Connective Tissue Diseases/inflammatory Myopathies

Arthritis, Musculoskeletal, Skin Dis

Investigators

Linked publications & trials

Abstract

The Connective Tissue and Diseases Section began studying inflammatory myopathies (polymyositis, dermatomyositis, and related diseases) some years ago in an attempt to understand the relationship of autoantibodies to autoimmune disease. At the time, these diseases seemed to offer the best example of autoimmune diseases associated with highly specific disease-related autoantibodies and evidence of a viral etiology. 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 began doing 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 most recently completed trial - a pilot trial of the anti-thyroid drug methimazole - was undertaken to make use of an unexpected property of the drug which was discovered by Dr. Leonard Kohn of NIDDK and Dr. Dinah Singer of NCI: that it can down-regulate MHC. We are currently enrolling patients in 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 is the evidence, admittedly modest, that TNF is present in the active lesions in myositis biopsies. The trial is being carried out with financial support from the manufacturer, Centocor, under a clinical CRADA. The patient population is similar to that we have used in other studies - those who have had unsatisfactory responses to conventional immunosuppressive therapy. A large number of patients have been screened over the past year for this trial; a smaller number has reached a final screening admission; and a smaller number still has been accepted into the trial, of whom several have completed the blinded phase, and a few have completed the full trial. As the new fiscal year begins, a number of patients have been scheduled for likely entry into the trial, with the hope that a clear outcome of the trial will become available within the next two fiscal years. 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 have joined with Eric Hoffman's lab in the Center for Genetic Medicine at the Children's National Medical Center to attempt to use gene expression to sharpen diagnosis. We have assembled a number of muscle biopsies from patients with freshly diagnosed and untreated myositis from colleagues at the Karolinksa Institutet in Sweden and at Johns Hopkins. The aim is to determine whether or not expression studies, particularly of inflammatory genes, can be used to separate primary inflammatory muscle disease (myositis) from diseases that can closely resemble it. With Dr. Lisa Christopher-Stine of Johns Hopkins and with the help of a new post-baccalaureate student, we plan to analyze the critical diagnostic and predictive prognostic features in the nearly 700 patients evaluated under our current Natural History protocol, 91-AR-0196. Biopsies and MRIs are available on a very large number of these patients, in addition to standard clinical and laboratory data.