Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies.

Background: In patients with idiopathic inflammatory myopathies (IIM), autoantibodies are associated with specific clinical phenotypes suggesting a pathogenic role of adaptive immunity. We explored if autoantibody profiles are associated with specific HLA genetic variants and clinical manifestations in IIM.
Methods: We included 1348 IIM patients and determined the occurrence of 14 myositis-specific or -associated autoantibodies. We used unsupervised cluster analysis to identify autoantibody-defined subgroups and logistic regression to estimate associations with clinical manifestations, HLA-DRB1, HLA-DQA1, HLA-DQB1 alleles, and amino acids imputed from genetic information of HLA class II and I molecules.
Findings: We identified eight subgroups with the following dominant autoantibodies: anti-Ro52, -U1RNP, -PM/Scl, -Mi2, -Jo1, -Jo1/Ro52, -TIF1γ or negative for all analysed autoantibodies. Associations with HLA-DRB1∗11, HLA-DRB1∗15, HLA-DQA1∗03, and HLA-DQB1∗03 were present in the anti-U1RNP-dominated subgroup. HLA-DRB1∗03, HLA-DQA1∗05, and HLA-DQB1∗02 alleles were overrepresented in the anti-PM/Scl and anti-Jo1/Ro52-dominated subgroups. HLA-DRB1∗16, HLA-DRB1∗07 alleles were most frequent in anti-Mi2 and HLA-DRB1∗01 and HLA-DRB1∗07 alleles in the anti-TIF1γ subgroup. The HLA-DRB1∗13, HLA-DQA1∗01 and HLA-DQB1∗06 alleles were overrepresented in the negative subgroup. Significant signals from variations in class I molecules were detected in the subgroups dominated by anti-Mi2, anti-Jo1/Ro52, anti-TIF1γ, and the negative subgroup.
Interpretation: Distinct HLA class II and I associations were observed for almost all autoantibody-defined subgroups. The associations support autoantibody profiles use for classifying IIM which would likely reflect underlying pathogenic mechanisms better than classifications based on clinical symptoms and/or histopathological features.
Funding: See a detailed list of funding bodies in the Acknowledgements section at the end of the manuscript.
Competing Interests: Declaration of interests Professor Lundberg has received consulting fees from Corbus Pharmaceuticals, Inc and research grants from Astra Zeneca and has been serving on the advisory board for Astra Zeneca, Bristol Myers Squibb, EMD Serono Research & Development Institute, Argenx, Octapharma, Kezaar, Orphazyme, Pfizer and Janssen and has stock shares in Roche and Novartis. Professor Vencovský has received speaker fees from Abbvie, Biogen, Boehringer, Eli Lilly, Gilead, MSD, Novartis, Pfizer, Roche, Sanofi, UCB, Werfen; and has received consulting fees from Abbvie, Argenx, Boehringer, Eli Lilly, Gilead, Octapharma, Pfizer, UCB. Professor Chinoy has received personal compensation for activities with Novartis, UCB, Eli Lilly, Biogen, Orphazyme, Astra Zeneca, Pfizer, Kezar Life Sciences, Galapagos, Argenx, GSK as a speaker, advisory board member or consultancy; grants via The University of Manchester from Eli Lilly and UCB; travel support from Abbvie and Janssen. Dr Mann has received honoraria from Abbvie, Biogen, BMS, Eli Lilly, MSD, Janssen, Novartis, UCB, Pfizer, SOBI and travel support by Abbvie. Dr Tansley received payment from Boehringer Ingelheim as a speaker. Dr Rönnblom received support from The Swedish Research Council (2018–02399), Reumatikerförbundet (R-939716) and GV:80 (FAI-2020-0658) foundation. Dr Holmqvist received support from The Swedish Research Council, Stockholm Regional Council (ALF), Reumatikerförbundet, Konung Gustaf V:80 year foundation, The Swedish Cancer Association and was a member of Medical Advisory Board of The Myositis Association. Dr Lamb received support from the Medical Research Council UK and Myositis UK. Other authors declare no competing interests.
(Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)