A single genetic variant in PTPN22 has been known for over a decade to convey risk for rheumatoid arthritis (RA), but exactly how remains a mystery. Led by rheumatologist and researcher Dr. I-Cheng Ho, investigators at BWH are using the JBC to understand PTPN22 as a regulator of citrullination, the post-translational protein modification of arginine that plays a leading role in RA biology. Read More
Conducting high-quality translational research in rheumatology is increasingly difficult. Major projects often require a range of methods, from patient recruitment to cutting-edge ‘omics technologies to big-data bioinformatics. Most research groups lack the expertise to cover this range, and so must either limit the scope of their work or expend substantial effort working outside their “comfort zone” to achieve their research goals. Neither of these options efficiently advances the science of rheumatology.
Iverson MD, Frits M, von Heideken J, Weinblatt M, Shadick NA. Physical activity and correlates of physical activity participation over three years in adults with rheumatoid arthritis. Arthritis Care Res (Hoboken) 2017;69(10):1535-1545. PMCID:PMC5436948
The Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Study (BRASS) was founded 14 years ago by Drs. Nancy A. Shadick and Michael Weinblatt to study genetic and clinical predictors of disease activity, biomarkers of disease response, and the natural history of patients with rheumatoid arthritis (RA) treated in the biologic DMARD era. Over 1,400 patients with either new onset or established RA disease have been recruited from the practices of Brigham and Women’s Hospital rheumatologists. At annual visits, information is collected on multiple variables, including demographics, disease activity score (DAS), medication use, co-morbidities, and functional status. More than 1,200 clinical variables are collected at each six month timepoint, which allows for the generation of extensive phenotyping and clinical analyses.
Brigham and Women’s Hospital Division of Rheumatology, Immunology and Allergy
In 1977, Dr. Matthew Liang founded the clinical research group in rheumatology at Brigham and Women’s Hospital (BWH). The original funding for this group derived from the NIH Multipurpose Arthritis Center program. Dr. Lawren Daltroy, a behavioral scientist, joined Dr Liang in 1982, and they pursued several innovative behavioral trials focusing on lupus, back pain, and Lyme disease. The faculty grew during the 1980s and 1990s with the addition of Drs. Jeffrey Katz, Nancy Shadick, and Elizabeth Karlson.
Andrea L. Roberts, PhD, Susan Malspeis, MS, Laura D. Kubzansky, PhD, Candace H. Feldman, MD, Shun-Chiao Chang, ScD, Karestan C. Koenen, PhD, Karen H. Costenbader, MD, MPH Arthritis & Rheumatology, 2017;69(11):2162-2169.
Systemic lupus erythematosus (SLE) is an enigmatic inflammatory autoimmune disease. A widely-accepted etiologic model for SLE is that environmental exposures “trigger” the disease in genetically-predisposed individuals. The epidemiology of SLE – 80-90% of cases occur in women, and disease severity is much greater in African-American and non-white populations – points to the obvious role of genetics, and genome-wide association studies have identified many genetic factors associated with SLE susceptibility. Meanwhile, there is a growing list of exposures which have also been associated with SLE risk in epidemiologic studies, which include current cigarette smoking, crystalline silica, pesticides, and oral contraceptives and postmenopausal hormones among women. Models for how these and other environmental exposures may contribute to autoimmune disease pathogenesis include elevating concentrations of systemic inflammatory cytokines, increasing oxidative stress, and impairing T-cell function.
Cumulative Incidence Curves of the Composite Endpoint of MI or Stroke
Cardiovascular Risks of Probenecid Versus Allopurinol in Older Patients with Gout. Seoyoung C. Kim, Tuhina Neogi, Eun Ha Kang, Jun Liu, Rishi J. Desai, MaryAnn Zhang, Daniel H. Solomon. Journal of the American College of Cardiology Mar 2018, 71 (9) 994-1004; DOI: 10.1016/j.jacc.2017.12.052
Inflammation plays a critical role in the pathogenesis of both gout and cardiovascular disease (CVD). It is well known that patients with gout are at an increased risk of CVD, including myocardial infarction (MI), stroke, and heart failure (HF). While it remains controversial whether uric acid is causally linked to the development of CVD, beneficial effects have been reported for allopurinol, the most commonly used urate-lowering drug, on lowering blood pressure and improving endothelial function and metabolic profile. Probenecid is another, older drug used for gout. It works as a competitive inhibitor of the organic anion transporter, producing uricosuria, as well as an inhibitor of pannexin 1 channels, an ATP release channel involved in the assembly and activation of the inflammasome. The NLRP3 inflammasome plays a critical role in production of IL-1β, which drives the inflammatory cascade that results in acute gout. Thus, it is possible that probenecid may have positive effect in gout patients not only by lowering serum urate levels, but also by reducing production of IL-1β.
Along with inflammatory arthritis, overproduction of autoantibodies is a defining feature of rheumatoid arthritis (RA), particularly autoantibodies against citrullinated proteins (ACPAs). The clinical significance of these ACPAs, other than for diagnosing RA, has been unclear. Previous studies have focused on association studies between a few ACPAs and one or two specific RA phenotypes – for example, an association between anti–citrullinated histone H2B antibodies and coronary artery calcium scores in patients with RA. But such an approach cannot identify potential associations with a wider array of untested phenotypes.
Big data will drive precision medicine in rheumatology. At Brigham and Women’s Hospital (BWH), the combination of massive databases with genomic and clinical data will open new capabilities for the diagnosis, care, and even prevention of rheumatic disease. BWH has invested in large-scale data collection that is now is bearing fruit. The Partners HealthCare Biobank repository of DNA, plasma, and serum samples now has more than 78,000 participants, with 20,000 genotyped samples, as well as survey data with family history, lifestyle and environmental information.
How does a healthy joint become inflamed? This question has engaged laboratories worldwide for decades, yet surprises continue. A particularly unexpected development emerged recently from the laboratory of Brigham and Women’s Hospital (BWH) rheumatologist Peter Nigrovic, MD, (www.nigroviclab.org) which implicated a lineage that until now has been of interest primarily to hematologists: the megakaryocyte. Read More