HLADQA105 genotype predicts anti‐drug antibody formation and loss of response during infliximab therapy for inflammatory bowel disease

• Published in: Alimentary pharmacology & therapeutics Vol. 51; no. 3; pp. 356 - 363
• Main Authors: Wilson, Aze, Peel, Celeste, Wang, Qian, Pananos, Athanasios Demetri, Kim, Richard B.
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.02.2020
• Subjects: Adult; Antibodies - metabolism; Antibody Formation - drug effects; Antibody Formation - genetics; Cohort Studies; Crohn's disease; Drug Resistance - genetics; Drug Resistance - immunology; Drug-Related Side Effects and Adverse Reactions - genetics; Drug-Related Side Effects and Adverse Reactions - immunology; Female; Genetic Association Studies; Genetic diversity; Genotype; Genotypes; Histocompatibility antigen HLA; HLA-DQ alpha-Chains - genetics; Humans; Immunomodulators; Immunosuppression; Immunotherapy; Inflammatory bowel disease; Inflammatory bowel diseases; Inflammatory Bowel Diseases - diagnosis; Inflammatory Bowel Diseases - drug therapy; Inflammatory Bowel Diseases - genetics; Inflammatory Bowel Diseases - immunology; Infliximab; Infliximab - immunology; Infliximab - therapeutic use; Intestine; Male; Monoclonal antibodies; Pharmacogenomic Testing; Prognosis; Retrospective Studies; Treatment Outcome; Tumor necrosis factor-α
• ISSN: 0269-2813; 1365-2036
• DOI: 10.1111/apt.15563

Summary Background Anti‐drug antibodies (ADAs) are a leading contributor to infliximab loss of response and adverse drug events. It is not feasible to identify patients at risk of antibody formation before initiating infliximab. The genetic variation HLADQA1*05 (rs2097432) has been linked to infliximab antibody formation in Crohn's disease (CD). Aims To evaluate the association between HLADQA1*05 and infliximab antibody formation, infliximab loss of response, treatment discontinuation and adverse drug events in patients with inflammatory bowel disease (IBD) Methods In a retrospective cohort study, infliximab‐exposed patients with IBD (n = 262) were screened for the genetic variation, HLADQA1*05A>G (rs2097432). Risk of infliximab ADA formation, infliximab loss of response, adverse events and discontinuation were assessed in wild‐type (GG) and variant‐carrying (AG or AA) individuals. Results Forty per cent of all participants were HLADQA1*05A>G variant carriers, with 79% of participants with infliximab antibodies carrying at least one variant allele. The risk of infliximab antibody formation was higher in HLADQA1*05A>G variant carriers (adjusted HR = 7.29, 95% confidence interval (CI) = 2.97‐17.191, P = 1.46 × 10−5) independent of age, sex, weight, dose and co‐immunosuppression with an immunomodulator. Variant carrier status was associated with an increased risk of infliximab loss of response (adjusted HR = 2.34, 95% CI = 1.41‐3.88, P = .001) and discontinuation (adjusted HR = 2.27, 95% CI = 1.46‐3.43, P = 2.53 × 10−4) although not with infliximab‐associated adverse drug events. Conclusions HLADQA1*05 is independently associated with a high risk of infliximab antibody formation in addition to infliximab loss of response and treatment discontinuation. There may be a role for genotype‐guided application of combination therapy in IBD.