Connective Tissue Diseases/inflammatory Myopathies--polymyositis/dermatomyositis

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

Investigators

Linked publications & trials

Abstract

The Connective Tissue and Diseases Section studies inflammatory myopathies (polymyositis, dermatomyositis, and related diseases) to understand the relationship of autoantibodies to autoimmune disease. They are very uncommon and hence relatively less studied than other autoimmune diseases, and they are very debilitating and hence in need of improved therapy. In order to attract patients here to allow more detailed clinical, immunological, genetic, and viral studies, we carry out trials of therapy and have completed a number of such studies. They are among the very few published controlled trials in this difficult to treat family of illnesses. These trials have encompassed a variety of approaches to immunosuppression. In the past year we have ended a trial of the ANTI-TNF AGENT, infliximab (REMICADE), a mouse-human chimeric antibody that has been approved for use in rheumatoid arthritis and inflammatory bowel disease. The rationale for carrying out the trial was the evidence, admittedly modest, that TNF is present in the active lesions in myositis biopsies. The trial was carried out with financial support from the manufacturer, Centocor, under a clinical CRADA. The patient population was similar to that we used in other studies - patients who had unsatisfactory responses to conventional immunosuppressive therapy. Enrollment was slower than in our earlier trials, but no single factor stands out as the cause for this. We decided to end the trial when we had reached 50% of the planned accrual. Only one patient remains to have a final evaluation - in 12-08. The partial results are under active analysis and will be presented at the 2008 ACR meeting in October 2008 and will be submitted for publication after completion of the trial. During the past year, Mark Gourley became the PI of this trial. A large, multinational cooperative trial of an anti-B cell agent, supported by NIH, was launched and is actively recruiting patients at a number of US centers including the myositis group in NIEHS for the same population as the infliximab trial. Our referral clinic continues to see quite a number of patients who have been diagnosed as having myositis and having been treated unsuccessfully with standard therapy. A substantial proportion of these patients have either a demonstrable genetic disease (such as McArdle's, PFK deficiency, acid maltase deficiency, one of the many types of limb girdle dystrophy) or a presumptive genetic disease awaiting precise diagnosis (undiagnosable dystrophy, undiagnosable vacuolar myopathy, undiagnosable channelopathy.) We continue to work with Eric Hoffman's lab in the Center for Genetic Medicine at the Children's National Medical Center, using gene expression to sharpen diagnosis. Dr. Lisa Christopher-Stine of Johns Hopkins has received K-23 funding to carry out an in depth analysis of the critical diagnostic and predictive prognostic features in over 700 patients evaluated under our current Natural History protocol, 91-AR-0196. Frozen muscle biopsy specimens and DNA from several hundred of the patients seen in the study in recent years have been gathered and catalogued for future studies. Certain dystrophy genes from selected patients with myositis are being sequenced by Dr. Hoffman's group at NIH to determine if treatment-resistant myositis is in some case a dystrophy with incidental inflammation that resembles myositis.