Aze Wilson1,2,3, Celeste Peel4, Qian Wang5, Athanasios Demetri Pananos6, Richard B Kim1,2. 1. Division of Clinical Pharmacology, Department of Medicine, Western University, London, ON, Canada. 2. Division of Gastroenterology, Department of Medicine, Western University, London, ON, Canada. 3. Department of Physiology & Pharmacology, Western University, London, ON, Canada. 4. London Health Sciences Centre, London, ON, Canada. 5. Schulich School of Medicine and Dentistry, Western University, London, ON, Canada. 6. Department of Epidemiology and Biostatistics, Western University, London, ON, Canada.
Abstract
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.
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 infliximabADA 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.
Authors: Mohammad Shehab; Hajer Alasfour; Israa Abdullah; Ghadeer Alhendi; Anwar Alhadab; Ahmad Alfadhli; Ali H Ziyab; Robert Battat Journal: Front Med (Lausanne) Date: 2021-12-23