CME Molecular profiles of inflammatory myopathies

Objective: To describe the use of large-scale gene expression profiles to distinguish broad categories of myopathy and subtypes of inflammatory myopathies (IM) and to provide insight into the pathogenesis of inclusion body myositis (IBM), polymyositis, and dermatomyositis. Methods: Using Affymetrix GeneChip microarrays, the authors measured the simultaneous expression of approximately 10,000 genes in muscle specimens from 45 patients in four major disease categories (dystrophy, congenital myopathy, inflammatory myopathy, and normal). The authors separately analyzed gene expression in 14 patients limited to the three major subtypes of IM. Bioinformatics techniques were used to classify specimens with similar expression profiles based on global patterns of gene expression and to identify genes with significant differential gene expression compared with normal. Results: Ten of 11 patients with IM, all normals and nemaline myopathies, and 10 of 12 patients with Duchenne muscular dystrophy were correctly classified by this approach. The various subtypes of inflammatory myopathies have distinct gene expression signatures. Specific sets of immunerelated genes allow for molecular classification of patients with IBM, polymyositis, and dermatomyositis. Analysis of differential gene expression identifies as relevant to disease pathogenesis previously reported cytokines, major histocompatibility complex class I and II molecules, granzymes, and adhesion molecules, as well as newly identified members of these categories. Increased expression of actin cytoskeleton genes is also identified. Conclusions: The molecular profiles of muscle tissue in patients with inflammatory myopathies are distinct and represent molecular signatures from which diagnostic insight may follow. Large numbers of differentially expressed genes are rapidly identified. NEUROLOGY 2002;59:1170–1182 Dermatomyositis, polymyositis, and inclusion body myositis (IBM) are the three major categories of idiopathic inflammatory myopathy (IM).1 Dermatomyositis is believed to be an autoimmune, humoral-mediated microangiopathy. Polymyositis results from an HLArestricted, antigen-specific, cell-mediated immune response directed against muscle fibers. The antigens to which these autoimmune attacks are generated or the trigger of these responses are not known. IBM may be a primary inflammatory myopathy, like dermatomyositis and polymyositis, or a primary degenerative myopathic disorder, such as a dystrophy with secondary inflammation.2 The inflammatory response and immunohistochemical studies support the hypothesis that IBM is an autoimmune disorder mediated by cytotoxic T cells.3 However, poor clinical response to immunosuppressive therapies argues against a primary autoimmune basis for IBM.4,5 Although clinically distinct, difficulties may arise in distinguishing these disorders by standard clinical and histopathologic criteria. Diagnostic inaccuracies, particularly in regard to inclusion body myositis, result in significant morbidity.6 As many as 20% to 30% of muscle biopsies are interpreted as polymyositis even by myopathologists quite familiar with IBM.6 Significant endomysial inflammation with invasion of non-necrotic muscle fibers and more commonly rimmed vacuoles, tubulofilaments, and amyloid deposition are not always evident and probably reflects sampling bias.2,6,7 A second or third biopsy may be required prior to histologically confirming the diagnosis of IBM. Significant morbidity can arise from the misclassification of patients with IBM as polymyositis because patients with IBM Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of