| 3. |
- Leclair, V, et al.
(författare)
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HLA-DRB1 ASSOCIATIONS WITH AUTOANTIBODY-DEFINED SUBGROUPS IN IDIOPATHIC INFLAMMATORY MYOPATHIES (IIM)
- 2022
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Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 104-105
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- There is a gap between how IIM patients are classified in practice and current validated classification criteria1. Also, different associations with genetic variations in HLA can inform about different T-cell mechanisms involved in disease pathogenesis.ObjectivesWe aimed to systematically study associations between HLA-DRB1 alleles, clinical manifestations, and autoantibody-defined IIM subgroups.MethodsWe included 1348 IIM patients from five European countries. An unsupervised cluster analysis was performed using 14 autoantibodies: anti-Jo1, -PL7, -PL12, -EJ, -OJ, -SRP, -U1RNP, -Ro52, -Mi2, -TIF1γ, -MDA5, -PMScl, -SAE1, and -NXP2 to identify patients’ subgroups. Logistic regressions were used to estimate the associations between HLA-DRB1 alleles, clinical manifestations and the identified subgroups.ResultsEight subgroups were defined by the autoantibody status (Table 1). Three of the subgroups (1, 2 and 6) have overlapping autoantibodies, while four are almost monospecific (3,4,5 and 7), and one (8) has patients negative for tested autoantibodies. Figure 1 represents the significant associations between HLA-DRB1 alleles and the eight subgroups. Heliotrope rash and Gottron’s sign were significantly more frequent in subgroups 3 (OR:2.2 95%CI:[1.1-4.8], OR:2.6 95%CI:[1.3-5.9], respectively), 4 (OR:12 95%CI:[3.6-75], OR:7.8 95%CI:[2.8-33], respectively) and 7 (OR:22 95%CI:[4.5-385], OR:10 95%CI:[3.1-65], respectively), and Raynaud’s phenomenon was significantly more frequent in subgroup 6 (OR:3.3 95%CI:[1.2-11]).Table 1.Autoantibody-defined subgroups using an unsupervised cluster analysis.Subgroups/ MedoidsVariables1 Ro522 U1RNP3 PMScl4 Mi25 Jo16 Jo1/Ro527 TIF18 None*Alln (%)137 (10)183 (14)107 (8)65 (5)119 (9)140 (10)78 (6)519 (39)1348 (100)Female (%)93 (68)116 (63)79 (74)45 (69)76 (64)96 (69)64 (82)313 (60)882 (65)Age at diagnosis, median (IQR)56 (16)51.5 (23)51 (25)57 (22.5)47.5 (23.25)52 (19.5)53.5 (21.75)58 (22)55 (23)AutoantibodiesAnti-Jo106 (3)01 (2)119 (100)140 (100)00266 (20)Anti-PL77 (5)13 (7)00000020 (1.5)Anti-PL125 (4)3 (2)1 (1)01 (1)00010 (0.7)Anti-EJ2 (2)00000002 (0.1)Anti-OJ07 (4)0000007 (0.5)Anti-TIF110 (7)2 (1)2 (2)00078 (100)092 (7)Anti-Mi21 (1)1 (1)1 (1)65 (100)02 (1)0070 (5)Anti-SAE18 (6)23 (13)00000031 (2)Anti-NXP21 (1)23 (13)1 (1)0000025 (2)Anti-MDA59 (7)10 (6)1 (1)1 (2)01 (1)0022 (2)Anti-SRP8 (6)32 (18)00000040 (3)Anti-Ro52137 (100)16 (9)000140 (100)00293 (22)Anti-PMScl11 (8)1 (1)107 (100)00000119 (9)Anti-U1RNP079 (43)0003 (2)0082 (6)*IIM patients negative for the tested autoantibodies.Figure 1.Forest plot of significant associations of HLA. *DRB1 alleles with autoantibody-defined subgroups. Scandinavia includes patients from Denmark, Norway, and Sweden.ConclusionOur study reveals that certain subgroups of IIM patients are characterized by overlap of myositis -specific and -associated autoantibodies, which in turn are associated with different HLA-DRB1 alleles including potential novel associations. These results point to different disease mechanisms in the subgroups, as well as suggest that IIM classification could be improved by integrating broader serological and genetic data.References[1]Parker MJS, Oldroyd A, Roberts ME, et al. The performance of the European League Against Rheumatism/American College of Rheumatology idiopathic inflammatory myopathies classification criteria in an expert-defined 10 year incident cohort. Rheumatology (Oxford). 2019;58(3):468-475.AcknowledgementsWe thank all the patients who participated in the study.Disclosure of InterestsValerie Leclair: None declared, Angeles Shunashy Galindo-Feria: None declared, Simon Rothwell: None declared, Olga Kryštůfková: None declared, Heřman Mann: None declared, Louise Pyndt Diederichsen: None declared, helena andersson: None declared, Martin Klein: None declared, Sarah Tansley: None declared, Neil McHugh: None declared, Janine Lamb: None declared, Jiří Vencovský Speakers bureau: Abbvie, Biogen, Boehringer, Eli Lilly, Gilead, MSD, Novartis, Pfizer, Roche, Sanofi, UCB, Werfen, Consultant of: Abbvie, Argenx, Boehringer, Eli Lilly, Gilead, Octapharma, Pfizer, UCB, Grant/research support from: Abbvie, Hector Chinoy: None declared, Marie Holmqvist: None declared, Leonid Padyukov: None declared, Ingrid E. Lundberg Shareholder of: Roche and Novartis, Consultant of: Corbus Pharmaceuticals Inc, Astra Zeneca, Bristol Myer´s Squibb, Corbus Pharmaceutical, EMD Serono Research & Development Institute, Argenx, Octapharma, Kezaar, Orphazyme, and Janssen, Grant/research support from: Astra Zeneca, Lina M. Diaz-Gallo: None declared
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| 5. |
- Leclair, Valerie, et al.
(författare)
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Distinct HLA associations with autoantibody-defined subgroups in idiopathic inflammatory myopathies
- 2023
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 96
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Tidskriftsartikel (refereegranskat)abstract
- 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,-TIF1 gamma 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-TIF1 gamma 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-TIF1 gamma, 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. Copyright (c) 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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