OP06 HLA-DQA1*05:01 is associated with loss of response to infliximab, and HLA DQA1*05:05 with loss of response to adalimumab in the Oxford OASIS study
Authors: Liao H , Al-Hillawi L , Neary E , Camesella Perez B , Bedke N , Brain O , Satsangi J , Ternette N ,   OASIS
Published: January 2025

Abstract

Background
The HLA allele DQA1*05 was initially identified as a risk factor for the development of anti-drug antibodies in patients undergoing infliximab and adalimumab treatment for Crohn's disease1. We found in our extended analyses that DQA1*05:01 is associated with the development of antibodies to infliximab only, while DQA1*05:05 is associated with immunogenicity to both drugs in the original cohort2. These observations were confirmed for adalimumab in the SERENE trial3. Here we present data from the Oxford OASIS study, which comprised 899 patients receiving both infliximab or adalimumab. Participants had a median age of 38 years at the start of the treatment. 279 patients were diagnosed with ulcerative colitis (UC), 599 with Crohn's disease (CD), and 20 with unclassified inflammatory bowel disease.

Methods
We interrogated the HLA allele associations of a 'primary loss of response (LOR)', defined as no documented clinical response ever recorded, with a drug treatment for less than 12 months, and a 'secondary loss of response', defined as the documentation of clinical response to either drug followed by later, documented LOR. Kaplan-Meier curves were used to examine the proportional hazard hypothesis and demonstrated the differences of immunogenicity rates between different HLA types. Further, log-rank tests were applied using R package 'survival' (10.32614/CRAN.package.survival) to compute the hazard ratios (HR) between two categories, and to estimate their 95% confidence intervals (CI) and p-values.

Results
Our analysis confirmed that HLA-DQA1*05:01 was associated with primary LOR to infliximab (HR=1.8, 95% CI=[0.911, 3.55], p=0.0368), while not associated with LOR to adalimumab (HR=0.754, 95% CI=[0.439, 1.29], p=0.338). Conversely, LOR to adalimumab was associated HLA DQA1*05:05 (HR=1.96, 95% CI=[1.05, 3.65], p=0.0086), while we did not see significant correlation with loss of response to infliximab (HR=1.49, 95% CI=[0.782, 2.83], p=0.178). When both alleles were grouped together as HLA-DQA1*05, a significant association of LOR was only detected for infliximab, and the significant association of adalimumab with HLA DQA1*05:05 would be obscured.

Conclusion
Our findings from the OASIS study reveal distinct association of HLA-DQA1*05:01 with LOR to infliximab, and HLA DQA1*05:05 with LOR to adalimumab, highlighting that these alleles cannot be considered or grouped together for HLA association studies as previously practised1. These results underscore the necessity of 4-digit high-resolution HLA typing to distinguish between closely related alleles and accurately identify treatment-specific immunogenicity risks3,4. Furthermore, the co-inheritance of other HLA alleles may also play an important role, warranting additional investigation2.

References
1.Sazonovs A, Kennedy NA, Moutsianas L, et al. HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn's Disease. Gastroenterology. Jan 2020;158(1):189-199. doi:10.1053/j.gastro.2019.09.041
2.Powell Doherty RD, Liao H, Satsangi JJ, Ternette N. Extended Analysis Identifies Drug-Specific Association of Two Distinct HLA Class II Haplotypes for Development of Immunogenicity to Adalimumab and Infliximab. Gastroenterology. Apr 7 2020;doi:10.1053/j.gastro.2020.03.073
3.Reppell M, Zheng X, Dreher I, et al. HLA-DQA1*05 associates with anti-TNF immunogenicity and low adalimumab trough concentrations in inflammatory bowel disease patients from the SERENE UC and CD studies. J Crohns Colitis. Aug 20 2024;doi:10.1093/ecco-jcc/jjae129
4.Ternette N, Liao H, Satsangi J. Association of the HLA DQA1*05 allelic gene variants with immunogenicity to anti-TNF therapeutics - important differences between infliximab and adalimumab. J Crohns Colitis. Nov 16 2024;doi:10.1093/ecco-jcc/jjae172