Ahmad T

Anderson CA

Barrett JC

Bewshea CM

Chanchlani N

Cummings JRF

Goodhand JR

Heap GA

Irving PM

Kennedy NA

Lees CW

Mansfield JC

McDonald TJ

McGovern D

Moutsianas L

PANTS Consortium

Parkes M

Perry MH

Reppell M

Rice DL

Sazonovs A

Walker GJ

\ua9 2020 AGA Institute. Background &amp; 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-na\uefve patients with Crohn\u27s 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 
7 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 
7 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

Newcastle University E-Prints

HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn\u27s Disease

https://eprint.ncl.ac.uk/fulltext.aspx?url=262473/AE384E8E-FD3E-4C7C-8A04-C44295E0713C.pdf&pub_id=262473

HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn\u27s Disease

Abstract

Similar works

Full text

Available Versions

Newcastle University E-Prints