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

Sazonovs, A; Kennedy, NA; Moutsianas, L; Heap, GA; Rice, DL; Reppell, M; Bewshea, CM; Chanchlani, N; Walker, GJ; Perry, MH; et al. Sazonovs, A; Kennedy, NA; Moutsianas, L; Heap, GA; Rice, DL; Reppell, M; Bewshea, CM; Chanchlani, N; Walker, GJ; Perry, MH; McDonald, TJ; Lees, CW; Cummings, JRF; Parkes, M; Mansfield, JC; Irving, PM; Barrett, JC; McGovern, D; Goodhand, JR; Anderson, CA; Ahmad, T; PANTS Consortium (2020) HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn's Disease. Gastroenterology, 158 (1). pp. 189-199. ISSN 1528-0012 https://doi.org/10.1053/j.gastro.2019.09.041
SGUL Authors: Pollok, Richard Charles G

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Abstract

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.

Item Type: Article
Additional Information: © 2020 by the AGA Institute. Published by Elsevier Inc. This is an openaccess article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Keywords: Drug Persistence, GWAS, Loss Of Response, PANTS, PANTS Consortium, PANTS, GWAS, Loss Of Response, Drug Persistence, 1103 Clinical Sciences, 1114 Paediatrics and Reproductive Medicine, 1109 Neurosciences, Gastroenterology & Hepatology
SGUL Research Institute / Research Centre: Academic Structure > Infection and Immunity Research Institute (INII)
Journal or Publication Title: Gastroenterology
ISSN: 1528-0012
Language: eng
Dates:
DateEvent
January 2020Published
7 October 2019Published Online
29 September 2019Accepted
Publisher License: Creative Commons: Attribution-Noncommercial-No Derivative Works 4.0
Projects:
Project IDFunderFunder ID
UNSPECIFIEDDepartment of HealthUNSPECIFIED
PubMed ID: 31600487
Web of Science ID: WOS:000502549500038
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/111605
Publisher's version: https://doi.org/10.1053/j.gastro.2019.09.041

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