Novel endotypes of antisynthetase syndrome identified independent of anti-aminoacyl transfer RNA synthetase antibody specificity that improve prognostic stratification

Abstract

ObjectivesTo systemically analyse the heterogeneity in the clinical manifestations and prognoses of patients with antisynthetase syndrome (ASS) and evaluate the transcriptional signatures related to different clinical phenotypes.MethodsA total of 701 patients with ASS were retrospectively enrolled. The clinical presentation and prognosis were assessed in association with four anti-aminoacyl transfer RNA synthetase (ARS) antibodies: anti-Jo1, anti-PL7, anti-PL12 and anti-EJ. Unsupervised machine learning was performed for patient clustering independent of anti-ARS antibodies. Transcriptome sequencing was conducted in clustered ASS patients and healthy controls.ResultsPatients with four different anti-ARS antibody subtypes demonstrated no significant differences in the incidence of rapidly progressive interstitial lung disease (RP-ILD) or prognoses. Unsupervised machine learning, independent of anti-ARS specificity, identified three endotypes with distinct clinical features and outcomes. Endotype 1 (RP-ILD cluster, 23.7%) was characterised by a high incidence of RP-ILD and a high mortality rate. Endotype 2 (dermatomyositis (DM)-like cluster, 14.5%) corresponded to patients with DM-like skin and muscle symptoms with an intermediate prognosis. Endotype 3 (arthritis cluster, 61.8%) was characterised by arthritis and mechanic’s hands, with a good prognosis. Transcriptome sequencing revealed that the different endotypes had distinct gene signatures and biological processes.ConclusionsAnti-ARS antibodies were not significant in stratifying ASS patients into subgroups with greater homogeneity in RP-ILD and prognoses. Novel ASS endotypes were identified independent of anti-ARS specificity and differed in clinical outcomes and transcriptional signatures, providing new insights into the pathogenesis of ASS.

Greetings from the editor 2024/2

“…As a new technology for developing vaccines, it seems timely to review the assets and risks of mRNA vaccines with a particular emphasis on their use in autoimmune conditions, and this review is also presented in the June issue. 17 Other articles address the benefits and risks of using CAR-T-cell technology in autoimmunity, 18 novel findings related to myositis 19 and new information on a rare autoinflammatory disease. 20 Papers on important and probably under-recognised aspects of hand osteoarthritis 21 and on a novel imaging technique 22 complement the original research reports in this issue.…”