Predicting drug immunogenicity to TNF inhibitors in patients with rheumatoid arthritis

Abstract

Background: rheumatoid arthritis (RA) is the most common inflammatory arthri-tis. There is no cure for RA; rather, the aim is early and effective control of the inflammation to prevent possible disability and premature mortality. TNF inhibi-tors are the most prescribed biologic drugs to control the progression of RA. However, approximately 40% of patients do not respond well to TNF inhibitors. One reason for the lack of effective response is immunogenicity (development of anti-drug antibodies). A recent robust study by Sazonovs et al. (2020) in a cohort of Crohn's disease affected patients treated by either infliximab or adalimumab (two types of TNF inhibitors) reported a strong genetic association between the HLA_DQA1*05 locus on chromosome 6 and immunogenicity to TNF inhibitors. Immunogenicity is a huge concern; thus, understanding how and why some pa-tients develop it could help personalise therapy choices. Therefore, this project aimed to investigate the association between HLA alleles, primarily HLA_DQA1*05, and immunogenicity to the TNF inhibitor adalimumab in RA patients. Methods: previously published anti-adalimumab antibody titre, measured after six months of treatment with adalimumab, and imputed HLA variants for 226 RA patients were made available for statistical analysis. The statistical analysis in-volved two approaches: the first explored the association between the HLA and SNP alleles and immunogenicity using logistic regression models; the second ex-plored the association between HLA amino acids and immunogenicity for func-tional significance using a logistic regression incorporating an omnibus test. Results: the strongest observed HLA allele associated with immunogenicity was the HLA_DQB1*02 allele, followed by the HLA_DQA1*05 allele. The strongest associated SNP was rs4351302, whereas the strongest associated amino acid was amino acid 66 and 67 in the HLA_DQB1 protein. Conclusion: based on the findings of the project and previously published work, variants within the HLA-DQ confer the strongest evidence for immunogenicity risk in RA patients receiving adalimumab. In addition, this project confirms that the observed association between HLA_DQA1*05 and immunogenicity is not re-stricted to Crohn's disease.