A208 HLA-DQA1*05 GENOTYPE PREDICTS ANTI-DRUG ANTIBODY FORMATION AND LOSS OF RESPONSE DURING INFLIXIMAB THERAPY FOR INFLAMMATORY BOWEL DISEASE

Background The underlying mechanism for immunogenicity in anti-TNFa-exposed patients with inflammatory bowel disease is poorly understood. Anti-drug antibodies are a leading contributor to infliximab loss of response and adverse drug events. Currently, it is not feasible to identify patients at risk of antibody formation prior to initiating infliximab. The genetic variation HLADQA1*05(rs2097432) has been linked to infliximab antibody formation in a cohort of patients with Crohn’s disease. Aims Due to the wide variation in the frequency of HLADQA1* 05 across ethnic groups, we aim to independently evaluate the association between HLADQA1*05and infliximab antibody formation, infliximab loss of response, treatment discontinuation and adverse drug events, in a Canadian inflammatory bowel disease cohort. Methods In a retrospective cohort study, infliximab-exposed patients with inflammatory bowel disease (n=262) were screened for the genetic variation, HLADQA1*05A>G(rs2097432). The risk of infliximab anti-drug antibody formation, infliximab loss of response, adverse events, and discontinuation were assessed in wild type (GG) and variant-carrying (AG or AA) individuals. Results Forty percent of all participants were HLADQA1*05A>Gvariant 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>Gvariant carriers in an IBD population (adjusted HR=7.29, 95%CI=2.97–17.191, p=1.46x10-5) 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=0.001) and discontinuation (adjusted HR=2.27, 95%CI=1.46–3.43, p=2.53x10-4) though 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. As a result, we propose that pre-emptive genetic screening for the HLADQA1* 05A>Gvariant would be useful in order to predict individuals at risk of developing immunogenicity. There may be a role for genotype-guided application of combination therapy in inflammatory bowel disease. Funding Agencies NoneWolfe Medical Research Chair in Pharmacogenomics (MOP-89753 to RBK), the Academic Medical Organization of Southwestern Ontario (INN18-005 to RBK and AW; S17-004 to AW), and Lawson Health Research Institute (IRF-05-19 to AW)