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. 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. It now appears that we will not be able to enroll enough patients to complete the trial as originally designed within a reasonable period. Enrollment has been slower than in earlier trials we have carried out in myositis, but no single factor stands out as the cause for this. We have patients in the trial at the moment and are evaluating several candidates, but there is another trial of anti-TNF agent open, and a large, multinational cooperative trial of an anti-B cell agent has just been launched and is actively recruiting patients at a number of US centers for the same population as our trial. When the CRADA supporting part of this trial comes up for renewal, we will consider how to proceed without imperiling the information already generated by the study. It is likely that a more limited publication will be planned. 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 recently 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. Dr. Alan Gelber of Johns Hopkins and I are co-mentors for this project, and Mr. Neel Pahlajani, a former post-baccalaureate student now working on contract, are analyzing biopsies and MRIs are available on a very large number of these patients, in addition to standard clinical and laboratory data. 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.
