The Role of Shared Epitope in Rheumatoid Arthritis Prognosis in Relation to Anti-Citrullinated Protein Antibody Positivity

Joe Zhuo, Qian Xia, Niyati Sharma, Sheng Gao, Sonie Lama, Jing Cui, Vivi Feathers, Nancy Shadick, Michael E Weinblatt, Joe Zhuo, Qian Xia, Niyati Sharma, Sheng Gao, Sonie Lama, Jing Cui, Vivi Feathers, Nancy Shadick, Michael E Weinblatt

Abstract

Introduction: Shared epitope (SE) is present in high proportions of anti-citrullinated protein antibody (ACPA) + patients with rheumatoid arthritis (RA) and is associated with poor prognosis. We assessed the role of SE in RA prognosis, in relation to ACPA positivity.

Methods: Patients enrolled in the Brigham and Women's RA Sequential Study were included. Changes from baseline in disease activity (Disease Activity Score in 28 joints using C-reactive protein [DAS28 (CRP)], Clinical Disease Activity Index [CDAI], Simplified Disease Activity Index [SDAI]) to 1 year were assessed. Baseline characteristics were compared by SE and ACPA status (±; chi-squared, Kruskal-Wallis). Association between number of SE alleles and ACPA status (logistic regression models), relationships between baseline characteristics and changes in disease activity (adjusted linear regression model), and effect of ACPA on the association between SE and changes in disease activity (mediation analysis) were studied.

Results: Nine hundred twenty-six patients were included. SE + versus SE - patients had significantly longer disease duration and higher disease activity scores and were more likely to have erosive disease, have higher comorbidity burden, and be RF + (all p < 0.05). Among patients with one or two SE alleles (vs. 0), odds of being ACPA + were 1.97 (p = 0.0003) and 3.82 (p < 0.0001), respectively. SE + versus SE - patients had worse disease activity scores as indicated by mean increases in DAS28 (CRP) of 0.22, CDAI of 2.07, and SDAI of 2.43 over 1 year (all p < 0.05). Direct effect of SE + accounted for 76.4-80.1% of total effect in disease activity increases.

Conclusions: SE is strongly associated with ACPA positivity and higher disease activity in patients with RA. SE was associated with greater increases in disease activity over 1 year, which was partially mediated by the presence of ACPA.

Trial registration: ClinicalTrials.gov identifier: NCT01793103; registration date: February 15, 2013, retrospectively registered.

Keywords: Anti-citrullinated protein antibody; Registry, rheumatoid arthritis; Shared epitope.

© 2022. The Author(s).

Figures

Fig. 1
Fig. 1
Linear regression model of the association between baseline characteristics and change in disease activity [26]. a Change in DAS28 (CRP), b change in CDAI, and c change in SDAI. BL baseline, CCI Charlson comorbidity index, CDAI Clinical Disease Activity Index, DAS28 (CRP) Disease Activity Score in 28 joints using C-reactive protein, SDAI Simple Disease Activity Index, SE shared epitope Figure reproduced from Zhuo J, et al. Ann Rheum Dis. 2020;79 (suppl 1):963 (abstract SAT0061)

References

    1. Smolen JS, Aletaha D, Barton A, et al. Rheumatoid arthritis. Nat Rev Dis Prim. 2018;4:18001. doi: 10.1038/nrdp.2018.1.
    1. Edwards JC, Cambridge G. B-cell targeting in rheumatoid arthritis and other autoimmune diseases. Nat Rev Immunol. 2006;6:394–403. doi: 10.1038/nri1838.
    1. McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. N Engl J Med. 2011;365:2205–2219. doi: 10.1056/NEJMra1004965.
    1. Darrah E, Andrade F. Rheumatoid arthritis and citrullination. Curr Opin Rheumatol. 2018;30:72–78. doi: 10.1097/BOR.0000000000000452.
    1. Rantapaa-Dahlqvist S, de Jong BA, Berglin E, et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 2003;48:2741–2749. doi: 10.1002/art.11223.
    1. Smolen JS, Landewe RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update. Ann Rheum Dis. 2020;79:685–699. doi: 10.1136/annrheumdis-2019-216655.
    1. Kurowska W, Kuca-Warnawin EH, Radzikowska A, Maslinski W. The role of anti-citrullinated protein antibodies (ACPA) in the pathogenesis of rheumatoid arthritis. Cent Eur J Immunol. 2017;42:390–398. doi: 10.5114/ceji.2017.72807.
    1. Meyer PW, Hodkinson B, Ally M, et al. HLA-DRB1 shared epitope genotyping using the revised classification and its association with circulating autoantibodies, acute phase reactants, cytokines and clinical indices of disease activity in a cohort of South African rheumatoid arthritis patients. Arthritis Res Ther. 2011;13:R160. doi: 10.1186/ar3479.
    1. Alemao E, Bryson J, Iannaccone CK, Frits M, Shadick NA, Weinblatt M. Association of shared epitope and poor prognostic factors in RA. Arthritis Rheumatol. 2018;70:71. doi: 10.1002/acr.23250.
    1. Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 1987;30:1205–1213. doi: 10.1002/art.1780301102.
    1. Raychaudhuri S, Sandor C, Stahl EA, et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet. 2012;44:291–296. doi: 10.1038/ng.1076.
    1. Jiang X, Frisell T, Askling J, et al. To what extent is the familial risk of rheumatoid arthritis explained by established rheumatoid arthritis risk factors? Arthritis Rheumatol. 2015;67:352–362. doi: 10.1002/art.38927.
    1. Klareskog L, Stolt P, Lundberg K, et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA–DR (shared epitope)–restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 2006;54:38–46. doi: 10.1002/art.21575.
    1. Huizinga TW, Amos CI, Helm-van AH, et al. Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins. Arthritis Rheum. 2005;2005(52):3433–3438. doi: 10.1002/art.21385.
    1. Terao C, Yano K, Ikari K, et al. Brief report: main contribution of DRB1*04:05 among the shared epitope alleles and involvement of DRB1 amino acid position 57 in association with joint destruction in anti–citrullinated protein antibody–positive rheumatoid arthritis. Arthritis Rheumatol. 2015;67:1744–1750. doi: 10.1002/art.39105.
    1. Moreno I, Valenzuela A, Garcia A, Yelamos J, Sanchez B, Hernanz W. Association of the shared epitope with radiological severity of rheumatoid arthritis. J Rheumatol. 1996;23:6–9.
    1. Wu H, Khanna D, Park G, et al. Interaction between RANKL and HLA-DRB1 genotypes may contribute to younger age at onset of seropositive rheumatoid arthritis in an inception cohort. Arthritis Rheum. 2004;50:3093–3103. doi: 10.1002/art.20555.
    1. Reneses S, González-Escribano MF, Fernández-Suárez A, et al. The value of HLA-DRB1 shared epitope, −308 tumor necrosis factor-α gene promoter polymorphism, rheumatoid factor, anti-citrullinated peptide antibodies, and early erosions for predicting radiological outcome in recent-onset rheumatoid arthritis. J Rheumatol. 2009;36:1143–1149. doi: 10.3899/jrheum.081075.
    1. Farragher TM, Goodson NJ, Naseem H, et al. Association of the HLA-DRB1 gene with premature death, particularly from cardiovascular disease, in patients with rheumatoid arthritis and inflammatory polyarthritis. Arthritis Rheum. 2008;58:359–369. doi: 10.1002/art.23149.
    1. Malmstrom V, Catrina AI, Klareskog L. The immunopathogenesis of seropositive rheumatoid arthritis: from triggering to targeting. Nat Rev Immunol. 2017;17:60–75. doi: 10.1038/nri.2016.124.
    1. Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheumatol. 1988;31:315–324. doi: 10.1002/art.1780310302.
    1. Bykerk VP, Shadick N, Frits M, et al. Flares in rheumatoid arthritis: frequency and management. A report from the BRASS registry. J Rheumatol. 2014;41:227–234. doi: 10.3899/jrheum.121521.
    1. Iannaccone CK, Lee YC, Cui J, et al. Using genetic and clinical data to understand response to disease-modifying anti-rheumatic drug therapy: data from the Brigham and Women's Hospital Rheumatoid Arthritis Sequential Study. Rheumatology (Oxford) 2011;50:40–46. doi: 10.1093/rheumatology/keq263.
    1. Iannaccone CK, Fossel A, Tsao H, Cui J, Weinblatt M, Shadick N. Factors associated with attrition in a longitudinal rheumatoid arthritis registry. Arthritis Care Res (Hoboken) 2013;65:1183–1189. doi: 10.1002/acr.21940.
    1. International Society for Pharmacoepidemiology. Guidelines for good pharmacoepidemiology practices (GPP) 2016. Accessed 7 Jul 2016. Available from: .
    1. Zhuo J, Bryson J, Xia Q, et al. Role of shared epitope in the prognosis of rheumatoid arthritis in relation to ACPA positivity. Ann Rheum Dis. 2020;79:963. doi: 10.1136/annrheumdis-2020-eular.4153.
    1. Gorman JD, Lum RF, Chen JJ, Suarez-Almazor ME, Thomson G, Criswell LA. Impact of shared epitope genotype and ethnicity on erosive disease: a meta-analysis of 3,240 rheumatoid arthritis patients. Arthritis Rheum. 2004;50:400–412. doi: 10.1002/art.20006.
    1. Favalli EG, Raimondo MG, Becciolini A, Crotti C, Biggioggero M, Caporali R. The management of first-line biologic therapy failures in rheumatoid arthritis: current practice and future perspectives. Autoimmun Rev. 2017;16:1185–1195. doi: 10.1016/j.autrev.2017.10.002.
    1. Bogas P, Plasencia-Rodriguez C, Navarro-Compán V, et al. Comparison of long-term efficacy between biological agents following tumor necrosis factor inhibitor failure in patients with rheumatoid arthritis: a prospective cohort study. Ther Adv Musculoskelet Dis. 2021;13:1759720x211060910. doi: 10.1177/1759720X211060910.
    1. Zhuo J, Bryson J, Xia Q, et al. Role of shared epitope on the effectiveness of TNFi treatment for patients with rheumatoid arthritis. Ann Rheum Dis. 2020;79:1000–1001.
    1. Harrold LR, Litman HJ, Connolly SE, et al. Effect of anticitrullinated protein antibody status on response to abatacept or antitumor necrosis factor-alpha therapy in patients with rheumatoid arthritis: a US national observational study. J Rheumatol. 2018;45:32–39. doi: 10.3899/jrheum.170007.
    1. Alemao E, Postema R, Elbez Y, Mamane C, Finckh A. Presence of anti-cyclic citrullinated peptide antibodies is associated with better treatment response to abatacept but not to TNF inhibitors in patients with RA: a meta-analysis. Arthritis Rheumatol. 2017;69:abstract 1034.
    1. Oryoji K, Yoshida K, Kashiwado Y, et al. Shared epitope positivity is related to efficacy of abatacept in rheumatoid arthritis. Ann Rheum Dis. 2018;77:1234–1236.

Source: PubMed

Sponsorer og samarbeidspartnere

Medisinsk tilstand

Legemiddelintervensjoner

3
Abonnere