Anti‐Synthetase Syndrome—Advancing Disease Phenotyping, Classification and Treatment

Anti-synthetase syndrome (ASyS) is characterized by the presence of antibodies against aminoacyl transfer RNA (tRNA) synthetase and distinct clinical constellations including interstitial lung disease (ILD), myositis, arthritis, mechanic's hands, fever and raynaud's phenomenon (RP).Since the discovery of anti-histidyl-tRNA synthetase (Anti-Jo1) antibody four decades ago, tremendous progress was made in discovering additional anti-synthetase antibodies [1].There are 20 different aminoacyl-tRNA synthetase enzymes, and 10 distinct anti-synthetase antibodies (ASA) have been identified so far (Table 1).These antibodies are central to disease classification and may influence clinical phenotypes.There are evolving insights into pathophysiology, clinical heterogeneity, and treatment approaches in ASyS.This article aims to review and discuss the recent research advancements in disease sub-phenotyping, classification and therapeutics in ASyS.ASyS exhibits significant clinical heterogeneity with varying disease courses and clinical manifestations among patients.Patients with non-Jo1 ASA were previously reported to have a worse survival than Jo1 patients (10-year cumulative survival of 47% vs. 70%, p < 0.005) by Aggarwal et al. [2], probably related to a delay in diagnosis by 8 months in the non-Jo1 positive patients.However, data from a multicenter registry in Hong Kong did not identify a similar survival difference between Jo1 and non-Jo1 positive patients [3].Clinical phenotypes might exert a greater impact on survival than the presence of specific ASA.Wu et al. performed cluster analysis on more than 700 ASyS patients from China and identified three unique clinical phenotypes independent of ASA specificity: rapidly-progressive ILD (RP-ILD) cluster (23.7% of patients), dermatomyositis (DM)-like cluster (14.5%) and arthritis cluster (61.8%) [4].The worst prognosis was observed in the RP-ILD cluster with a 10-year survival rate of 37.0%, compared to 69.5% in the DM-like cluster and 87.4%