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

Autor:	Sazonovs A; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK., Kennedy NA; Department of Gastroenterology, Royal Devon and Exeter Hospital National Health Service Foundation Trust, Exeter, UK; Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, University of Exeter, Exeter, UK., Moutsianas L; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK., Heap GA; Department of Gastroenterology, Royal Devon and Exeter Hospital National Health Service Foundation Trust, Exeter, UK; AbbVie Inc, North Chicago, Illinois., Rice DL; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK., Reppell M; AbbVie Inc, North Chicago, Illinois., Bewshea CM; Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, University of Exeter, Exeter, UK., Chanchlani N; Department of Gastroenterology, Royal Devon and Exeter Hospital National Health Service Foundation Trust, Exeter, UK; Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, University of Exeter, Exeter, UK., Walker GJ; Department of Gastroenterology, Royal Devon and Exeter Hospital National Health Service Foundation Trust, Exeter, UK; Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, University of Exeter, Exeter, UK., Perry MH; Department of Blood Science, Royal Devon and Exeter Hospital National Health Service Foundation Trust, Exeter, UK., McDonald TJ; Department of Blood Science, Royal Devon and Exeter Hospital National Health Service Foundation Trust, Exeter, UK., Lees CW; Department of Gastroenterology, Western General Hospital, National Health Service Lothian, Edinburgh, UK., Cummings JRF; Department of Gastroenterology, University Hospital Southampton National Health Service Foundation Trust, Southampton, UK; Faculty of Experimental Medicine, University of Southampton, Southampton, UK., Parkes M; Department of Gastroenterology, Addenbrooke's Hospital, Cambridge University Hospitals National Health Service Foundation Trust, Cambridge, UK., Mansfield JC; Department of Gastroenterology, Newcastle Upon Tyne Hospitals National Health Service Foundation Trust, Newcastle upon Tyne, UK., Irving PM; Department of Gastroenterology, Guy's and St Thomas' NHS Foundation, Trust, London, UK., Barrett JC; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK., McGovern D; F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California., Goodhand JR; Department of Gastroenterology, Royal Devon and Exeter Hospital National Health Service Foundation Trust, Exeter, UK; Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, University of Exeter, Exeter, UK., Anderson CA; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK. Electronic address: carl.anderson@sanger.ac.uk., Ahmad T; Department of Gastroenterology, Royal Devon and Exeter Hospital National Health Service Foundation Trust, Exeter, UK; Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, University of Exeter, Exeter, UK. Electronic address: tariq.ahmad1@nhs.net.
Jazyk:	angličtina
Zdroj:	Gastroenterology [Gastroenterology] 2020 Jan; Vol. 158 (1), pp. 189-199. Date of Electronic Publication: 2019 Oct 07.
DOI:	10.1053/j.gastro.2019.09.041
Abstrakt:	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. (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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