OA24 Predicting drug immunogenicity to tumour necrosis factor inhibitors in patients with rheumatoid arthritis

Abstract

Abstract Background/Aims Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease that irreversibly damages synovial joints. Tumour necrosis factor inhibitors (TNFi) may be prescribed for patients with moderate to severe RA. However, approximately 40% of patients do not respond well to TNFi, with a lack of effectiveness underpinned by immunogenicity (development of anti-drug antibodies) in some patients. A recent well-powered study by Sazonovs et al. (2020) reported a strong genetic association between the HLA-DQA1 locus and immunogenicity to TNFi in a cohort of Crohn's disease patients treated with either infliximab or adalimumab. The current study aimed to investigate the association between HLA alleles, primarily HLA-DQA1, and immunogenicity to adalimumab in RA patients. Methods Anti-adalimumab antibody titres were measured using radioimmunoassay in serum samples from RA patients following six months of treatment. Genetic datasets were generated using the Illumina OmniExpress genotyping array and, following standard quality control filtering, variants were imputed using SNP2HLA statistical software. Following imputation, filtering was performed to exclude variants in linkage disequilibrium or with low minor allele frequency. Logistic regression models were developed to explore the association between HLA alleles and amino acids and immunogenicity (all models were adjusted for sex). Amino acid positions of interest were annotated using P2Rank; a ligand binding site prediction tool. Results A total of 171 HLA alleles and 339 amino acid positions were analysed in 226 RA patients. The strongest association observed between HLA alleles and immunogenicity was for HLA-DQB1*02 (coefficient = 0.87; 95% CI, 0.31-1.43; p value = 2.10E-3), followed by HLA-DQA1*05 (coefficient = 0.91; 95% CI, 0.29-1.53; p value = 3.95E-3). The strongest associated amino acid positions were amino acids 66 and 67 within the ligand binding domain of the HLA-DQB1 protein. Conclusion In keeping with previous findings in Crohn's disease, variants within HLA-DQ molecules confer the strongest evidence for immunogenicity risk in RA patients receiving adalimumab. RA patients carrying these variants could be redirected to receive etanercept, an effective alternative to monoclonal antibodies that is not immunogenic. Further well-powered studies in RA are now warranted to replicate these findings. Disclosure M. Alshehri: None. N. Nair: None. C. Yap: None. J.D. Isaacs: None. K. Hyrich: Honoraria; Abbvie. A.W. Morgan: None. A.G. Wilson: None. A. Barton: None. D. Plant: None.