Development of a New Classification System for Idiopathic Inflammatory Myopathies Based on Clinical Manifestations and Myositis-Specific Autoantibodies

Abstract

Importance: Idiopathic inflammatory myopathies are heterogeneous in their pathophysiologic features and prognosis. The emergence of myositis-specific autoantibodies suggests that subgroups of patients exist.

Objective: To develop a new classification scheme for idiopathic inflammatory myopathies based on phenotypic, biological, and immunologic criteria.

Design, setting, and participants: An observational, retrospective cohort study was performed using a database of the French myositis network. Patients identified from referral centers for neuromuscular diseases were included from January 1, 2003, to February 1, 2016. Of 445 initial patients, 185 patients were excluded and 260 adult patients with myositis who had complete data and defined historical classifications for polymyositis, dermatomyositis, and inclusion body myositis were enrolled. All patients were tested for anti-histidyl-ARN-t- synthetase (Jo1), anti-threonine-ARN-t-synthetase (PL7), anti-alanine-ARN-t-synthetase (PL12), anti-complex nucleosome remodeling histone deacetylase (Mi2), anti-Ku, anti-polymyositis/systemic scleroderma (PMScl), anti-topoisomerase 1 (Scl70), and anti-signal recognition particle (SRP) antibodies. A total of 708 variables were collected per patient (eg, cancer, lung involvement, and myositis-specific antibodies).

Main outcomes and measures: Unsupervised multiple correspondence analysis and hierarchical clustering analysis to aggregate patients in subgroups.

Results: Among 260 participants (163 [62.7%] women; mean age, 59.7 years; median age [range], 61.5 years [48-71 years]), 4 clusters of patients emerged. Cluster 1 (n = 77) included patients who were male, white, and older than 60 years and had finger flexor and quadriceps weakness and findings of vacuolated fibers and mitochondrial abnormalities. Cluster 1 regrouped patients who had inclusion body myositis (72 of 77 patients [93.5%]; 95% CI, 85.5%-97.8%; P < .001). Cluster 2 (n = 91) regrouped patients who were women and had high creatine phosphokinase levels, necrosis without inflammation, and anti-SRP or anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) antibodies corresponding to immune-mediated necrotizing myopathy (53 of 91 [58.2%]; 95% CI, 47.4%-68.5%; P < .001). Cluster 3 (n = 52) regrouped patients who had dermatomyositis rash and anti-Mi2, anti-melanoma differentiation-associated protein 5 (MDA5), or anti-transcription intermediary factor-1γ (TIF1γ) antibodies, mainly corresponding with patients who had dermatomyositis (43 of 52 [82.7%]; 95% CI, 69.7%-91.8%; P < .001). Cluster 4 (n = 40) was defined by the presence of anti-Jo1 or anti-PL7 antibodies corresponding to antisynthetase syndrome (36 of 40 [90.0%]; 95% CI, 76.3%-97.2%; P < .001). The classification of an independent cohort (n = 50) confirmed the 4 clusters (Cohen κ light, 0.8; 95% CI, 0.6-0.9).

Conclusions and relevance: These findings suggest a classification of idiopathic inflammatory myopathies with 4 subgroups: dermatomyositis, inclusion body myositis, immune-mediated necrotizing myopathy, and antisynthetase syndrome. This classification system suggests that a targeted clinical-serologic approach for identifying idiopathic inflammatory myopathies may be warranted.

Figure 1.. Dendrogram and Hierarchical Cluster Analysis on Multiple Correspondence Analysis Factor Map

A, Dendogram generated using euclidean distance and the Ward agglomerative method. The bold vertical line indicates the height of fusion into clusters proposed and the x-axis indicates the individuals (n = 260) at the bottom of the dendrogram (leaf nodes). B, Factor map showing the raw data (individuals) used to generate the dendogram. The first 2 dimensions cumulatively explained 16.7% of the total variance. We obtained a hierarchical tree positioned on the factorial map on which colors indicate individuals according to the cluster to which they belong.

Figure 2.. Pruned Model of Prediction Without Histology Criteria

A pruned model was built (ie, by cutting terminal branches, a number of smaller and less complex trees was derived from the maximal previous tree) (information on the tree is given in the Statistical Analysis subsection of the Methods section). Dermatomyositis (DM) rash includes Gottron papules, periungual erythema, purplish rash, holster sign, and eruption on the dorsal hands. MRC5 indicates Medical Research Council 5-point scale (scale of 0 to 5 with lower numbers indicating more weakness).