Inflammatory Myopathies

Definition

The inflammatory myopathies are a heterogeneous group of acquired disorders in which the immune system is thought to play a major pathogenic role. Though some genetic disorders affecting muscle also have significant involvement of the immune system and are treated with immunosuppressive therapy as the standard of care (e.g., treatment of Duchenne muscular dystrophy with corticosteroids), these genetic disorders are not classified as inflammatory myopathies. The four major subtypes of inflammatory myopathy are dermatomyositis, polymyositis, immune-mediated necrotizing myopathy, and inclusion body myositis (also called sporadic inclusion body myositis). These disorders have distinct clinical and pathologic features and pathophysiologies ( Table 248-1 ). ^,

Epidemiology

The prevalence of dermatomyositis has been estimated at 100 to 210 per million. The estimated prevalence of polymyositis is confounded by frequent misdiagnosis of inclusion body myositis and muscular dystrophies as polymyositis. Studies show a prevalence of 35 per million for polymyositis, approximately half of the 70 per million prevalence of inclusion body myositis. Inclusion body myositis is the most common acquired muscle disease after age 50 years. The prevalence of immune-mediated necrotizing myopathy is unknown.

Dermatomyositis has biphasic peaks in incidence in childhood (ages 7 to 15 years) and in midlife (ages 30 to 50 years), whereas polymyositis peaks in incidence in midlife. Inclusion body myositis is rarely diagnosed before the age of 40 years and is most common after the age of 50 years. Dermatomyositis and polymyositis have female predominance, whereas inclusion body myositis has male predominance.

Pathobiology

The pathophysiologies of various forms of inflammatory myopathy are poorly understood. These disorders do share in common injury to muscle by the immune system. Much of the theory of pathophysiology of these disorders comes from microscopic examination of muscle biopsies and the distinct pathologies of these disorders ( Fig. 248-1 ).

The muscle pathology of dermatomyositis involves loss of blood vessels and injury to myofibers at the edges of muscle fascicles (i.e., perifascicular atrophy; see Fig. 248-1 ). It is likely that a common factor injures both myofibers and capillaries. Skin pathology shows features analogous to that of muscle, with an interface dermatitis consisting of injury to the basal layer of keratinocytes.

Evidence points toward dermatomyositis as mediated by the type 1 interferon cytokine family, consisting mainly of interferon (IFN)-α and IFN-β. Studies of dermatomyositis skin and muscle samples show marked upregulation of type 1 IFN-inducible transcripts and proteins uniquely in dermatomyositis among muscle diseases and similarly to systemic lupus erythematosus ( Chapter 245 ) among skin diseases. The presence of autoantibodies in some patients with dermatomyositis, such as antibodies to the type 1 IFN-inducible protein MDA5, is of uncertain significance but seems likely due to an immune reaction to proteins that are not normally expressed at high levels or exposed to the immune system. The paraneoplastic associations of dermatomyositis suggest that an immune reaction against an underlying malignancy results in bystander injury to muscle and skin in such patients.

Because polymyositis is a diverse group of disorders, the mechanisms involved are likely to be varied. Pathologically, nonspecific inflammation varies among the increasingly recognized distinct subtypes, such as the antisynthetase syndrome.

Immune-mediated necrotizing myopathy is also a poorly understood disorder. It can also be paraneoplastic, thereby suggesting cross-reactions by the immune system with the underlying malignancy and with muscle antigens. More commonly, immune-mediated necrotizing myopathy occurs in association with treatment with statin drugs ( Chapter 190 ). The identification of autoantibodies against the target of statins, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), in the majority of patients who develop immune-mediated necrotizing myopathy in association with statin use suggests that the upregulation of HMGCR in muscle is directly toxic to muscle and triggers an immune reaction against it. Anti–signal recognition particle (SRP) autoantibodies have also been identified in some patients with immune-mediated necrotizing myopathy. Anti-SRP myopathy, anti-HMGCR myopathy, and autoantibody-negative myopathy have been considered to be three distinct subtypes of immune-mediated necrotizing myopathy.

A genetic basis of inclusion body myositis has been suggested by its significant association with the class II MHC allele HLA-DRB1∗03:01. The pathogenesis of inclusion body myositis includes the destruction of myofibers by highly differentiated cytotoxic T cells. ^, Degeneration of myofibers and of myonuclei in particular, evident as formation of rimmed vacuoles, is likely a consequence of very chronic immune destruction of muscle (see Fig. 248-1A-C ) and involvement of the immune system. Among all the inflammatory myopathies, inclusion body myositis has the greatest evidence of a highly refined, antigen-driven, adaptive immune system response ( Chapter 35 ). Pathology shows very chronic and often marked but variable inflammatory infiltrates of T cells, myeloid dendritic cells, and plasma cells in muscle. Studies of the T-cell receptors have strongly suggested that T-cell autoimmunity is driven by one or more specific antigens, though the identity of any of these antigens is unknown.

Studies of a B-cell pathway in inclusion body myositis have led to identification of circulating autoantibodies against a 43-kD muscle protein, identified as cytoplasmic 5′ nucleotidase 1 A (cN1A; NT5C1A). cN1A is a nucleotidase that is most abundant in skeletal muscle and is involved in the metabolism of nucleic acids. Serum anti-cN1A autoantibodies are present in 50 to 70% of patients with inclusion body myositis, depending on which assays and what cutoffs are used, and they are highly specific (>90 to 95%) for inclusion body myositis among muscle diseases.

Clinical Manifestations and Diagnosis

A diagnosis of inflammatory myopathy is considered when a patient presents with proximal or distal weakness without sensory symptoms or patients develop the characteristic skin lesions of dermatomyositis. Less frequently, asymptomatic elevated levels of creatine kinase lead to a diagnosis of inflammatory myopathy. Most patients with dermatomyositis, polymyositis, or immune-mediated necrotizing myopathy present with subacute proximal weakness of the arms and legs progressing over months, though these diseases may present acutely. Patients with inclusion body myositis present later in life, usually symptomatic from slowly progressive weakness of knee extensors and finger flexors. More specific diagnostic features of these disorders are considered individually ( Table 248-2 ). Most patients undergo muscle biopsy (or skin biopsy in the case of suspected dermatomyositis) as part of the diagnostic evaluation.