Article

HLA class II antigen (DRB1 and DQB1) and rheumatoid arthritis in a Tunisian population: Relation to autoantibodies and disease severity

Downloads

Boussaid, S., Tbini, H., Makhlouf, Y., Hassayoun, M., Lagha, A., Ghazouani, E., Kochbati, S., & Rekik, S. (2023). HLA class II antigen (DRB1 and DQB1) and rheumatoid arthritis in a Tunisian population: Relation to autoantibodies and disease severity. Trends in Immunotherapy, 7(2). https://doi.org/10.24294/ti.v7.i2.2929

Authors

  • Soumaya Boussaid Department of Rheumatology, La Rabta Hospital, Tunis 1007, Tunisia; Faculty of Medicine of Tunis, University Tunis el Manar, Tunis 1068, Tunisia
  • Houssem Tbini
    Department of Rheumatology, La Rabta Hospital, Tunis 1007, Tunisia; Faculty of Medicine of Tunis, University Tunis el Manar, Tunis 1068, Tunisia
  • Yasmine Makhlouf Department of Rheumatology, La Rabta Hospital, Tunis 1007, Tunisia; Faculty of Medicine of Tunis, University Tunis el Manar, Tunis 1068, Tunisia
  • Maroua Hassayoun Department of Rheumatology, La Rabta Hospital, Tunis 1007, Tunisia; Faculty of Medicine of Tunis, University Tunis el Manar, Tunis 1068, Tunisia
  • Aouatef Lagha Faculty of Medicine of Tunis, University Tunis el Manar, Tunis 1068, Tunisia; Department of Immunology, Military Hospital of Tunis, Tunis 1008, Tunisia
  • Ezzeddine Ghazouani Faculty of Medicine of Tunis, University Tunis el Manar, Tunis 1068, Tunisia; Department of Immunology, Military Hospital of Tunis, Tunis 1008, Tunisia
  • Samir Kochbati Faculty of Medicine of Tunis, University Tunis el Manar, Tunis 1068, Tunisia; Department of Rheumatology, Habib Thameur Hospital, Tunis 1008, Tunisia
  • Sonia Rekik Department of Rheumatology, La Rabta Hospital, Tunis 1007, Tunisia; Faculty of Medicine of Tunis, University Tunis el Manar, Tunis 1068, Tunisia

We aimed to evaluate the association of HLA DRB1 and DQB1 alleles with rheumatoid arthritis (RA), and to investigate their relationship with anti-citrullinated peptide antibodies (ACPA) and RA severity. We performed a case-control study of 81 RA patients compared with 100 healthy controls. Sociodemographic data, disease activity scores, functional impact, structural damage, ACPA, rheumatoid factor (RF), and HLA DRB1 and DQB1 alleles were determined. Forty-six patients expressed HLA DRB1, predominantly DRB1*04. These alleles were more frequent in RA patients than in controls. DRB1*04:05 was the most associated allele with RA susceptibility, 54.5% of RF-positive patients expressed DRB1*04:05 with a significant correlation. Similarly, a highly significant association with DRB1*15:01 and RF positivity was found. DRB1*01:01, 04:05, 11:01, and 15:01 were associated with the presence of ACPA. Patients with DRB1 alleles had more extraarticular manifestations (EAM). Multivariate analysis concluded that DRB1*04:05 was only associated with ACPA positivity. Regarding DQB1, DQB1*03:02 was the most associated with RA. DQB1*02:01, 03:01, 03:02, 05:01, and 06:01 were associated with RF-positive RA. DQB1*06:01 was associated with ACPA. Only HLA DQB1*02:01 and 06:01 were associated with the presence of EAM. DAS28 was reduced in the presence of DQB1. HAQ > 0.5 were correlated with DQB1 alleles. In addition, there was more structural damage in RA encoding for DQB1. In linear regression, DQB1*06:01 were associated with RF positivity, but there was no association with the other parameters. Our study confirmed that DRB1 and DQB1 expression was significantly associated with ACPA, increased HAQ, increased sharp score, and the presence of EAM.

Keywords:

HLA antigen rheumatoid arthritis ACPA autoantibodies disease severity

References

  1. Shapira Y, Agmon-Levin N, Shoenfeld Y. Geoepidemiology of autoimmune rheumatic diseases. Nature Reviews Rheumatology 2010; 6(8): 468–476. doi: 10.1038/nrrheum.2010.86
  2. Almutairi K, Nossent J, Preen D, et al. The global prevalence of rheumatoid arthritis: A meta-analysis based on a systematic review. Rheumatology International 2021; 41(5): 863–877. doi: 10.1007/s00296-020-04731-0
  3. Gravallese EM, Firestein GS. Rheumatoid arthritis—Common origins, divergent mechanisms. The New England Journal of Medicine 2023; 388(6): 529–542. doi: 10.1056/NEJMra2103726
  4. Croia C, Bursi R, Sutera D, et al. One year in review 2019: Pathogenesis of rheumatoid arthritis. Clinical and Experimental Rheumatology 2019; 37(3): 347–357.
  5. Scherer HU, Häupl T, Burmester GR. The etiology of rheumatoid arthritis. Journal of Autoimmunity 2020; 110: 102400. doi: 10.1016/j.jaut.2019.102400
  6. Matuszewska A, Madej M, Wiland P. Immunological markers of rheumatoid arthritis (Polish). Postępy Higieny i Medycyny Doświadczalnej 2016; 70: 251–7. doi: 10.5604/17322693.1198270
  7. Degboé Y. Pre-rheumatoid arthritis and ACPA: Contribution of ACPAs in the pathogeny of pre-disease stage. Joint Bone Spine 2021; 88(3): 105098. doi: 10.1016/j.jbspin.2020.105098
  8. Wouters F, Maurits MP, van Boheemen L, et al. Determining in which pre-arthritis stage HLA-shared epitope alleles and smoking exert their effect on the development of rheumatoid arthritis. Annals of the Rheumatic Diseases 2022; 81(1): 48–55. doi: 10.1136/annrheumdis-2021-220546
  9. Umeda N, Matsumoto I, Sumida T. The pathogenic role of ACPA in rheumatoid arthritis (Japanese). Nihon Rinsho Meneki Gakkai Kaishi 2017; 40(6): 391–395. doi: 10.2177/jsci.40.391
  10. Dhaouadi T, Sfar I, Abdelmoula L, et al. Association of specific amino acid sequence (QRRAA) of HLA-DRB1*0405 with rheumatoid arthritis in a Tunisian population. Archives de l'Institut Pasteur de Tunis 2010; 87(1–2): 53–59.
  11. Lagha A, Messadi A, Boussaidi S, et al. HLA DRB1/DQB1 alleles and DRB1‐DQB1 haplotypes and the risk of rheumatoid arthritis in Tunisians: A population‐based case—Control study. HLA 2016; 88(3): 100–109. doi: 10.1111/tan.12855
  12. Ben Hamad M, Mahfoudh N, Marzouk S, et al. Association study of human leukocyte antigen-DRB1 alleles with rheumatoid arthritis in south Tunisian patients. Clinical Rheumatology 2012; 31(6): 937–942. doi: 10.1007/s10067-012-1954-z
  13. Kay J, Upchurch KS. ACR/EULAR 2010 rheumatoid arthritis classification criteria. Rheumatology 2012; 51(Suppl 6): vi5–vi9. doi: 10.1093/rheumatology/kes279
  14. Cherni L, Pakstis AJ, Boussetta S, et al. Genetic variation in Tunisia in the context of human diversity worldwide. American Journal of Physical Anthropology 2016; 161(1): 62–71. doi: 10.1002/ajpa.23008
  15. van Riel PLCM, Renskers L. The disease activity score (DAS) and the disease activity score using 28 joint counts (DAS28) in the management of rheumatoid arthritis. Clinical and Experimental Rheumatology 2016; 34(5 Suppl 101): S40–S44.
  16. Lee KE, Choi SE, Xu H, et al. HAQ score is an independent predictor of sustained remission in patients with rheumatoid arthritis. Rheumatology International 2017; 37(12): 2027–2034. doi: 10.1007/s00296-017-3833-z
  17. Sun Y, Liu J, Xin L, et al. Factors influencing the Sharp score of 1057 patients with rheumatoid arthritis and anemia: A retrospective study. Journal of International Medical Research 2022; 50(3): 030006052210885. doi: 10.1177/03000605221088560
  18. Baddoura R, Haddad S, Awada H, et al. Severity of rheumatoid arthritis: The SEVERA study. Clinical Rheumatology 2005; 25(5): 700–704. doi: 10.1007/s10067-005-0136-7
  19. Min HK, Kim SH, Lee SH, Kim HR. Baseline bony erosions and time-averaged DAS28 predict discontinuation of TNF inhibitors in rheumatoid arthritis. Scientific Reports 2022; 12(1): 19951. doi: 10.1038/s41598-022-24027-6
  20. Wen J, Liu J, Xin L, et al. Effective factors on Sharp Score in patients with rheumatoid arthritis: A retrospective study. BMC Musculoskeletal Disorders 2021; 22(1): 865. doi: 10.1186/s12891-021-04742-3
  21. Perez ML, Gomara MJ, Ercilla G, et al. Antibodies to citrullinated human fibrinogen synthetic peptides in diagnosing rheumatoid arthritis. Journal of Medicinal Chemistry 2007; 50(15): 3573–3584. doi: 10.1021/jm0701932
  22. Stastny P. Association of the B-cell alloantigen DRw4 with rheumatoid arthritis. New England Journal of Medicine 1978; 298(16): 869–871. doi: 10.1056/NEJM197804202981602
  23. Trier NH, Houen G. Antibody cross-reactivity in auto-immune diseases. International Journal of Molecular Sciences 2023; 24(17): 13609. doi: 10.3390/ijms241713609
  24. Thomsen M, Morling N, Snorrason E, et al. HLA—Dw4 and rheumatoid arthritis. Tissue Antigens 1979; 13(1): 56–60. doi: 10.1111/j.1399-0039.1979.tb01137.x
  25. Arango MT, Perricone C, Kivity S, et al. HLA-DRB1 the notorious gene in the mosaic of autoimmunity. Immunologic Research 2017; 65(1): 82–98. doi: 10.1007/s12026-016-8817-7
  26. Okada Y, Kim K, Han B, et al. Risk for ACPA-positive rheumatoid arthritis is driven by shared HLA amino acid polymorphisms in Asian and European populations. Human Molecular Genetics 2014; 23(25): 6916–6926. doi: 10.1093/hmg/ddu387
  27. Weyand CM, Goronzy JJ. The immunology of rheumatoid arthritis. Nature Immunology 2021; 22(1): 10–18. doi: 10.1038/s41590-020-00816-x
  28. Vetchinkina EA, Mikhaylenko DS, Kuznetsova EB, et al. Genetic factors of predisposition and clinical characteristics of rheumatoid arthritis in Russian patients. Journal of Personalized Medicine 2021; 11(6): 469. doi: 10.3390/jpm11060469
  29. Sparks JA. Clinical application of personalized rheumatoid arthritis risk information: Translational epidemiology leading to precision medicine. Expert Review of Precision Medicine and Drug Development 2021; 6(3): 147–149. doi: 10.1080/23808993.2021.1857237
  30. Naito T, Okada Y. HLA imputation and its application to genetic and molecular fine-mapping of the MHC region in autoimmune diseases. Seminars in Immunopathology 2022; 44(1): 15–28. doi: 10.1007/s00281-021-00901-9
  31. Bizzari S, Nair P, Al Ali MT, Hamzeh AR. Meta-analyses of the association of HLA-DRB1 alleles with rheumatoid arthritis among Arabs. International Journal of Rheumatic Diseases 2016; 20(7): 832–838. doi: 10.1111/1756-185X.12922
  32. Reviron D, Foutrier C, Guis S, et al. DRB1 alleles in polymyalgia rheumatica and rheumatoid arthritis in southern France. European Journal of Immunogenetics 2001; 28(1): 83–87. doi: 10.1046/j.1365-2370.2001.00228.x
  33. Balandraud N, Picard C, Reviron D, et al. HLA-DRB1 genotypes and the risk of developing anti citrullinated protein antibody (ACPA) positive rheumatoid arthritis. PLoS One 2013; 8(5): e64108. doi: 10.1371/journal.pone.0064108
  34. Liu WX, Jiang Y, Hu QX, You XB. HLA-DRB1 shared epitope allele polymorphisms and rheumatoid arthritis: A systemic review and meta-analysis. Clinical & Investigative Medicine 2016; 39(6): E182–E203. doi: 10.25011/cim.v39i6.27487
  35. Castro-Santos P, Olloquequi J, Verdugo RA, et al. HLA-DRB1*07:01 and *08:02 alleles confer a protective effect against ACPA-positive rheumatoid arthritis in a Latin American admixed population. Biology (Basel) 2020; 9(12): 467. doi: 10.3390/biology9120467
  36. Wysocki T, Olesińska M, Paradowska-Gorycka A. Current understanding of an emerging role of HLA-DRB1 gene in rheumatoid arthritis—From research to clinical practice. Cells 2020; 9(5): 1127. doi: 10.3390/cells9051127
  37. Padyukov L. Genetics of rheumatoid arthritis. Seminars in Immunopathology 2022; 44(1): 47–62. doi: 10.1007/s00281-022-00912-0
  38. Busch R, Kollnberger S, Mellins ED. HLA associations in inflammatory arthritis: Emerging mechanisms and clinical implications. Nature Reviews Rheumatology 2019; 15(6): 364–381. doi: 10.1038/s41584-019-0219-5
  39. van der Woude D, Lie BA, Lundström E, et al. Protection against anti-citrullinated protein antibody-positive rheumatoid arthritis is predominantly associated with HLA-DRB1*1301: A meta-analysis of HLA-DRB1 associations with anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis in four European populations. Arthritis & Rheumatism 2010; 62(5): 1236–1245. doi: 10.1002/art.27366
  40. Oka S, Furukawa H, Kawasaki A, et al. Protective effect of the HLA-DRB1*13:02 allele in Japanese rheumatoid arthritis patients. PLoS One 2014; 9(6): e99453. doi: 10.1371/journal.pone.0099453
  41. Maurits MP, Wouters F, Niemantsverdriet E, et al. The role of genetics in clinically suspect arthralgia and rheumatoid arthritis development: A large cross-sectional study. Arthritis & Rheumatology 2023; 75(2): 178–186. doi: 10.1002/art.42323
  42. Liu J, Gao J, Wu Z, et al. Anti-citrullinated protein antibody generation, pathogenesis, clinical application, and prospects. Frontiers in Medicine 2022; 8: 802934. doi: 10.3389/fmed.2021.802934
  43. Begum M, Sattar H, Haq SA, et al. Study on association of human leukocyte antigen-DRB1 alleles amongst Bangladeshi patients with rheumatoid arthritis. International Journal of Rheumatic Diseases 2018; 21(8): 1543–1547. doi: 10.1111/1756-185X.13291
  44. Mackie SL, Taylor JC, Martin SG, et al. A spectrum of susceptibility to rheumatoid arthritis within HLA-DRB1: Stratification by autoantibody status in a large UK population. Genes & Immunity 2012; 13(2): 120–128. doi: 10.1038/gene.2011.60
  45. Konda Mohan V, Ganesan N, Gopalakrishnan R, Venkatesan V. HLA-DRB1 shared epitope alleles in patients with rheumatoid arthritis: relation to autoantibodies and disease severity in a south Indian population. International Journal of Rheumatic Diseases 2017; 20(10): 1492–1498. doi: 10.1111/1756-185X.12948
  46. Zhao M, Mauer L, Sayles H, et al. HLA-DRB1 haplotypes, shared epitope, and disease outcomes in US veterans with rheumatoid arthritis. The Journal of Rheumatology 2019; 46(7): 685–693. doi: 10.3899/jrheum.180724
  47. Tan LK, Too CL, Diaz-Gallo LM, et al. The spectrum of association in HLA region with rheumatoid arthritis in a diverse Asian population: Evidence from the MyEIRA case-control study. Arthritis Research & Therapy 2021; 23(1): 46. doi: 10.1186/s13075-021-02431-z
  48. Chen YC, Huang CM, Liu TY, et al. Effects of human leukocyte antigen drb1 genetic polymorphism on anti-cyclic citrullinated peptide (ANTI-CCP) and rheumatoid factor (RF) expression in rheumatoid arthritis (RA) patients. International Journal of Molecular Sciences 2023; 24(15): 12036. doi: 10.3390/ijms241512036
  49. Barton A, Thomson W, Ke X, et al. Re-evaluation of putative rheumatoid arthritis susceptibility genes in the post-genome wide association study era and hypothesis of a key pathway underlying susceptibility. Human Molecular Genetics 2008; 17(15): 2274–2279. doi: 10.1093/hmg/ddn128
  50. Chun-Lai T, Padyukov L, Dhaliwal JS, et al. Shared epitope alleles remain a risk factor for anti-citrullinated proteins antibody (ACPA)—Positive rheumatoid arthritis in three Asian ethnic groups. PLoS One 2011; 6(6): e21069. doi: 10.1371/journal.pone.0021069
  51. Plenge RM, Padyukov L, Remmers EF, et al. Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: Association of susceptibility with PTPN22, CTLA4, and PADI4. The American Journal of Human Genetics 2005; 77(6): 1044–1060. doi: 10.1086/498651
  52. Raslan HM, Attia HR, Hamed Ibrahim M, et al. Association of anti-cyclic citrullinated peptide antibodies and rheumatoid factor isotypes with HLA-DRB1 shared epitope alleles in Egyptian rheumatoid arthritis patients. International Journal of Rheumatic Diseases 2020; 23(5): 647–653. doi: 10.1111/1756-185X.13819
  53. Alvandpur N, Tabatabaei R, Tahamoli-Roudsari A, et al. Circulating IFN-γ producing CD4+ T cells and IL-17A producing CD4+ T cells, HLA-shared epitope and ACPA may characterize the clinical response to therapy in rheumatoid arthritis patients. Human Immunology 2020; 81(5): 228–236. doi: 10.1016/j.humimm.2020.02.008
  54. Mourad J, Monem F. HLA DRB1 allele association with rheumatoid arthritis susceptibility and severity in Syria. Revista Brasileira de Reumatologia 2013; 53(1): 47–56. doi: 10.1016/s2255-5021(13)70005-1
  55. Kissel T, van Schie KA, Hafkenscheid L, et al. On the presence of HLA-SE alleles and ACPA-IgG variable domain glycosylation in the phase preceding the development of rheumatoid arthritis. Annals of the Rheumatic Diseases 2019; 78(12): 1616–1620. doi: 10.1136/annrheumdis-2019-215698
  56. Charpin C, Balandraud N, Guis S, et al. HLA-DRB1*0404 is strongly associated with high titers of anti-cyclic citrullinated peptide antibodies in rheumatoid arthritis. Clinical and Experimental Rheumatology 2008; 26(4): 627–631.
  57. Atouf O, Benbouazza K, Brick C, et al. HLA polymorphism and early rheumatoid arthritis in the Moroccan population. Joint Bone Spine 2008; 75(5): 554–558. doi: 10.1016/j.jbspin.2008.01.027
  58. van Gaalen FA, van Aken J, Huizinga TWJ, et al. Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis. Arthritis & Rheumatism 2004; 50(7): 2113–2121. doi: 10.1002/art.20316
  59. Reviron D, Perdriger A, Toussirot E, et al. Influence of shared epitope-negative HLA-DRB1 alleles on genetic susceptibility to rheumatoid arthritis. Arthritis & Rheumatism 2001; 44(3): 535–540. doi: 10.1002/1529-0131(200103)44:3<535::AID-ANR101>3.0.CO;2-Z
  60. Woodrow JC, Nichol FE, Zaphiropoulos G. DR antigens and rheumatoid arthritis: A study of two populations. British Medical Journal 1981; 283(6302): 1287–1288. doi: 10.1136/bmj.283.6302.1287
  61. Wu J, Li J, Li S, et al. Association of HLA-DQB1 polymorphisms with rheumatoid arthritis: A meta-analysis. Postgraduate Medical Journal 2017; 93(1104): 618–625. doi: 10.1136/postgradmedj-2016-134724
  62. Beri R, Peterlana D, Puccetti A, et al. HLA-DRB1 alleles and rheumatoid arthritis in northern Italy: Lack of correlation with disease severity and extra-articular manifestations (Italian). Recenti Progressi in Medicine 2005; 96(3): 139–143.
  63. Citera G, Padulo LA, Fernandez G, et al. Influence of HLA-DR alleles on rheumatoid arthritis: Susceptibility and severity in Argentine patients. The Journal of Rheumatology 2001; 28(7): 1486–1491.
  64. Viatte S, Plant D, Han B, et al. Association of HLA-DRB1 haplotypes with rheumatoid arthritis severity, mortality, and treatment response. JAMA 2015; 313(16): 1645–1656. doi: 10.1001/jama.2015.3435
  65. Hirose W, Harigai M, Amano K, et al. Impact of the HLA-DRB1 shared epitope on responses to treatment with tofacitinib or abatacept in patients with rheumatoid arthritis. Arthritis Research & Therapy 2021; 23(1): 228. doi: 10.1186/s13075-021-02612-w
  66. Rigby W, Buckner JH, Louis Bridges S, et al. HLA-DRB1 risk alleles for RA are associated with differential clinical responsiveness to abatacept and adalimumab: Data from a head-to-head, randomized, single-blind study in autoantibody-positive early RA. Arthritis Research & Therapy 2021; 23(1): 245. doi: 10.1186/s13075-021-02607-7
  67. Jung SM, Park YJ, Park KS, Kim KJ. Clinical implications of shared epitope and anti-citrullinated peptide antibody in patients with rheumatoid arthritis. Journal of Rheumatic Diseases 2022; 29(3): 171–180. doi: 10.4078/jrd.2022.29.3.171