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Novel endotypes of antisynthetase syndrome identified independent of anti-aminoacyl transfer RNA synthetase antibody specificity that improve prognostic stratification
  1. Shiyu Wu1,2,
  2. Xinyue Xiao2,
  3. Yingfang Zhang1,2,
  4. Xinxin Zhang1,2,
  5. Guochun Wang1,2,
  6. Qinglin Peng1,2
  1. 1 Peking University China-Japan Friendship School of Clinical Medicine, Beijing, People's Republic of China
  2. 2 Department of Rheumatology, Key Lab of Myositis, China-Japan Friendship Hospital, Beijing, People's Republic of China
  1. Correspondence to Dr Qinglin Peng, Department of Rheumatology, Key Lab of Myositis, China-Japan Friendship Hospital, Beijing, Beijing 100029, People's Republic of China; pqinglin{at}163.com; Dr Guochun Wang, Department of Rheumatology, Key Lab of Myositis, China-Japan Friendship Hospital, Beijing, Beijing 100029, People's Republic of China; guochunwang{at}hotmail.com

Abstract

Objectives To 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.

Methods A 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.

Results Patients 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.

Conclusions Anti-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.

  • Dermatomyositis
  • Machine Learning
  • Mortality

Data availability statement

Data are available on reasonable request.

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Data availability statement

Data are available on reasonable request.

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Footnotes

  • Handling editor Josef S Smolen

  • Correction notice This article has been corrected since it published Online First. The title has been corrected.

  • Contributors SW, QP and GW conceived and designed the study. QP is responsible for the overall content as the guarantor. SW, YZ and XZ participated in data collection. SW and XX helped with the sample collection and performed the statistical analysis. SW wrote the manuscript. All authors contributed to data acquisition and analysis, manuscript revision, read and approved the submitted version.

  • Funding This work was supported by the National High Level Hospital Clinical Research Funding (2022-NHLHCRF-YS-02), the National Natural Science Foundation of China (82171788, 82371810, 82372320) and the Elite Medical Professionals project of China-Japan Friendship Hospital (No. ZRJY2021-GG13).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.