Background/Purpose: Immunogenicity is a leading cause of treatment failure to TNF inhibitors, and also affects drug safety. Variations in HLA class II genes have been suggested to predispose to anti-drug antibody formation (ADA), but characterization of biologically relevant HLA haplotypes, based on high-resolution genotyping, is lacking. The aim was to assess associations between HLA loci and formation of ADA to infliximab across different immune mediated inflammatory diseases.

Methods: Patients with immune mediated inflammatory diseases on infliximab therapy (N=612; 181 spondyloarthritis, 120 rheumatoid arthritis, 72 psoriatic arthritis, 114 ulcerative colitis, 80 Crohn’s disease and 45 psoriasis) participating in the Norwegian Drug Monitoring (NOR-DRUM) trials (1, 2) were included in the present analyses. Neutralizing ADA were assessed with an automated fluorescence assay at each infusion. Next generation sequencing-based HLA typing was performed (Histogenetics®). Associations with ADA formation were assessed at locus, allele, haplotype and amino acid level. Peptide binding predictions for infliximab were performed.

Results: ADA were detected in 147 patients (24%). Significant associations were shown between ADA and several HLA loci, whereas conditional analyses indicated HLA-DQB1 (p=1.4×10-6) as the primary risk locus. Highest risk of ADA formation was seen for patients carrying at least one of the HLA-DQ2 haplotypes; DQB1*02:01~DQA1*05:01 and DQB1*02:02~DQA1*02:01 (OR 3.18, 95% CI 2.15 to 4.69, p=5.9×10-9) (Figure). These findings were consistent across diagnoses (Table), and remained significant when adjusting for other possible predictors of ADA. Computational predictions indicated that both these HLA-DQ2 haplotypes could strongly bind two peptide motifs (INTVESEDI and VYACEVTHQ) in the infliximab heavy and light chain.

Conclusion: The risk of ADA to infliximab was three-fold higher in patients carrying the HLA-DQ2 risk haplotypes across diseases. A biological role for the HLA-DQ2 molecules encoded by the two different HLA-DQ2 risk haplotypes in the formation of ADA was further supported by peptide binding predictions. These novel findings provide promise for future incorporation of HLA-DQ2 testing to facilitate personalized treatment decisions.

1. Syversen SW et al. Jama. 2021;326(23):2375-84.

2. Syversen SW et al. Jama. 2021;325(17):1744-54.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/hla-dq2-is-associated-with-anti-drug-antibody-formation-to-infliximab-across-immune-mediated-inflammatory-diseases/