HLA-DQA1*05 is associated with the development of antibodies to anti-TNF therapy

Sazonovs, A.; Kennedy, N.; Moutsianas, L.; Heap, G. A.; Rice, D. L.; Reppell, M.; Bewshea, C.; Walker, G.; Perry, M.; McDonald, T. J.; Lees, C.; Cummings, F.; Parkes, M.; Mansfield, J.; Barrett, J. C.; McGovern, D.; Goodhand, J.; Anderson, C. A.; Ahmad, T.; PANTS consortium,

doi:10.1101/410035

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bioRxiv · 10.1101/410035

HLA-DQA1*05 is associated with the development of antibodies to anti-TNF therapy

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Abstract

BackgroundAnti-tumour necrosis factor (anti-TNF) therapies are the most widely used biologic therapies for treating immune-mediated diseases. Their efficacy is significantly reduced by the development of anti-drug antibodies which can lead to treatment failure and adverse reactions. The biological mechanisms underlying antibody development are unknown but the ability to identify subjects at higher risk would have significant clinical benefits.\n\nMethodsThe PANTS cohort consists of Crohns disease patients recruited prior to first administration of anti-TNF, with serial measurements of anti-drug antibody titres. We performed a genome-wide association study across 1240 individuals from this cohort to identify genetic variants associated with anti-drug antibody development.\n\nFindingsThe Human Leukocyte Antigen allele, HLA-DQA1*05, carried by approximately 40% of Europeans, significantly increased the rate of anti-drug antibody development (hazard ratio [HR], 1.90; 95% confidence interval [CI], 1.60 to 2.25; P=5.88x10-13). This association was consistent for patients treated with adalimumab (HR, 1.89; 95% CI, 1.32 to 2.70) and infliximab (HR, 1.92; 95% CI, 1.57 to 2.33), and for patients treated with mono-(HR, 1.75; 95% CI, 1.37 to 2.22) or combination therapy with immunomodulators (HR, 2.0; 95% CI, 1.57 to 2.58).\n\nInterpretationHLA-DQA1*05 is significantly associated with an increased rate of anti-drug antibody formation in patients with Crohns disease treated with infliximab and adalimumab. Pre-treatment HLA-DQA1*05 genetic testing may help personalise the choice of anti-TNF therapy and allow the targeted use of immunomodulator therapy to minimise risk and maximise response.

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Sazonovs, A., Kennedy, N., Moutsianas, L., Heap, G. A., Rice, D. L., Reppell, M., Bewshea, C., Walker, G., Perry, M., McDonald, T. J., Lees, C., Cummings, F., Parkes, M., Mansfield, J., Barrett, J. C., McGovern, D., Goodhand, J., Anderson, C. A., Ahmad, T., PANTS consortium,. 2018-09-09. HLA-DQA1*05 is associated with the development of antibodies to anti-TNF therapy. https://doi.org/10.1101/410035

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