Possible future avenues for myositis therapeutics: DM, IMNM and IBM

The inflammatory myopathies, commonly described as idiopathic, are the largest group of acquired and potentially treatable myopathies. On the basis of unique clinical, histopathological, immunological, and demographic features, they can be differentiated into three major and distinct subsets: dermatomyositis, polymyositis, and inclusion-body myositis. Use of new diagnostic criteria is essential to discriminate between them and to exclude other disorders. Dermatomyositis is a microangiopathy affecting skin and muscle; activation and deposition of complement causes lysis of endomysial capillaries and muscle ischaemia. In polymyositis and inclusion-body myositis, clonally expanded CD8-positive cytotoxic T cells invade muscle fibres that express MHC class I antigens, which leads to fibre necrosis via the perforin pathway. In inclusion-body myositis, vacuolar formation with amyloid deposits coexists with the immunological features. The causative autoantigen has not yet been identified. Upregulated vascular-cell adhesion molecule, intercellular adhesion molecule, chemokines, and their receptors promote T-cell transgression, and various cytokines increase the immunopathological process. Early initiation of therapy is essential, since both polymyositis and dermatomyositis respond to immunotherapeutic agents. New immunomodulatory agents currently being tested in controlled trials may prove promising for difficult cases.

Dermatomyositis is a clinically distinct myopathy characterized by rash and a complement-mediated microangiopathy that results in the destruction of muscle fibers. In some patients the condition becomes resistant to therapy and causes severe physical disabilities. We conducted a double-blind, placebo-controlled study of 15 patients (age, 18 to 55 years) with biopsy-proved, treatment-resistant dermatomyositis. The patients continued to receive prednisone (mean daily dose, 25 mg) and were randomly assigned to receive one infusion of immune globulin (2 g per kilogram of body weight) or placebo per month for three months, with the option of crossing over to the alternative therapy for three more months. Clinical response was gauged by assessing muscle strength, neuromuscular symptoms, and changes in the rash. Changes in immune-mediated muscle abnormalities were determined by repeated muscle biopsies. The eight patients assigned to immune globulin had a significant improvement in sores of muscle strength (P < 0.018) and neuromuscular symptoms (P < 0.035), whereas the seven patients assigned to placebo did not. With crossovers a total of 12 patients received immune globulin. Of these, nine with severe disabilities had a major improvement to nearly normal function. Their mean muscle-strength scores increased from 74.5 to 84.7, and their neuromuscular symptoms improved. Two of the other three patients had mild improvement, and one had no change in his condition. Of 11 placebo-treated patients, none had a major improvement, 3 had mild improvement, 3 had no change in their condition, and 5 had worsening of their condition. Repeated biopsies in five patients of muscles whose strength improved to almost normal showed an increase in muscle-fiber diameter (P < 0.04), an increase in the number and a decrease in the diameter of capillaries (P < 0.01), resolution of complement deposits on capillaries, and a reduction in the expression of intercellular adhesion molecule 1 and major-histocompatibility-complex class I antigens. High-dose intravenous immune globulin is a safe and effective treatment for refractory dermatomyositis.