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Immune-Mediated Necrotizing Myopathy

This type of myopathy has recently been added to the previously discussed inflammatory myopathies. It is felt to be a distinct myopathy that is immune mediated. It represents up to 20% of all inflammatory myopathies and occurs more frequently than polymyositis. It can affect any age group but usually occurs in adults. Clinically, the onset is similar to DM and PM with symptoms of proximal muscle weakness that progresses over days to weeks. Muscle pain may be more prominent than in other myopathies. Necrotizing myopathy often occurs in association with other

connective tissue diseases such as scleroderma or mixed-connective tissue disease. It may occur following viral infections or in association with cancer (GI tract adenocarcinomas, small cell carcinoma of the lung). Onset may coincide with use of statin drugs to lower cholesterol. The myopathy may persist following withdrawal of the statin [2, 5, 6]. These cases are often associated with antibodies against signal recognition particle (SRP) or 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) [11].

Diagnostic findings are similar to other myopathies. The creatine kinase is often very high, up to 50 times the upper limit of normal in acute stage. EMG shows typical changes associated with myopathy and is not significantly different from changes in DM and PM. It is important to screen for other autoimmune disorders with appropriate testing and to also carefully screen for underlying cancers. Presence of antisignal recognition particle (anti-SRP) antibody may be associated with a dilated cardiomyopathy that may not respond to usual treatment with immunosuppressants. Positive HMGCR antibodies may be found in patients who have taken statin drugs [11]. These antibodies are not present in patients whose muscle symptoms have improved after cessation of the statin. MRI of muscles may reveal evidence of inflammation and edema. MRI of muscles, particularly the vastus lateralis, vastus medialis, and medial head of the gastrocnemius, soleus, and anterior tibial muscles, shows hyperintensity of short tau inversion recovery images (STIR) that is associated with fatty infiltration [9].

Main inflammatory features of polymyositis, inclusion body myositis, and necrotizing autoimmune myositis and a proposed immunopathogenic scheme for polymyositis and inclusion body myositis

Fig. 12.2 Main inflammatory features of polymyositis, inclusion body myositis, and necrotizing autoimmune myositis and a proposed immunopathogenic scheme for polymyositis and inclusion body myositis. Panels a and b show cross sections of hematoxylin and eosin-stained muscle biopsy samples from a patient with polymyositis (Panel a) and a patient with inclusion body myositis (Panel b), in which scattered inflammatory foci with lymphocytes invading or surrounding healthy- appearing muscle fibers are visible. In inclusion body myositis, there are also chronic myopathic features (increases in connective tissue and atrophic and hypertrophic fibers) and autophagic vacuoles with bluish-red material, most prominent in fibers not invaded by T cells (arrow). In both polymyositis and inclusion body myositis, the cells surrounding or invading healthy fibers are CD8+ T cells, stained in green with an anti-CD8+ monoclonal antibody (Panel c); also visible is widespread expression of MHC class I, shown in green in Panel d, even in fibers not invaded by T cells. In contrast, in necrotizing autoimmune myositis (a cross section stained with trichrome is shown in Panel e), there are scattered necrotic fibers invaded by macrophages (Panel f), which are best visualized with an acid phosphatase reaction (in red). Panel g shows a proposed mechanism of T cell-mediated muscle damage in polymyositis and inclusion body myositis. Antigen-specific CD8+ cells, expanded in the periphery and subsequently in the endomysium, cross the endothelial cell wall and bind directly to aberrantly expressed MHC class I on the surface of muscle fibers through their T cell receptors, forming the MHC-CD8 complex. Upregulation of costimulatory molecules (BB1 and ICOSL) and their ligands (CD28, CTLA-4, and ICOS), as well as ICAM-1 or LFA-1, stabilizes the synaptic interaction between CD8+ cells and MHC class I on muscle fibers. Regulatory Th17 cells play a fundamental role in T cell activation. Perforin granules released by the autoaggressive T cells mediate muscle fiber necrosis. Cytokines, such as interferon-y, interleukin-1, and tumor necrosis factor (TNF) released by the activated T cells, may enhance MHC class I upregulation and T cell cytotoxicity. Activated B cells or plasmacytoid dendritic cells are clonally expanded in the endomysium and may participate in the process in a still-undefined role, either as antigen-presenting cells or through the release of cytokines and antibody production (The figure and legend obtained from Dalakas [6] Copyright permission obtained)

Muscle biopsy shows evidence of muscle necrosis with macrophages surrounding the necrotic fibers. Unlike PM and IBM, no CD8+ cells or vacuoles are seen. Non-necrotic fibers may express MHC-1 and membrane attack complex deposition [2, 5, 6].

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