Cluster analysis identifies anti‐synthetase syndrome as a distinct and heterogeneous clinical entity: Analysis from the Classification Criteria for Anti‐Synthetase Syndrome project database

OBJECTIVE: To better characterize the clinical phenotypes and heterogeneity of anti-synthetase syndrome (ASyS), we performed unsupervised cluster analyses using clinical and serological data from the Classification Criteria for Anti-Synthetase Syndrome (CLASS) project database. METHODS: The CLASS database comprised 2,035 ASyS cases and 2,140 comparators with mimicking conditions, namely systemic autoimmune rheumatic diseases and/or interstitial lung disease (ILD), contributed by 103 centers worldwide. We applied multiple correspondence analysis followed by hierarchical clustering using 19 clinical and serological variables to classify ASyS and comparators in the entire CLASS cohort into distinct subgroups. We then repeated the cluster analysis in the ASyS cohort alone to identify phenotypic subgroups of ASyS. RESULTS: Cluster analysis of the entire cohort identified three subgroups. Whereas Cluster 1 (n = 1,311) and Cluster 3 (n = 1,468) predominantly comprised ASyS and comparators, respectively, Cluster 2 (n = 1,105) included both groups. Interstitial pneumonia with autoimmune features (without anti-synthetase autoantibodies) and systemic sclerosis were more prevalent in Cluster 2, whereas dermatomyositis and polymyositis were predominantly represented in Cluster 3. Cluster analysis of the ASyS cohort identified three distinct subgroups: Cluster 1 (anti-Jo-1-positive, "full-spectrum" ASyS with myositis, ILD, and arthritis; n = 1,034), Cluster 2 (ILD-predominant; n = 581), and Cluster 3 (without ILD; n = 248). CONCLUSION: Cluster analyses identified ASyS as a distinct and heterogeneous clinical entity. Three distinct phenotypic clusters emerged among patients with ASyS, with ILD-predominant cases representing the second largest subgroup, underscoring the need for classification criteria that adequately capture patients presenting with isolated ILD.