| 4. |
- Leclair, V, et al.
(author)
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HLA-DRB1 ASSOCIATIONS WITH AUTOANTIBODY-DEFINED SUBGROUPS IN IDIOPATHIC INFLAMMATORY MYOPATHIES (IIM)
- 2022
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In: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 81, s. 104-105
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Conference paper (other academic/artistic)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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| 10. |
- Zhou, D, et al.
(author)
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Low copy numbers of complement C4 and C4A deficiency are risk factors for myositis, its subgroups and autoantibodies
- 2023
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In: Annals of the rheumatic diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 82:2, s. 235-245
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Journal article (peer-reviewed)abstract
- Idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterised by myositis-related autoantibodies plus infiltration of leucocytes into muscles and/or the skin, leading to the destruction of blood vessels and muscle fibres, chronic weakness and fatigue. While complement-mediated destruction of capillary endothelia is implicated in paediatric and adult dermatomyositis, the complex diversity of complementC4in IIM pathology was unknown.MethodsWe elucidated the gene copy number (GCN) variations of totalC4,C4AandC4B, longandshort genesin 1644 Caucasian patients with IIM, plus 3526 matched healthy controls using real-time PCR or Southern blot analyses. Plasma complement levels were determined by single radial immunodiffusion.ResultsThe large study populations helped establish the distribution patterns of variousC4GCN groups. Low GCNs ofC4T(C4T=2+3) andC4Adeficiency (C4A=0+1) were strongly correlated with increased risk of IIM with OR equalled to 2.58 (2.28–2.91), p=5.0×10−53forC4T, and 2.82 (2.48–3.21), p=7.0×10−57forC4Adeficiency. Contingency and regression analyses showed that among patients withC4Adeficiency, the presence ofHLA-DR3became insignificant as a risk factor in IIM except for inclusion body myositis (IBM), by which 98.2% hadHLA-DR3with an OR of 11.02 (1.44–84.4). Intragroup analyses of patients with IIM for C4 protein levels and IIM-related autoantibodies showed that those with anti-Jo-1 or with anti-PM/Scl had significantly lower C4 plasma concentrations than those without these autoantibodies.ConclusionsC4Adeficiency is relevant in dermatomyositis,HLA-DRB1*03is important in IBM and bothC4Adeficiency andHLA-DRB1*03contribute interactively to risk of polymyositis.
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