HLA‐DQ2 is associated with anti‐drug antibody formation to infliximab in patients with immune‐mediated inflammatory diseases

• Published in: Journal of internal medicine Vol. 293; no. 5; pp. 648 - 655
• Main Authors: Brun, Marthe Kirkesæther, Bjørlykke, Kristin Hammersbøen, Viken, Marte K., Stenvik, Grethe‐Elisabeth, Klaasen, Rolf A., Gehin, Johanna E., Warren, David John, Sexton, Joseph, Sandanger, Øystein, Kvien, Tore K., Mørk, Cato, Haavardsholm, Espen A., Jahnsen, Jørgen, Goll, Guro Løvik, Lie, Benedicte A., Bolstad, Nils, Jørgensen, Kristin Kaasen, Syversen, Silje Watterdal
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.05.2023; Blackwell Science Ltd
• Subjects: Alleles; Antibodies; Antibody Formation; Antigens; autoimmune disease; Celiac Disease; Computer applications; DQA1 protein; gastroenterology; Genetic Predisposition to Disease; genetics; Genomes; Haplotypes; Health services; Histocompatibility antigen HLA; HLA-DQ alpha-Chains - genetics; Humans; Immunogenicity; immunology; Immunomodulation; Immunomodulators; immunosuppressive treatment; Inflammatory diseases; Infliximab; Infliximab - therapeutic use; Monoclonal antibodies; Next-generation sequencing; Patients; rheumatology; Risk; Tissue typing; Tumor necrosis factor-α; Tumors; rheumatology; genetics; gastroenterology; immunosuppressive treatment; autoimmune disease; immunology
• ISSN: 0954-6820; 1365-2796
• DOI: 10.1111/joim.13616

Background Immunogenicity to tumour necrosis factor inhibitors is a significant clinical problem leading to treatment failure and adverse events. The study aimed to assess human leukocyte antigen (HLA) associations with anti‐drug antibody (ADAb) formation to infliximab. Methods Immune‐mediated inflammatory disease patients on infliximab therapy (n = 612) were included. Neutralising ADAb were assessed with a drug‐sensitive assay. Next generation sequencing‐based HLA typing was performed. Results Overall, 147 (24%) patients developed ADAb. Conditional analyses indicated HLA‐DQB1 (p = 1.4 × 10−6) as a primary risk locus. Highest risk of ADAb was seen when carrying at least one of the HLA‐DQ2 haplotypes; DQB1*02:01–DQA1*05:01 or DQB1*02:02–DQA1*02:01 (OR 3.18, 95% CI 2.15–4.69 and p = 5.9 × 10−9). Results were consistent across diseases and when adjusting for concomitant immunomodulator. Computational predictions indicated that these HLA‐DQ2 haplotypes bind to peptide motifs from infliximab light chain. Conclusion A genome‐wide significant association between two HLA‐DQ2 haplotypes and the risk of ADAb formation to infliximab was identified, suggesting that HLA‐DQ2 testing may facilitate personalised treatment decisions.