Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease that primarily affects the synovial joints. Tumour Necrosis Factor inhibitor (TNFi) therapy has transformed the clinical management of RA. However, monoclonal antibody derived TNFi is associated with development of immunogenicity and subsequent loss of therapeutic effects. Previous studies have observed associations between certain HLA alleles and TNFi immunogenicity. For example HLA-DQA1 and HLA-DRB1 have been associated with immunogenicity in inflammatory bowel disease ^1,2 and RA ^3,4 , respectively.

Objectives: The aims of this study were to identify associations between HLA alleles and immunogenicity to TNFi in an observational cohort of RA patients and to replicate findings from previous studies.

Methods: Anti-drug antibody titres were measured using radioimmunoassay in serum samples from RA patients participating in Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS). An anti-drug antibody titre of ≥12 AU/mL following six months on treatment was used to define positive immunogenicity. Genotype data were generated using Illumina HumanCoreExome Arrays. Standard quality control (QC) was applied prior to HLA imputation using SNP2HLA software before low minor allele frequency markers were removed. Logistic regression was used to study the association between HLA alleles and immunogenicity, whilst the omnibus test was applied to amino acid positions; sex and concurrent conventional synthetic DMARD use were included as a covariate in all the models.

Results: In total, 445 RA patients were analysed, 377 patients (70 immunogenicity events) were underdoing adalimumab therapy and 68 certolizumab (30 immunogenicity events) therapy. Following QC, 162 HLA alleles and 361 amino acids positions were available for analysis. The strongest HLA allele association was observed for HLA-DQA1 *03 when all patients were analysed (OR = 0.61; 95% CI = 0.43 – 0.86; p-value = 5e-3). The amino acids positions 187 (p-value = 5e-3) and 26 (p-value = 5e-3) within the HLA-DQA1 gene were significantly associated with immunogenicity events. When both drugs were analysed separately, they produced similar effect size for HLA-DQA1*03 association; patients treated with adalimumab (OR = 0.59; 95% CI = 0.38 – 0.88; p-value = 1e-2) and certolizumab (OR = 0.52; 95% CI = 0.24 – 1.1; p-value = 1e-1). Another strong association was found in HLA-DRB1*04 (OR = 0.62; 95% CI = 0.44 – 0.88; p-value = =7e-3) and the amino acid position of 180 (p-value = 7e-3) and 33 (p-value = 7e-3) of HLA-DRB1 gene. Additionally, the similar protective effect between the two presented alleles suggested possibility of linkage disequilibrium, upon investigation the r ² between the 2 alleles is 0.69.

Conclusion: The current study increases the evidence for association between immunogenicity development with HLA-DQA1 and HLA-DRB1 alleles in patients receiving monoclonal antibody derived TNFi therapy. Further well powered studies are now required to determine the utility of HLA markers as a potential tool to aid the clinical management of RA.

REFERENCES:

[1]Sazonovs, A. et al. HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn’s Disease. Gastroenterology 158 , 189–199 (2020).

[2]Billiet, T. et al. Immunogenicity to infliximab is associated with HLA-DRB1. Gut 64 , 1344–1345 (2015).

[3]Liu, M. et al. Identification of HLA-DRB1 association to adalimumab immunogenicity. PLoS One 13 , e0195325 (2018).

[4]Rigby, W. 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 Res. Ther. 23 , 245 (2021).

Disclosure of Interests: Chuan Fu Yap: None declared, Nisha Nair: None declared, Kimme Hyrich Speakers bureau: Abbvie, Grant/research support from: Pfizer and BMS, Anthony G Wilson: None declared, John Isaacs Speakers bureau: Abbvie, Gilead, Roche, UCB, Grant/research support from: GSK, Janssen, Pfizer, Ann Morgan Speakers bureau: Roche, Chugai, Consultant of: GSK, Roche, Chugai, AstraZeneca, Regeneron, Sanofi, Vifor, Grant/research support from: Roche, Kiniksa Pharmaceuticals, Anne Barton Grant/research support from: I have received grant funding from Pfizer, Galapagos, Scipher Medicine and Bristol Myers Squibb., Darren Plant: None declared