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. Defining diagnostic boundaries. 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. Our first study has been an attempt to separate dysferlin deficiency (which causes Miyoshi myopathy and type IIb limb girdle dystrophy) from myositis. We chose this problem because inflammation is present in dysferlin deficiency. The major findings are that a number of membrane remodeling genes are up-regulated or down-regulated, and the levels of a number of inflammatory genes are altered, consonant with and substantially extending published histological findings. The analysis of gene expression in dysferlin deficiency, including a comparison to Duchenne Muscular Dystrophy, is under review. Analysis of the effects on inflammatory genes is in process. We have assembled a number of muscle biopsies from patients with freshly diagnosed and untreated myositis from colleagues at the Karolinksa and at Johns Hopkins.
The aim i s 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. We will also study the effect of infliximab on gene expression in muscle specimens from patients in the infliximab treatment trial.
