HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn's Disease

Gastroenterology. 2020 Jan;158(1):189-199. doi: 10.1053/j.gastro.2019.09.041. Epub 2019 Oct 7.


Background & aims: Anti-tumor necrosis factor (anti-TNF) therapies are the most widely used biologic drugs for treating immune-mediated diseases, but repeated administration can induce the formation of anti-drug antibodies. The ability to identify patients at increased risk for development of anti-drug antibodies would facilitate selection of therapy and use of preventative strategies.

Methods: We performed a genome-wide association study to identify variants associated with time to development of anti-drug antibodies in a discovery cohort of 1240 biologic-naïve patients with Crohn's disease starting infliximab or adalimumab therapy. Immunogenicity was defined as an anti-drug antibody titer ≥10 AU/mL using a drug-tolerant enzyme-linked immunosorbent assay. Significant association signals were confirmed in a replication cohort of 178 patients with inflammatory bowel disease.

Results: The HLA-DQA1*05 allele, carried by approximately 40% of Europeans, significantly increased the rate of immunogenicity (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.60-2.25; P = 5.88 × 10-13). The highest rates of immunogenicity, 92% at 1 year, were observed in patients treated with infliximab monotherapy who carried HLA-DQA1*05; conversely the lowest rates of immunogenicity, 10% at 1 year, were observed in patients treated with adalimumab combination therapy who did not carry HLA-DQA1*05. We confirmed this finding in the replication cohort (HR, 2.00; 95% CI, 1.35-2.98; P = 6.60 × 10-4). This association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32-2.70) or infliximab (HR, 1.92; 95% CI, 1.57-2.33), and for patients treated with anti-TNF therapy alone (HR, 1.75; 95% CI, 1.37-2.22) or in combination with an immunomodulator (HR, 2.01; 95% CI, 1.57-2.58).

Conclusions: In an observational study, we found a genome-wide significant association between HLA-DQA1*05 and the development of antibodies against anti-TNF agents. A randomized controlled biomarker trial is required to determine whether pretreatment testing for HLA-DQA1*05 improves patient outcomes by helping physicians select anti-TNF and combination therapies. ClinicalTrials.gov ID: NCT03088449.

Keywords: Drug Persistence; GWAS; Loss Of Response; PANTS.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adalimumab / immunology*
  • Adalimumab / therapeutic use
  • Adult
  • Alleles
  • Crohn Disease / blood
  • Crohn Disease / therapy*
  • Female
  • Genome-Wide Association Study
  • HLA-DQ alpha-Chains / genetics*
  • Heterozygote
  • Humans
  • Infliximab / immunology*
  • Infliximab / therapeutic use
  • Male
  • Middle Aged
  • Patient Selection
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors*
  • Tumor Necrosis Factor-alpha / immunology
  • Young Adult


  • HLA-DQ alpha-Chains
  • HLA-DQA1 antigen
  • TNF protein, human
  • Tumor Necrosis Factor-alpha
  • Infliximab
  • Adalimumab

Associated data

  • ClinicalTrials.gov/NCT03088449