Elsevier

Autoimmunity Reviews

Volume 11, Issue 3, January 2012, Pages 203-206
Autoimmunity Reviews

Review
Pathogenesis and therapies of immune-mediated myopathies

https://doi.org/10.1016/j.autrev.2011.05.013Get rights and content

Abstract

The most common autoimmune muscle disorders include dermatomyositis (DM), polymyositis (PM), necrotizing autoimmune myositis (NAM) and sporadic inclusion body myositis (sIBM). DM is a complement-mediated microangiopathy leading to destruction of capillaries, hypoperfusion and inflammatory cell stress on the perifascicular regions. NAM is an increasingly recognized subacute myopathy triggered by statins, viral infections, cancer or autoimmunity with macrophages as the final effector cells causing fiber injury. PM and IBM are T cell-mediated disorders where cytotoxic CD8+ T cells clonally expand in situ and invade major histocompatibility complex class I expressing muscle fibers. In sIBM, in addition to autoreactive T cells, there are degenerative features characterized by vacuolization and accumulation of stressor or amyloid-related misfolded proteins; an interrelationship between inflammatory and degeneration-associated molecules is prominent and enhances the cascade of pathogenic factors. These disorders are treatable, hence the need to make the correct diagnosis from the outset. The applied therapeutic strategies are outlined and the promising new agents are reviewed.

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

  • Dermatomyositis is a complement-mediated muscle and skin disease affecting first the intramuscular capillaries leading to muscle weakness.

  • 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.

  • NAM is an overlooked, acute or subacute, inflammatory myopathy

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