TY - JOUR
T1 - HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn's Disease
AU - Sazonovs, Aleksejs
AU - Kennedy, Nicholas A.
AU - Moutsianas, Loukas
AU - Heap, Graham A.
AU - Rice, Daniel L.
AU - Reppell, Mark
AU - Bewshea, Claire M.
AU - Chanchlani, Neil
AU - Walker, Gareth J.
AU - Perry, Mandy H.
AU - McDonald, Timothy J.
AU - Lees, Charlie W.
AU - Cummings, J. R.Fraser
AU - Parkes, Miles
AU - Mansfield, John C.
AU - Irving, Peter M.
AU - Barrett, Jeffrey C.
AU - McGovern, Dermot
AU - Goodhand, James R.
AU - Anderson, Carl A.
AU - Ahmad, Tariq
AU - PANTS Consortium
AU - Patel, Vinod
AU - Mazhar, Zia
AU - Saich, Rebecca
AU - Colleypriest, Ben
AU - Tham, Tony C.
AU - Iqbal, Tariq H.
AU - Kaushik, Vishal
AU - Murugesan, Senthil
AU - Singh, Salil
AU - Weaver, Sean
AU - Preston, Cathryn
AU - Butt, Assad
AU - Smith, Melissa
AU - Basude, Dharamveer
AU - Beale, Amanda
AU - Langlands, Sarah
AU - Direkze, Natalie
AU - Torrente, Franco
AU - De La Revella Negro, Juan
AU - Ewen MacDonald, Chris
AU - Evans, Stephen M.
AU - Gunasekera, Anton V.J.
AU - Thakur, Alka
AU - Elphick, David
AU - Shenoy, Achuth
AU - Nwokolo, Chuka U.
AU - Dhar, Anjan
AU - Cole, Andrew T.
AU - Mowat, Craig
N1 - Publisher Copyright:
© 2020 AGA Institute
PY - 2020/1/1
Y1 - 2020/1/1
N2 - 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.
AB - 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.
KW - Drug Persistence
KW - GWAS
KW - Loss Of Response
KW - PANTS
UR - http://www.scopus.com/inward/record.url?scp=85076249485&partnerID=8YFLogxK
U2 - 10.1053/j.gastro.2019.09.041
DO - 10.1053/j.gastro.2019.09.041
M3 - Article
C2 - 31600487
AN - SCOPUS:85076249485
SN - 0016-5085
VL - 158
SP - 189
EP - 199
JO - Gastroenterology
JF - Gastroenterology
IS - 1
ER -