Idiopathic inflammatory myopathies

Abstract

Idiopathic inflammatory myopathies (IIM), also known as myositis, are a heterogeneous group of autoimmune disorders with varying clinical manifestations, treatment responses and prognoses. Muscle weakness is usually the classical clinical manifestation but other organs can be affected, including the skin, joints, lungs, heart and gastrointestinal tract, and they can even result in the predominant manifestations, supporting that these are systemic inflammatory disorders. Different myositis-specific autoantibodies have been identified and, on the basis of clinical, histopathological and serological features, IIMs can be classified into several subgroups — dermatomyositis (including amyopathic dermatomyositis), antisynthetase syndrome, immune-mediated necrotizing myopathy, inclusion body myositis, polymyositis and overlap myositis. The prognoses, treatment responses and organ manifestations vary among these groups, implicating different pathophysiological mechanisms in each subtype. A deeper understanding of the molecular pathways underlying the pathogenesis and identifying the autoantigens of the immune reactions in these subgroups is crucial to improve outcomes. New, more homogeneous subgroups defined by autoantibodies may help define disease mechanisms, and will also be important in future clinical trials to develop targeted therapies and in identifying biomarkers to guide treatment decisions for the individual patient.

Figure 1.. Manifestations of idiopathic inflammatory myopathies (IIM).

IIM exhibits not only myositis but also various extra-muscular complications. Some manifestations are strongly associated with the presence of specific circulating autoantibodies. MDA5, melanoma differentiation-associated gene 5; NXP2, nuclear matrix protein 2; SAE, small ubiquitin-like modifier activating enzyme; SRP, signal recognition particle; TIF1, transcriptional intermediary factor 1.

Figure 2.. Clinical manifestations in patients with dermatomyositis with anti-TIF1gamma, anti.NXP2 and anti.Mi-2 autoantibodies

Dermatomyositis (DM), including amyopathic DM, is one of the classical subgroups of IIMs. DM can be further subclassified based on specific autoantibodies, which demonstrate various characteristic manifestations such as distribution of muscle weakness and extramuscular manifestations: a. anti-transcriptional intermediary 1 (TIF1) DM; b. anti-nuclear matrix protein 2 (NXP2) DM; c. anti-Mi-2 DM.

Figure 3.. Clinical manifestations in patients with dermatomyositis with anti-MDA5 and anti-SAE autoantibodies.

Dermatomyositis (DM), including amyopathic DM, is one of the classical subgroups of IIMs. DM can be further subclassified based on specific autoantibodies, which demonstrate various characteristic manifestations such as distribution of muscle weakness and extramuscular manifestations: a. anti-melanoma differentiation-associated gene 5 (MDA5) DM; and b. anti-small ubiquitin-like modifier activating enzyme (SAE) DM.

Figure 4. Clinical manifestations of anti-synthetase syndrome.

Antisynthetase syndrome is characterized by the presence of one of the eight known autoantibodies against aminoacyl transfer RNA (tRNA) synthetases. The frequency and combination of symptoms may vary according to the type of aminoacyl tRNA synthetase autoantibody. Some patients can have only lung disease with no muscle involvement.

Figure 5.. Clinical manifestations in immune-mediated necrotizing myopathy.

A majority of patients with immune mediated necrotizing myopathy (IMNM) have autoantibodies recognizing either 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) or the signal recognition particle (SRP). Severe muscle disease is the predominant manifestation of IMNM. Anti-SRP positive patients usually have more serious disease often accompanied with dysphagia and sometimes with cardiac involvement. In patients positive for anti-HMGCR necrotizing myopathy prevails.

Figure 6.. Clinical manifestations of inclusion body myositis.

Inclusion body myositis (IBM) is characterized by slowly progressive muscle weakness affecting mainly quadriceps muscle and forearm muscles. Muscle involvement can be asymmetrical. The disease leads to significant muscle atrophy and severe disability. Dysphagia is present in more than 50% of patients.

Figure 7.. Typical histopathological changes in IIM subgroups.

Dermatomyositis: a) perifascicular atrophy and perivascular inflammatory infiltrate, b) inflammatory infiltrate with CD4+ cells, c) inflammatory infiltrate with B cells, d) MHC I expression on muscle fibres, particularly in perifascicular distribution, e) membrane attack complex depositions in capillaries. Antisynthetase syndrome: f) perifascicular myofiber necrosis, perifascicular atrophy, perimysial fragmentation. Immune mediated necrotizing myopathy: g) necrotic muscle fibres, h) MHC I hyperexpression on sarcolemma of muscle fibres, i) membrane attack complex deposition on capillaries and sarcolemma of muscle fibres. Inclusion body myositis: j) lymphocytic and macrophage aggregates in endomysium and invasion into muscle fibres, k) CD8+ positive inflammatory infiltrate, l) rimmed vacuoles (arrows), m) p62 staining (arrows). Polymyositis: n4) endomysial infiltrate surrounding and invading non-necrotic muscle fibres, o) CD8+ cells surrounding and invading non-necrotic muscle fibres. Original magnification 40x (1, 6) and 200x (2–5, 7–15).

Figure 8.. Common pharmacological and other therapies for idiopathic inflammatory myopathies (IIM) except inclusion body myositis (IBM).

Note: IVIg: Intravenous Immunoglobulins; ILD: Interstitial Lung Disease; ASyS: Anti-synthetase syndrome.

Figure 9.. Treatment considerations in patients with refractory myositis based on the clinico-serologic presentation.

Note: IVIg: Intravenous Immunoglobulins; ILD: Interstitial Lung Disease; DM: Dermatomyositis; JDM: Juvenile Dermatomyositis; Anti-SRP: Anti-Signal Recognition Particle; Anti-HMGCR: 3-hydroxy-3-methylglutaryl CoA reductase