HLA DQA1∗05 and Risk of Antitumor Necrosis Factor Treatment Failure and Anti-Drug Antibody Development in Children with Crohn's Disease

Abstract

INTRODUCTION:Human leukocyte antigen (HLA) DQA1∗05 has been associated with the development of anti-drug antibodies (ADA) to tumor necrosis factor antagonists (anti-TNFα) and treatment failure among adults with Crohn's disease (CD). However, findings from other studies have been inconsistent with limited pediatric data.METHODS:We analyzed banked serum from patients with CD aged <21 years enrolled in clinical outcomes of Methotrexate Binary Therapy in practice, a multicenter, prospective randomized trial of anti-TNFα monotherapy vs combination with methotrexate. The primary outcome was a composite of factors indicative of treatment failure. The secondary outcome was ADA development.RESULTS:A trend toward increased treatment failure among HLA DQA1∗05-positive participants was not significant (hazard ratio 1.58, 95% confidence interval [CI] 0.95-2.62; P = 0.08). After stratification by HLA DQA1∗05 and by methotrexate vs placebo, patients who were HLA DQA1∗05 negative and assigned to methotrexate experienced less treatment failures than HLA DQA1∗05-positive patients on placebo (hazard ratio 0.31, 95% CI 0.13-0.70; P = 0.005). A trend toward increased ADA development among HLA DQA1∗05-positive participants was not significant (odds ratio 1.96, 95% CI 0.90-4.31, P = 0.09). After further stratification, HLA DQA1∗05-negative participants assigned to methotrexate were less likely to develop ADA relative to HLA DQA1∗05-positive patients on placebo (odds ratio 0.12, 95% CI 0.03-0.55; P = 0.008).DISCUSSION:In a randomized trial of children with CD initiating anti-TNFα, 40% were HLA DQ-A1∗05 positive, which was associated with a trend toward increased risk of both treatment failure and ADA. These risks were mitigated, but not eliminated, by adding oral methotrexate. HLA DQ-A1∗05 is an important biomarker for prognosis and risk stratification.