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 completed 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 evidencethat TNF is present in the active lesions in myositis biopsies;that it diminishes muscle cell contractility;and that it impairs myogenesis. 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. This 40-week randomized, double-blind, placebo-controlled trial included subjects >18 years old who: fulfilled Bohan &Peter criteria;had evidence of active disease with muscle enzyme elevation, STIR MRI signal abnormalities, baseline manual muscle testing (MMT) score of 80-120 (out of 160);stable prednisone <0.5 mg/kg/day and DMARD doses for 4 weeks prior to participation;and who failed previous immunosuppressive treatment or had intolerance to therapy. Exclusion criteria included malignancy, CNS disease, prior infliximab therapy, infection, lupus and heart failure. Enrollment was slower than in our earlier trials, but no single factor stands out as the cause for this. We ended the trial when we had reached 50% of the planned accrual. Participants received four blinded infusions of either placebo or infliximab 5 mg/kg at 0, 2, 6 and 14 weeks. Unblinding occurred at week 16 following assessment of improvement by the primary (15% MMT improvement from week 0) and secondary outcomes (improvement as defined by the International Myositis Assessment and Clinical Studies Group (IMACS) criteria). Subjects in the infliximab arm who did not improve based on MMT criteria (nonresponders) were increased to open-label infliximab 7.5 mg/kg at weeks 22, 30, 38. Nonresponders in the placebo arm received open-label 5 mg/kg at weeks 16, 18, 22, 30, 38. Responders in each arm had the option of either continuing the same treatment or changing to the non-responder treatment for that study arm. Outcomes were reassessed at week 40. Twelve subjects (11F/1M;6 African American, 5 Caucasian, 1 Asian;11 PM /1 DM) completed the study to week 16. For these subjects, the mean age was 45.4 + 10.9 years, mean disease duration 5.6 + 4.0 years, mean corticosteroid dose was 17.3 + 10.8 mg/day;mean methotrexate dose (N=9) was 16.4 + 11.3 mg/week and mean azathioprine dose (N=3) 50.0 + 86.1 mg/day. Mean baseline MMTs were 104.2 + 9.9 (placebo arm, N=6) vs. 104.2 + 17.3 (infliximab arm, N=6). Three subjects in the infliximab arm withdrew after week 16;3 subjects completed the infliximab 7.5 mg/kg dosing regimen. All 6 patients in the placebo arm crossed over to the 5 mg/kg dosing regimen after week 16. On the infliximab arm 3/12 subjects improved by manual muscle testing at 16 weeks and one additional subject improved by MMT at 40 weeks None of the 6 subjects improved with placebo treatment(p=0.50 for the primary outcome and p=0.63 for the secondary outcome). No clinical or laboratory differences were detected between responders and nonresponders. Two SAEs, unrelated to study drug, occurred during the study. Adverse events were otherwise mild and reversible. This first randomized, controlled clinical trial of infliximab reported in patients with myositis suggests that infliximab is well tolerated but has only limited efficacy in adult PM and DM. In a large, multinational cooperative trial of an anti-B cell agent, supported by NIH, and of which NIAMS and NIEHS were a part, was completed and the results are currently being analysed. 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.

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National Institute of Arthritis and Musculoskeletal and Skin Diseases
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Rider, Lisa G; Koziol, Deloris; Giannini, Edward H et al. (2010) Validation of manual muscle testing and a subset of eight muscles for adult and juvenile idiopathic inflammatory myopathies. Arthritis Care Res (Hoboken) 62:465-72