ReviewPathogenesis and therapies of immune-mediated myopathies
Introduction
Based on distinct clinicopathologic features, the most common inflammatory myopathies are dermatomyositis (DM), polymyositis (PM), necrotizing autoimmune myositis (NAM) and inclusion body myositis [1], [2], [3], [4], [5], [6]. DM presents with proximal muscle weakness accompanied or preceded by typical skin changes. PM is rare as a single entity and remains a diagnosis of exclusion; it presents subacutely in people above the age of 18 with proximal muscle weakness and creatine kinase (CK) elevation. Because PM lacks a unique clinical phenotype it is often misdiagnosed, most frequently as IBM. Sporadic IBM (sIBM), has a distinct clinical phenotype characterized by slow-onset weakness and atrophy of distal and proximal muscles in people above the age of 50. NAM has a multifactorial etiology; it may have an acute or subacute onset, can be severe, may have a seasonal variation or cancer association and may be triggered by statins or viral infections; it is often misdiagnosed as PM, toxic myopathy or a metabolic myopathy owing to the acute onset of hyper-CKemia.
This review outlines the fundamental differences in the immunopathology of these subsets and summarizes the most significant developments on their pathogenesis and therapies.
Section snippets
Immunopathology of DM
The disease begins with activation of the complement and formation of membrane attack complexes (MAC) which are deposited on the endomysial capillaries very early in the disease process causing lysis of the endothelial cells, destruction of capillaries and muscle ischemia [1], [2], [3], [4], [5], [6], [7], [8], [9]. As a result, the number of capillaries is reduced throughout the muscle, while the lumen of the remaining ones is dilated to compensate for the ischemic process. The pathology is
Immunobiolgy of PM and IBM
In both, PM and IBM, the fundamental immune process is mediated by CD8+ cytotoxic T cells which invade non-necrotic muscle fibers that express MHC-I antigen [1], [2], [3], [4], [5], [6], [9], [10]. The autoinvasive endomysial CD8+ T cells, especially those that are activated and express co-stimulatory molecules [18], contain perforin and granzyme granules, which are vectorially directed towards the surface of the muscle fiber, inducing necrosis upon release[2], [3]. In PM and IBM there is
IBM: a complex disorder with inflammation and degeneration
IBM is a complex disorder because in addition to immunopathology described above, demonstrates degenerative features consisting of rimmed vacuoles, intracellular deposition of Congo-red-positive amyloid and variable accumulation of amyloid-related molecules including APP, amyloid-β 42, phosphorylated tau, apolipoprotein Ε, and a number of oxidative or cell stress-related proteins [10], [21], [35]. This accumulation, is not unique to IBM because they are also observed in other vacuolar
Necrotizing autoimmune myositis (NAM)
Patients with NAM present with high CK, in the thousands, moderate to severe muscle weakness of acute or subacute onset and with histological features of muscle fiber necrosis mediated by macrophages as the main effector cells. There are no T cell infiltrates or MHC-I expression as seen in PM and IBM. A number of patients have deposition of complement on blood vessels. Of interest, antibodies against signal recognition particles (SRP) [35] or 100–200 kD proteins have been recently identified
Therapeutic strategies in DM and PM and challenges in IBM
Based on experience, but not controlled studies, the majority of patients with PM and DM respond to corticosteroids to some degree and for a period of time [44]. Intravenous immunoglobulin (IVIg) tested in a controlled study is effective in DM as a second, and at times, first line therapy. IVIg appears also effective in PM and NAM. Immunosuppressants are used as steroid-sparing agents but their efficacy remains unclear. New agents in the form of monoclonal antibodies or fusion proteins that
Disclosure statement
Prof Dalakas has nothing to disclose in reference to this paper.
Take-home messages
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Dermatomyositis is a complement-mediated muscle and skin disease affecting first the intramuscular capillaries leading to muscle weakness.
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Polymyositis and IBM are T cell-mediated disorders, where cytotoxic CD8+ cells invade MHC-I-expressing muscle fibers. IBM has, in addition, activation of degenerative pathways with vacuolization and congophilic amyloid deposits that render the disease relatively resistant to immunotherapies.
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NAM is an overlooked, acute or subacute, inflammatory myopathy
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