of Science ID 000270901200009

    View details for PubMedID 19220532

  • Characterizing systemic sclerosis in Northern California: focus on Asian and Hispanic patients CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Schmajuk, G., Bush, T. M., Burkham, J., Krishnan, E., Chung, L. 2009; 27 (3): S22-S25
  • Characterizing systemic sclerosis in Northern California: focus on Asian and Hispanic patients. Clinical and experimental rheumatology Schmajuk, G., Bush, T. M., Burkham, J., Krishnan, E., Chung, L. 2009; 27 (3): 22-25

    Abstract

    Previous studies suggest that Asian and Hispanic patients with systemic sclerosis (SSc) may have more severe disease than their Caucasian counterparts. The purpose of this study is to compare the clinical features of a group of Asian, Hispanic, and Caucasian patients with SSc in Northern California.We performed a cross-sectional study of patients receiving care at Stanford University Medical Center, Palo Alto Veterans Affairs Hospital, Santa Clara Valley Medical Center and San Francisco General Hospital between 1996 and 2006. Patients included in the analyses fulfilled the American College of Rheumatology criteria for SSc and could be classified as Caucasian, Asian, or Hispanic. Analyses using Caucasians as the reference group were performed.One hundred and ninety-nine patients met the criteria for SSc, and 165 of these patients were classified as Caucasian (47%), Asian (26%), or Hispanic (27%). Disease subtype did not differ significantly among the three groups. Asian patients were less likely to have digital ulcers (26% vs. 47%, p=0.02) or anemia (26% vs. 45%, p=0.04) than Caucasians, and Hispanic patients had a lower frequency of lung disease than Caucasians (48% vs. 67%, p=0.04), but there were no other significant differences in disease manifestations.In our cohort of SSc patients living in Northern California, clinical manifestations in Asian and Hispanic patients did not differ substantially from Caucasians. Further research is necessary to confirm these results and to investigate gene-environment interactions which may affect the clinical expression of disease in different racial groups.

    View details for PubMedID 19796557

  • MQX-503, a Novel Formulation of Nitroglycerin, Improves the Severity of Raynaud's Phenomenon A Randomized, Controlled Trial ARTHRITIS AND RHEUMATISM Chung, L., Shapiro, L., Fiorentino, D., Baron, M., Shanahan, J., Sule, S., Hsu, V., Rothfield, N., Steen, V., Martin, R. W., Smith, E., Mayes, M., Simms, R., Pope, J., Kahaleh, B., Csuka, M. E., Gruber, B., Collier, D., Sweiss, N., Gilbert, A., Dechow, F. J., Gregory, J., Wigley, F. M. 2009; 60 (3): 870-877

    Abstract

    Raynaud's phenomenon (RP) affects 3-9% of the general population and >90% of patients with systemic sclerosis. Nitrates are often prescribed for the treatment of RP, but currently available formulations are limited by side effects, particularly headaches, dizziness, and skin irritation. The purpose of this study was to evaluate the tolerability and efficacy of a novel formulation of topical nitroglycerin, MQX-503, in the treatment of RP in an ambulatory setting.We conducted a multicenter, randomized, placebo-controlled study with a 2-week single-blind run-in period to determine baseline severity, followed by a 4-week double-blind treatment phase. Two hundred nineteen adult patients with a clinical diagnosis of primary or secondary RP received 0.9% MQX-503 gel or matching placebo during the treatment period. Gel was applied immediately before or within 5 minutes of the beginning of an episode of RP (maximum of 4 applications daily). End points included the change in the mean Raynaud's Condition Score (RCS; scale 0-10), the frequency and duration of episodes, and subjective assessments at the target week (the week during the treatment phase that most closely matched the run-in period in terms of ambient temperature) compared with baseline.The mean (%) change in the RCS at the target week compared with baseline was significantly greater in the MQX-503 group (0.48 [14.3%]) than that in the placebo group (0.04 [1.3%]; P = 0.04). Changes in the frequency and duration of RP episodes and subjective assessments were not statistically different between the groups. MQX-503 had a side effect profile similar to that of placebo.MQX-503 is well tolerated and more effective than placebo for the treatment of RP.

    View details for DOI 10.1002/art.24351

    View details for Web of Science ID 000264211900029

    View details for PubMedID 19248104

  • Molecular Framework for Response to Imatinib Mesylate in Systemic Sclerosis ARTHRITIS AND RHEUMATISM Chung, L., Fiorentino, D. F., Benbarak, M. J., Adler, A. S., Mariano, M. M., Paniagua, R. T., Milano, A., Connolly, M. K., Ratiner, B. D., Wiskocil, R. L., Whitfield, M. L., Chang, H. Y., Robinson, W. H. 2009; 60 (2): 584-591

    Abstract

    Systemic sclerosis (SSc) is an autoimmune disease in which the tyrosine kinases platelet-derived growth factor receptor (PDGFR) and Abl are hypothesized to contribute to the fibrosis and vasculopathy of the skin and internal organs. Herein we describe 2 patients with early diffuse cutaneous SSc (dcSSc) who experienced reductions in cutaneous sclerosis in response to therapy with the tyrosine kinase inhibitor imatinib mesylate. Immunohistochemical analyses of skin biopsy specimens demonstrated reductions of phosphorylated PDGFRbeta and Abl with imatinib therapy. By gene expression profiling, an imatinib-responsive signature specific to dcSSc was identified (P < 10(-8)). The response of these patients and the findings of the analyses suggest that PDGFRbeta and Abl play critical, synergistic roles in the pathogenesis of SSc, and that imatinib targets a gene expression program that is frequently dysregulated in dcSSc.

    View details for DOI 10.1002/art.24221

    View details for Web of Science ID 000263276400032

    View details for PubMedID 19180499

    View details for PubMedCentralID PMC2638060

  • Pulmonary arterial hypertension in systemic sclerosis Scleroderma: Modern aspects of pathogenesis, diagnosis and therapy Chung, L., Zamanian, R., Ghofrani, H. Unimed Publishers. 2009; 1: 37–43
  • Malignancy in the Setting of the Anti-Synthetase Syndrome JCR-JOURNAL OF CLINICAL RHEUMATOLOGY Rozelle, A., Trieu, S., Chung, L. 2008; 14 (5): 285-288

    Abstract

    Malignancy and interstitial lung disease (ILD) are 2 conditions associated with dermatomyositis (DM) that are responsible for a significant portion of the morbidity and mortality related to this disease; however, they rarely occur in the same patient. The antisynthetase syndrome consists of several characteristics, including ILD, arthritis, Raynaud phenomenon, "mechanic's hands," and positive antibodies to tRNA synthetases, which have each been negatively associated with cancer. When patients with DM present with such characteristics, clinicians may be falsely reassured that a thorough malignancy screen is unnecessary. We describe a patient who presented with the antisynthetase syndrome and was subsequently found to have colon cancer. Removal of the cancer led to resolution of the myositis and lung disease, but the patient's rash and arthritis persisted and ultimately required immunosuppressive therapy. We provide a review of the literature describing the concurrence of both this syndrome and ILD alone, with malignancy. We conclude that a thorough and expedited age-appropriate malignancy work up is indicated in all patients with a new diagnosis of DM, despite the presence of disease characteristics that are usually not associated with cancer.

    View details for DOI 10.1097/RHU.0b013e31817d116f

    View details for Web of Science ID 000260154000008

    View details for PubMedID 18664993

  • Molecular framework for response to imatinib mesylate in systemic sclerosis 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals Chung, L., Fiorentino, D. F., Benbarak, M. J., Adler, A. S., Mariano, M. M., Paniagua, R. T., Milano, A., Connolly, M. K., Ratiner, B. D., Wiskocil, R. L., Whitfield, M. L., Chang, H. Y., Robinson, W. H. WILEY-BLACKWELL. 2008: S819–S820
  • Pulmonary hypertension assessment and recognition of outcomes in scleroderma (PHAROS): Patients with pulmonary hypertension Hinchcliff, M. E., Hsu, V., Bolster, M., Hummers, L., Seibold, J., Csuka, M., Chung, L., Shapiro, L., Derk, C., Fischer, A., Wigley, F., Steen, V. WILEY-LISS. 2008: S948
  • "PHAROS" pulmonary hypertension (PH) assessment and recognition of outcomes in systemic sclerosis (SSc): Pre-pulmonary arterial hypertension (PAH) preliminary outcomes Fischer, A., Impens, A., Hsu, V., Shapiro, L., Mayes, M., Hummers, L., Csuka, M., Chung, L., Hinchcliff, M., Varga, J., Derk, C., Seibold, J., Steen, V. WILEY-LISS. 2008: S377
  • A clinical comparison of systemic sclerosis-versus systemic lupus erythematosus-pulmonary arterial hypertension using the REVEAL registry Chung, L., Liu, J., Parsons, L., McGoon, M., Badesch, D., Nicholls, M., Zamanian, R. WILEY-LISS. 2008: S948
  • Safety and tolerability of MQX-503, a novel investigational topical formulation of nitroglycerin for the treatment of Raynaud's phenomenon Rothfield, N., Shapiro, L., Fiorentino, D., Chung, L., Denton, C., Herrick, A., Baron, M., Shanahan, J., Hsu, V., Belch, J., Steen, V., Scheja, A., Martin, R., Smith, E., Mayes, M., Simms, R., Pope, J., Kahaleh, B., Csuka, M., Gruber, B., Collier, D., Sweiss, N., Sule, S., Emery, P., Wigey, F. M. WILEY-LISS. 2008: S821
  • Pregnancy outcomes in systemic sclerosis, primary pulmonary hypertension, and sickle cell disease OBSTETRICS AND GYNECOLOGY Chakravarty, E. F., Khanna, D., Chung, L. 2008; 111 (4): 927-934

    Abstract

    Systemic sclerosis, primary pulmonary hypertension, and sickle cell disease are uncommon vasculopathic diseases affecting women. We estimated the nationwide occurrence of pregnancies in women with these conditions and compared pregnancy outcomes to the general obstetric population.We studied the 2002-2004 Nationwide Inpatient Sample, of the Healthcare Cost and Utilization Project to estimate the number of obstetric hospitalizations and deliveries among women with systemic sclerosis, primary pulmonary hypertension, sickle cell disease, and women in the general population. Pregnancy outcomes included length of hospital stay, hypertensive disorders including preeclampsia, intrauterine growth restriction (IUGR), and cesarean delivery. Multivariable regression analyses were performed using maternal age, race or ethnicity, antiphospholipid antibody syndrome, diabetes mellitus, and renal failure as covariates.Of an estimated 11.2 million deliveries, 504 occurred in women with systemic sclerosis, 182 with primary pulmonary hypertension, and 4,352 with sickle cell disease. Systemic sclerosis, was associated with an increased risk of hypertensive disorders including preeclampsia (odds ratio [OR] 3.71, 95% confidence interval [CI] 2.25-6.15), IUGR (OR 3.74, 95% CI 1.51-9.28), and increased length of hospital stay. Primary pulmonary hypertension was associated with an increase in the odds of antenatal hospitalization (OR 4.67, 95% CI 2.88-7.57), hypertensive disorders including preeclampsia (OR 5.62, 95% CI 2.60-12.15) and a substantial increase in length of hospital stay. Sickle cell disease was associated with an increased odds of antenatal hospitalization (OR 5.56 95% CI 5.08-6.09), hypertensive disorders including preeclampsia (OR 1.78, 95% CI 1.48-2.14), and IUGR (OR 2.91, 95% CI 2.16-3.93), with a modest increase in length of hospital stay.Women with systemic sclerosis, primary pulmonary hypertension, and sickle cell disease have significantly increased rates of adverse pregnancy outcomes, requiring extensive preconceptional counseling about the risks of pregnancy.

    View details for Web of Science ID 000254433700017

    View details for PubMedID 18378753

    View details for PubMedCentralID PMC3171290

  • Cutaneous Vasculitis Dermatology Chung, L., Kea, B., Fiorentino, D. Mosby. 2008; 2: 347–367
  • Hospitalizations and mortality in systemic sclerosis: results from the Nationwide Inpatient Sample RHEUMATOLOGY Chung, L., Krishnan, E., Chakravarty, E. F. 2007; 46 (12): 1808-1813

    Abstract

    To study the causes of hospitalizations and predictors of subsequent adverse outcomes for contemporary cohorts of patients with systemic sclerosis (SSc) in the USA.The data source was the 2002 and 2003 Healthcare Cost and Utilization Project-Nationwide Inpatient Sample (HCUP-NIS) databases. We identified all discharges with an International Classification of Diseases-Clinical Modification (ICD9-CM) code of 710.1 (limited and diffuse SSc), then excluded those with concomitant diagnoses for lupus or rheumatoid arthritis. We calculated hospitalization rates, in-hospital mortality rates and mean length of stay (LOS). Multivariate logistic and linear regression models for in-hospital death and LOS were performed adjusting for sociodemographic and comorbidity covariates.The overall in-hospital mortality rate was 6.3% and the mean LOS was 6.6 days. Hospitalization rates were 4.5 times higher in women than in men, but in-hospital mortality was approximately 25% lower (P = 0.005). SSc was the most common principal diagnosis for all SSc hospitalizations, with the most common secondary diagnosis (24%) being pulmonary fibrosis. After SSc, respiratory failure was the second most common principal diagnosis in patients who died. Pulmonary fibrosis increased the odds of in-hospital death by 2.63 [95% confidence interval (CI) 1.98-3.49] fold and increased LOS by 7.25% (95% CI 0.90-13.60).Women with SSc had higher rates of hospitalization but lower in-hospital mortality than men. Pulmonary fibrosis was the major predictor of poor hospitalization outcomes in SSc patients in recent years, emphasizing the importance of continuing to develop more effective therapies for this fatal complication of the disease.

    View details for DOI 10.1093/rheumatology/kem273

    View details for Web of Science ID 000251197900014

    View details for PubMedID 17986481

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

    Abstract

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

    View details for Web of Science ID 000247116600019

    View details for PubMedID 17516620

  • Therapeutic options for digital ulcers in patients with systemic sclerosis. Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG Chung, L. 2007; 5 (6): 460-465

    Abstract

    Digital ulcers (DU) affect up to half of all patients with systemic sclerosis at some point during their disease. These lesions are extremely painful, heal slowly, and lead to substantial disability. DU arise from recurrent ischemic injury and microtrauma. Treatments for DU include non-pharmacologic modalities such as avoiding cold,stress,and trauma,as well as smoking cessation. Possible pharmacologic therapies for the prevention of DU include vasodilating agents to treat Raynaud phenomenon, statins, and oral agents used in the treatment of pulmonary hypertension (endothelin receptor antagonists, phosphodiesterase-5 inhibitors). The treatment of existing DU includes hydrocolloid occlusion, wound care, pain control, antibiotics, and the use of vasodilating medications. Intravenous or subcutaneous prostacyclins and digital or cervical sympathectomy should be considered for severe cases.

    View details for PubMedID 17537038

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

    Abstract

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

    View details for Web of Science ID 000247207400012

    View details for PubMedID 17576943

  • Outcome of pregnancies complicated by systemic sclerosis and mixed connective tissue disease. 70th Annual Scientific Meeting of the American-College-of-Rheumatology/41st Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals Chung, L., Flyckt, R. L., Colon, I., Shah, A. A., Drusin, M., Chakravarty, E. F. WILEY-BLACKWELL. 2006: 4077–77
  • Successful use of rituximab for cutaneous vasculitis ARCHIVES OF DERMATOLOGY Chung, L., Funke, A. A., Chakravarty, E. F., Callen, J. P., Fiorentino, D. F. 2006; 142 (11): 1407-1410

    View details for Web of Science ID 000242157600002

    View details for PubMedID 17116830

  • Systemic and locatized scleroderma CLINICS IN DERMATOLOGY Chung, L., Lin, J., Furst, D. E., Fiorentino, D. 2006; 24 (5): 374-392

    Abstract

    Sclerosing conditions of the skin are manifested by a full spectrum of presentations that includes skin-limited forms as well as those which can involve internal organs and result in death. At this point, we are just beginning to understand the mechanisms of tissue fibrosis, and it is likely that the fibrotic processes are a heterogeneous group of disorders in which perturbation of multiple molecular pathways, including vascular and immunologically mediated pathways, can lead to fibrosis. We now have some moderately effective therapies for vascular aspects of systemic sclerosis (eg, bosentan for pulmonary arterial hypertension, calcium-channel blockers for Raynaud's, or angiotensin-converting enzyme inhibitors for renal crisis). We also are beginning to find treatments interrupting the immunologic pathways that manifest as systemic sclerosis (eg, methotrexate for the skin or cyclophosphamide for the lungs). The basic process of fibrosis, however, awaits proven, effective therapy.

    View details for DOI 10.1016/j.clindermatol.2006.07.004

    View details for Web of Science ID 000240864500004

    View details for PubMedID 16966019

  • A pilot study of TNF inhibition in Erosive/Inflammatory osteoarthritis of the hands. 70th Annual Scientific Meeting of the American-College-of-Rheumatology/41st Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals Magnano, M. D., Chakravarty, E. F., Broudy, C., Chung, L., Kelman, A., Hillygus, J. J., Genovese, M. C. WILEY-BLACKWELL. 2006: S674–S674
  • A pilot trial of treprostinil for the treatment and prevention of digital ulcers in patients with systemic sclerosis JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY Chung, L., Fiorentino, D. 2006; 54 (5): 880-882

    Abstract

    We performed a pilot trial of subcutaneous treprostinil for the treatment of digital ulcers in scleroderma. Of the 5 patients completing therapy, ulcer size significantly decreased and no new ulcers occurred on continuous therapy. Although effective, the high rate of injection site reactions may limit the utility of this therapy.

    View details for DOI 10.1016/j.jaad.2006.02.004

    View details for Web of Science ID 000237119600019

    View details for PubMedID 16635673

  • Digital ulcers in patients with systemic sclerosis CIS Spring School on Systemic Autoimmune Diseases Chung, L., Fiorentino, D. ELSEVIER SCIENCE BV. 2006: 125–28

    Abstract

    Digital ulcers (DU), defined as necrotic lesions located at distal digits or overlying bony prominences, occur in up to 50% of patients with limited or diffuse systemic sclerosis (SSc). These lesions are extremely painful and lead to substantial functional disability. The pathogenesis of DU differs depending on their location. DU located at distal aspects of digits are thought to be related to tissue ischemia from several processes, including vasospasm secondary to Raynaud's phenomenon, intimal fibro-proliferation, and thrombosis of digital arteries. DU located over bony prominences, such as the phalangeal joints and elbows, are thought to be due to repetitive microtrauma and difficulty healing due to atrophic, avascular tissue overlying the joints. Management of DU include non-pharmacologic and pharmacologic modalities. This review summarizes the current available and investigational therapies for the treatment and prevention of DU in patients with SSc.

    View details for DOI 10.1016/j.autrev.2005.08.004

    View details for Web of Science ID 000235349400011

    View details for PubMedID 16431342

  • Outcome of pregnancies complicated by systemic sclerosis and mixed connective tissue disease LUPUS Chung, L., Flyckt, R. L., Colon, I., Shah, A. A., Druzin, M., Chakravarty, E. F. 2006; 15 (9): 595-599

    Abstract

    Systemic sclerosis (SSc) and mixed connective tissue disease (MCTD) are rare autoimmune diseases which share the common feature of non-inflammatory vasculopathy. Studies evaluating pregnancy outcomes in these patients have yielded conflicting results. We sought to describe the outcomes of pregnancies associated with SSc and MCTD followed at our center utilizing a retrospective review of all pregnant women with SSc and MCTD followed at Stanford University from 1993 to 2003. We identified 20 pregnancies occurring in 13 women with SSc or MCTD. Twelve pregnancies occurred in seven women with SSc and eight pregnancies occurred in six women with MCTD. The overall preterm delivery rate was 39% and small for gestational age infants occurred in 50% and 63% of pregnancies associated with SSc and MCTD, respectively. Fetal loss complicated two pregnancies in women with severe diffuse SSc and the antiphospholipid antibody syndrome. There were no cases of congenital heartblock among infants, and only one case of pre-eclampsia was observed. Maternal flares of disease during pregnancy were generally mild. Most pregnancies in women with SSc and MCTD in this cohort were uncomplicated. The high rates of prematurity and small for gestational age infants underscore the risk for growth restriction consistent with the vasculopathy associated with these diseases.

    View details for DOI 10.1177/0961203306071915

    View details for Web of Science ID 000241996300007

    View details for PubMedID 17080915

  • Current and future trends in systemic lupus erythematosus The Rheumatology Report Chung, L. 2006; 1 (2)
  • Systemic and localized scleroderma Clinics in Dermatology Chung, L., Lin, J., Furst, D., Fiorentino, D. 2006; 24 (5)
  • Coronary artery disease in patients with systemic lupus erythematosus NATURE CLINICAL PRACTICE RHEUMATOLOGY Galindo, M., Chung, L., Crockett, S. D., Chakravarty, E. F. 2005; 1 (1): 55-59

    Abstract

    A 24-year-old woman with an 11-year history of systemic lupus erythematosus presented with exacerbation of chronic abdominal pain followed by substernal chest pain. She had a history of pericarditis secondary to systemic lupus erythematosus and of varicella-zoster reactivation secondary to immunosuppression. Long-term medications included prednisolone, hydroxychloroquine, aspirin, and mycophenolate mofetil.Physical examination, mesenteric angiography, CT of the abdomen, esophagogastroduodenoscopy, colonoscopy, pelvic ultrasound, laboratory testing, serologic testing, cardiac echocardiography, electrocardiography and coronary angiography.Acute myocardial infarction secondary to severe multivessel atherosclerotic coronary artery disease.Intra-aortic balloon pump followed by emergent four-vessel coronary artery bypass grafting. Aspirin, hydroxychloroquine, and mycophenolate mofetil were continued and a judicious tapering of prednisolone was initiated.

    View details for DOI 10.1038/ncprheum0037

    View details for Web of Science ID 000235082200008

    View details for PubMedID 16932628

  • Bleeding complications in patients on celecoxib and warfarin 68th Annual Scientific Meeting of the American-College-of-Rheumatology/39th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals Chung, L., Chakravarty, E. F., Kearns, P., Wang, C., Bush, T. M. WILEY-BLACKWELL PUBLISHING, INC. 2005: 471–77

    Abstract

    Non-selective non-steroidal anti-inflammatory drugs (nNSAIDs) used in combination with warfarin are associated with an approximately 3-fold increased risk of upper gastrointestinal bleeding (UGIB) compared with warfarin alone. Celecoxib, a selective inhibitor of cyclo-oxygenase 2 (COX-2), is associated with less gastric mucosal injury and platelet dysregulation than nNSAIDs. We compared rates of bleeding complications in patients taking celecoxib and warfarin with those taking warfarin alone.We performed a retrospective analysis using data from our Protime Clinic and pharmacy databases from January 2001 to April 2004. We identified 123 patients who took celecoxib and warfarin concurrently (overlap group). We compared rates of bleeding complications in this group with 1022 control patients who were taking warfarin alone. Bleeding complications were defined as major if they resulted in hospitalization, blood transfusion or death.During approximately 1063 months of exposure to both celecoxib and warfarin, 10 bleeding complications were identified, only one of which was considered major. No patients had UGIB. In the control group, 116 bleeding complications were identified over approximately 16 520 months of exposure to warfarin alone, with 101 minor and 15 major events, including six episodes of UGIB. The relative risk of all bleeding complications was 1.34 (95% CI: 0.70-2.57) in the overlap vs. control groups, and for major bleeds was 1.04 (95% CI: 0.14-7.85).There is a mild but non-significant increase in bleeding complications in patients taking celecoxib and warfarin compared with those taking warfarin alone.

    View details for Web of Science ID 000231677200010

    View details for PubMedID 16164494

  • Giant cell myocarditis: a rare cardiovascular manifestation in a patient with systemic lupus erythematosus. Lupus Chung, L., Berry, G. J., Chakravarty, E. F. 2005; 14 (2): 166-169

    Abstract

    Giant cell myocarditis (GCM) is a rare form of myocarditis with a median survival of less than one year. It has been reported to occur in patients with various underlying autoimmune diseases; however, no cases of GCM have been described in patients with clear evidence of underlying systemic lupus erythematosus (SLE). The presentation of GCM may mimic that of lupus myocarditis, including an initial response to immunosuppression. Despite initial clinical similarities, lupus myocarditis and GCM are histologically distinct entities with dramatic differences in prognosis. We report herein a patient with a longstanding history of SLE, who presented acutely with myocarditis, responded well to initial immunosuppression and then subsequently died of progressive heart failure that was found to be due to GCM. Endomyocardial biopsy can help define diagnosis and prognosis of lupus patients presenting with myocarditis, and early referral for cardiac transplantation should be considered in patients diagnosed with GCM.

    View details for PubMedID 15751823

  • Cutaneous vasculitis Orphanet encyclopedia Chung, L., Fiorentino, D. 2005
  • Incidence of bleeding complications in patients on celecoxib and warfarin. 68th Annual Scientific Meeting of the American-College-of-Rheumatology/39th Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals Chung, L., Wang, C., Kearns, P., Chakravarty, E. F., Bush, T. M. WILEY-BLACKWELL. 2004: 4087–88
  • Antibodies in scleroderma: direct pathogenicity and phenotypic associations. Current rheumatology reports Chung, L., Utz, P. J. 2004; 6 (2): 156-163

    Abstract

    Scleroderma is an autoimmune disease involving endothelial cell damage and fibroblast overproduction of extracellular matrix. Several autoantibodies present in the sera of patients with scleroderma, including anti-endothelial cell, antifibroblast, anti-matrix metalloproteinase, and antifibrillin-1 antibodies, may directly contribute to disease pathogenesis. Scleroderma also is characterized by the presence of antinuclear and antinucleolar antibodies, which correlate with particular phenotypes. These include antitopoisomerase-I, anticentromere, antihistone, anti-polymyositis/scleroderma, anti-Th/To, anti-U3-small nucleolar ribonucleoprotein particle, anti-U1-small nuclear ribonucleoprotein particle, anti-RNA polymerase, and anti-B23 antibodies. Other antibodies classically associated with other autoimmune diseases, such as antiphospholipid, antineutrophil cytoplasmic, and antimitochondrial antibodies, also have been described in patients with scleroderma. This review will summarize the various autoantibodies associated with scleroderma, their putative pathogenic roles, and their phenotypic correlations.

    View details for PubMedID 15016347

  • EXTRACELLULAR-MATRIX AND ANDROGEN RECEPTOR EXPRESSION ASSOCIATED WITH SPONTANEOUS TRANSFORMATION OF RAT PROSTATE FIBROBLASTS CANCER RESEARCH Freeman, M. R., Song, Y., Carson, D. D., Guthrie, P. D., Chung, L. W. 1991; 51 (7): 1910-1916

    Abstract

    Spontaneous transformation in continuous culture of the androgen-sensitive rat prostate fibroblast cell line, NbF-1, resulted in an aggressively tumorigenic nonmetastatic phenotype that coincided with few gross chromosome abnormalities. This study identified transformation-associated alterations in extracellular matrix and androgen receptor expression in the NbF-1 cell line. Substantial levels of procollagens I, III, and IV and fibronectin mRNAs were detected in nontumorigenic NbF-1 cells. Laminin B1 and B2 mRNAs were also detectable, but at lower levels. Expression of all six extracellular matrix mRNAs was nonuniformly lower in tumorigenic NbF-1 cells. This decrease in expression was greatest for alpha 2 procollagen IV mRNA, which was reduced 17-fold. Proteoglycans and glycosaminoglycans synthesized by the NbF-1 cultures were also characterized. The NbF-1 cell line expressed chondroitin sulfate proteoglycans predominantly, and expression was reduced 5- to 10-fold in tumorigenic cultures. In contrast to the extensive alterations in the extracellular matrix, measurement of high-affinity androgen binding and androgen receptor mRNA levels showed substantial expression of androgen receptors in both NbF-1 cultures. Cultures of early and late passage NbF-1 cells demonstrated a mitogenic response to dihydrotestosterone. These data indicate (a) that alterations in expression of extracellular matrix components may represent early markers for tumorigenic transformation in prostatic mesenchymal cells and (b) that these changes can occur without disrupting androgen receptor expression and androgen sensitivity.

    View details for Web of Science ID A1991FE04100025

    View details for PubMedID 2004375