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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
Open accessAbstract
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.
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Self-citationInfliximab, Azathioprine, or Combination Therapy for Crohn's Disease
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Cited by
Dolinger, M., Torres, J., & Vermeire, S. (2024) · The Lancet · doi:10.1016/s0140-6736(23)02586-2 · Cited by 580
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Antidrug antibodies to tumor necrosis factor α inhibitors in patients with noninfectious uveitis
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Metadata
- Authors
- Sazonovs, A., Kennedy, N. A., Moutsianas, L., Heap, G. A., Rice, D. L., Reppell, M., Bewshea, C. M., Chanchlani, N., Walker, G. J., Perry, M. H., McDonald, T. J., Lees, C. W., Cummings, J. R. F., Parkes, M., Mansfield, J. C., Irving, P. M., Barrett, J. C., McGovern, D., Goodhand, J. R., Anderson, C. A., Ahmad, T., Patel, V., Mazhar, Z., Saich, R., Colleypriest, B., Tham, T. C., Iqbal, T. H., Kaushik, V., Murugesan, S., Singh, S., Weaver, S., Preston, C., Butt, A., Smith, M., Basude, D., Beale, A., Langlands, S., Direkze, N., Parkes, M., Torrente, F., De La Revella Negro, J., Ewen MacDonald, C., Evans, S. M., Gunasekera, A. V. J., Thakur, A., Elphick, D., Shenoy, A., Nwokolo, C. U., Dhar, A., Cole, A. T., Agrawal, A., Bridger, S., Doherty, J., Cooper, S. C., de Silva, S., Mowat, C., Mayhead, P., Lees, C., Jones, G., Ahmad, T., Hart, J. W., Gaya, D. R., Russell, R. K., Gervais, L., Dunckley, P., Mahmood, T., Banim, P. J. R., Sonwalkar, S., Ghosh, D., Phillips, R. H., Azaz, A., Sebastian, S., Shenderey, R., Armstrong, L., Bell, C., Hariraj, R., Matthews, H., Jafferbhoy, H., Selinger, C. P., Zamvar, V., De Caestecker, J. S., Willmott, A., Miller, R., Sathish Babu, P., Tzivinikos, C., Bloom, S. L., Chung-Faye, G., Croft, N. M., Fell, J. M., Harbord, M., Hart, A., Hope, B., Irving, P. M., Lindsay, J. O., Mawdsley, J. E., McNair, A., Monahan, K. J., Murray, C. D., Orchard, T., Paul, T., Pollok, R., Shah, N., Bouri, S., Johnson, M. W., Modi, A., Dawa Kabiru, K., Baburajan, B. K., Bhaduri, B., Adebayo Fagbemi, A., Levison, S., Limdi, J. K., Watts, G., Foley, S., Ramadas, A., MacFaul, G., Mansfield, J., Grellier, L., Morris, M.-A., Tremelling, M., Hawkey, C., Kirkham, S., Charlton, C. P., Rodrigues, A., Simmons, A., Lewis, S. J., Snook, J., Tighe, M., Goggin, P. M., De Silva, A. N., Lal, S., Smith, M. S., Panter, S., Cummings, F., Dharmisari, S., Carter, M., Watts, D., Mahmood, Z., McLain, B., Sen, S., Pigott, A. J., Hobday, D., Wesley, E., Johnston, R., Edwards, C., Beckly, J., Vani, D., Ramakrishnan, S., Chaudhary, R., Trudgill, N. J., Cooney, R., Bell, A., Prasad, N., Gordon, J. N., Brookes, M. J., Li, A., & Gore, S.
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2020-01
- Volume
- 158
- Issue
- 1
- Pages
- 189-199
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2978880955
- Cited by
- 423
- References
- 35
- FWCI
- 26.95
- Type
- journal article
- Language
- en
- Open access
- hybrid
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- Sazonovs, A., Kennedy, N. A., Moutsianas, L., Heap, G. A., Rice, D. L., Reppell, M., Bewshea, C. M., Chanchlani, N., Walker, G. J., Perry, M. H., McDonald, T. J., Lees, C. W., Cummings, J. R. F., Parkes, M., Mansfield, J. C., Irving, P. M., Barrett, J. C., McGovern, D., Goodhand, J. R., . . . Gore, S. (2020). HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn’s Disease. Gastroenterology. https://doi.org/10.1053/j.gastro.2019.09.041
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