Idiopathic Inflammatory Myopathies: Recent Evidence Linking Pathogenesis and Clinical Features

Abstract

Idiopathic inflammatory myopathies are rare and complex representatives of systemic connective tissue diseases. Described initially as only two entities, recent advances in molecular and imaging techniques now divide them into many subtypes, each with unique pathogenesis and clinical phenotypes. Dermatomyositis and its juvenile form are the most prevalent subtypes and are characterized by systemic vasculopathy and humoral autoimmunity. Genetic predisposition and environmental triggers initiate immune tolerance breakdown, leading to autoantibody production, complement activation, and tissue damage. Anti-synthetase syndrome primarily affects the lungs, where immune responses to aminoacyl-RNA synthetases drive vasculopathy, lung inflammation, and fibrosis. Immune-mediated necrotizing myopathies are muscle-specific, with autoantibodies inducing fiber necrosis and atrophy. Lastly, sporadic inclusion body myositis is a slowly progressive myopathy in which dysfunctional protein handling and autophagy are more important pathogenic elements than muscle inflammation itself. The expanding body of basic science evidence can be overwhelming, making it challenging to connect pathogenic mechanisms to clinical manifestations. This review aims to address this challenge by presenting recent insights into myositis pathogenesis from a practical perspective, reinforcing the links between basic science and clinical semiology.

Keywords: anti-synthetase syndrome; dermatomyositis; immune-mediated necrotizing myopathy; inclusion body myositis; pathogenesis.

Figure 1

Illustration depicting the pathogenesis and key clinical features of dermatomyositis. Dermatomyositis and its juvenile form are the most prevalent idiopathic inflammatory myopathies. Although differences exist between adult and childhood-onset disease, they are archetypes of systemic vasculopathy with humoral autoimmunity [10]. (a) Presumable triggering agents, such as viruses or sunlight, promote antigen expression in genetically predisposed individuals with a type I interferon signature [34]. This leads to immune tolerance breakdown and production of myositis antibodies [35]. (b) Circulating autoantibodies are deposited on endothelial cells in the muscle and skin, initiating the complement cascade and formation of the membrane attack complex in the capillaries [16]. Aggression to the capillaries leads to the expression of adhesion molecules and recruitment of lymphocytes and macrophages that migrate to the perifascicular region [36,37]. Eventually, the capillaries may be completely occluded, leading to perifascicular ischemia [10]. (c) Because the blood vessel is the core of immune aggression, infiltrates tend to concentrate around them. Continuous ischemia impairs muscle regeneration and leads to perifascicular atrophy [10]. (d) The main clinical manifestations of dermatomyositis include polymorphic forms of rashes, representing perivascular dermatitis [10]. In the extremities, vasculopathy can lead to nailfold disease and skin ulceration [37]. Muscle manifestations are frequent and involve weakness, especially in the scapular and pelvic girdles and neck flexors. Lung disease is less well understood but may be related to the activation of lung macrophages and fibroblasts induced by neutrophil extracellular traps, which are activated by autoantibodies [38]. The latter is also associated with calcinosis [39]. C’: aggregated complement fractions; C1q: complement 1q component; RBC: red blood cell; ICAM-1: intercellular adhesion molecule 1; IFNαβ: Type I interferons alpha and beta; ILD: interstitial lung disease; LyB: B-lymphocyte; MSA: myositis-specific antibodies; LyT: T-lymphocyte; APC: antigen presenting cell; MAC: membrane attack complex; Mo: monocyte; MP: macrophage.

Figure 2

Pathogenesis and clinical manifestations of anti-synthetase syndrome. The lung is the main organ involved in anti-synthetase syndrome. (a) Environmental triggers cause lung injury [77] and expose wild aminoacyl-RNA-synthetases to granzyme B action, promoting the formation of neoantigens [78] that can act as chemokines for T-lymphocytes [79]. In genetically predisposed individuals, this can lead to immune tolerance breakdown and the production of anti-RNA-synthetases. (b) Anti-RNA-synthetases deposit in the sarcolemma [86] and, mediated by interferon γ [82], interleukin-6, tumor necrosis factor α, and possibly interleukin-17 [91,92], promote inflammatory infiltration, cytotoxicity, and myofiber necrosis. (c) Alternatively, anti-RNA-synthetases can deposit in blood vessels, causing complement-mediated vasculopathy [86]. (d) Interstitial lung disease is almost universal and represents the main site of neoantigen formation, so the lungs may harbor germinal center-like formations [81]. Vasculopathy is responsible not only for muscle ischemic dysfunction and perifascicular necrosis but also for the Raynaud phenomenon, which occurs in a large percentage of patients. Arthritis is frequent and can be erosive, though its pathogenesis is unclear, presumably related to humoral mechanisms. In contrast, thickening of the palms and soles is a clinical manifestation of skin hyperkeratosis, focal parakeratosis, and psoriasiform acanthosis [93]. Since mononuclear cell infiltrates around blood vessels usually accompany these alterations [93], one could hypothesize that they represent a dysfunctional form of skin regeneration. ARS: anti-RNA-synthetase antibodies; C’: aggregated complement fractions; C1q: complement 1q component; CCR5: C-C chemokine receptor type 5; GB: granzyme B; IFNγ: interferon gamma; ILD: interstitial lung disease; LyB: B-lymphocyte; LyT: T-lymphocyte; Mo: monocyte; MP: macrophage; RBC: red blood cell; TCD4+: CD4+ T-lymphocyte; TNFα: tumor necrosis factor alpha; tRS: amino-acyl-tRNA-synthetase; tRS’: modified neoantigen of amino-acyl-tRNA-synthetase.

Figure 3

Illustration representing the main manifestations and pathogeneses of immune-mediated necrotizing myopathies. Immune-mediated necrotizing myopathies (IMNMs) are conditions relatively restricted to the muscle (skeletal and myocardial). (a) Regenerating fibers express the targets of the disease on their membrane, enabling the immune tolerance breakdown and subsequently deposition of autoantibodies on the sarcolemma [99,100]. In the case of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, statins can participate in the phenomenon. Antibodies adhered to the myocytes activate the complement cascade, with membrane attack complex formation and myofiber necrosis [98,102]. Infiltrating lymphocytes overexpress programmed cell death protein 1 and become anergic and apoptotic (Knauss) [103], so the infiltrate is mainly composed of necrosis-induced macrophages. Autoantibodies also induce the overexpression of atrogenes, promoting early-onset muscle atrophy [100]. (b) Marked muscle weakness and atrophy are the hallmarks of IMNM. Although pathogenic mechanisms do not satisfactorily explain the disease topography, unlike the other idiopathic inflammatory myopathies, IMNM has a predilection for the adductor and flexor compartments of the thighs, with sparing of the semitendinosus [116]. Overt heart failure is unusual, but subclinical myocardial involvement can occur [111,112,113,114]. C’: aggregated complement fractions; C1q: complement 1q component; MAC: membrane attack complex; MP: macrophage; NMAb: necrotizing myopathy autoantibodies.