The juvenile idiopathic inflammatory myopathies: pathogenesis, clinical and autoantibody phenotypes, and outcomes

Abstract

The aim of this review was to summarize recent advances in the understanding of the clinical and autoantibody phenotypes, their associated outcomes and the pathogenesis of the juvenile idiopathic inflammatory myopathies (JIIMs). The major clinical and autoantibody phenotypes in children have many features similar to those in adults, and each has distinct demographic and clinical features and associated outcomes. The most common myositis autoantibodies in JIIM patients are anti-p155/140, anti-MJ and anti-MDA5. Higher mortality has been associated with overlap myositis as well as with the presence of anti-synthetase and anti-MDA5 autoantibodies; a chronic illness course and lipodystrophy have been associated with anti-p155/140 autoantibodies; and calcinosis has been associated with anti-MJ autoantibodies. Histologic abnormalities of JIIMs detectable on muscle biopsy have also been correlated with myositis-specific autoantibodies; for example, patients with anti-MDA5 show low levels of inflammatory infiltrate and muscle damage on biopsy. The first genome-wide association study of adult and juvenile dermatomyositis revealed three novel genetic associations, BLK, PLCL1 and CCL21 and confirmed that the human leucocyte antigen region is the primary risk region for juvenile dermatomyositis. Here, we review the well-established pathogenic processes in JIIMs, including the type 1 interferon and endoplasmic reticulum stress pathways. Several novel JIIM-associated inflammatory mediators, such as the innate immune system proteins, myeloid-related peptide 8/14, galectin 9 and eotaxin, have emerged as promising biomarkers of disease. Advances in our understanding of the phenotypes and pathophysiology of the JIIMs are leading to better tools to help clinicians stratify and treat these heterogeneous disorders.

Keywords: chemokine; interferon alpha; juvenile dermatomyositis; juvenile polymyositis; myositis autoantibodies; outcomes.

Fig. 1

Juvenile dermatomyositis (JDM) presents with characteristic rash and symmetric muscle weakness in the extremities. Juvenile polymyositis (JPM) presents with more severe muscle weakness and frequent cardiac involvement but the rashes of JDM are absent. JPM is more common in black female patients. Patients with overlap myositis meet the criteria for myositis as well as another autoimmune disease. Common illness features include interstitial lung disease, Raynaud’s phenomenon, arthritis, and sclerodactyly [8]. Clinically amyopathic JDM presents primarily with characteristic skin rashes, with mild or no muscle weakness [24].

Fig. 2

Distribution of myositis autoantibodies by clinical subgroup in patients with juvenile idiopathic inflammatory myopathies. Data are from Rider and Miller [6] and Shah et al. [8]. JDM, juvenile dermatomyositis; JPM, juvenile polymyositis; JCTM, JDM overlapping with another connective tissue disease.

Fig. 3

The myositis autoantibodies seen most frequently in children with juvenile idiopathic inflammatory myopathies (JIIMs) are anti-p155/140, anti-MJ, and anti-MDA5 autoantibodies. These frequencies differ from those seen most frequently in adults. Anti-p155/140 autoantibodies are present in 23–30% of JIIM patients, particularly in those with juvenile dermatomyositis (JDM) or overlap myositis with JDM. Most patients with anti-p155/140 autoantibodies are white and have extensive photosensitive skin rashes. Anti-p155/140 is also associated with a chronic course of illness and generalized lipodystrophy [, –32]. Anti-MJ autoantibodies are present in 12–23% of JIIM patients and are seen primarily in those with JDM. Most patients are white. Anti-MJ autoantibodies are associated with muscle cramps, muscle atrophy, joint contractures, dysphonia, and an absence of truncal rashes. Patients with anti-MJ autoantibodies tended to be weaker and have decreased physical function [7, 34, 35]. Anti-MDA5 autoantibodies were present in 33% of a Japanese cohort but only 7% of a UK cohort. Interstitial lung disease was more common in both cohorts with this autoantibody, compared to patients without these antibodies. In the UK patients, other common features included oral and cutaneous ulceration, arthritis, and milder muscle disease, which was similar to findings in US and European adult cohorts with MDA5 autoantibodies [36, 37].

Fig. 4

Traditional myositis autoantibodies have similar phenotypes in children and adults with the same autoantibodies. Anti-tRNA synthetase autoantibodies are less common in juvenile than in adult myositis. These autoantibodies are more often seen in patients with juvenile polymyositis or juvenile overlap myositis. Patients with anti-synthetase autoantibodies frequently have interstitial lung disease, arthritis, fever, Raynaud’s phenomenon and mechanic’s hands, and a high mortality [7, 42]. Anti-Mi-2 is associated with juvenile dermatomyositis and its cutaneous features but, unlike in adults, is not associated with V- and shawl-sign rashes or cuticular overgrowth [7]. Anti-signal recognition particle (SRP) autoantibodies are seen primarily in African-American teenage girls with severe immune-mediated necrotizing myopathy who have proximal and distal muscle weakness, frequent falling episodes, Raynaud’s phenomenon, high creatine kinase levels, and a chronic illness course, as well as the need to use a wheelchair. Approximately 50% of pediatric patients with anti-SRP autoantibodies also present with cardiac disease, and, similar to adult patients with that autoantibody, their disease is refractory to many therapies [7, 44]. Although 28% of patients have no identified autoantibodies, they might have currently unrecognized autoantibody phenotypes. These patients have mild disease [7].

Fig. 5

Muscle biopsies from patients with juvenile dermatomyositis (JDM; magnification ×10) and juvenile immune-mediated necrotizing myopathy [anti-signal recognition particle (SRP)] were stained with hematoxylin and eosin (H&E; a and d), major histocompatability class I (MHC I; b and e), and neonatal myosin (c and f). a) Perivascular cellular inflammation (long arrow) and perifascicular atrophy (short arrow). b) Diffuse MHC I staining on the sarcolemma and the sarcoplasm of many fibers. c) Neonatal myosin stains for damaged muscle fibers that are regenerating in the perifascicular zone (arrow). d) Fiber size variation and smaller pale necrotic muscle fibers (large arrows) surrounded by infiltrating macrophages and scattered atrophic regenerating fibers (small arrow; magnification ×40). e) Increased expression of MHC class I on muscle fibers; atypical for anti-SRP myositis (magnification ×20). g) Smaller regenerating fibers staining for neonatal myosin spread throughout the muscle (magnification ×20).