作者
Aleksejs Sazonovs,Nicholas A. Kennedy,Loukas Moutsianas,Graham A. Heap,Rice Dl,Mark Reppell,Claire Bewshea,Neil Chanchlani,Gareth Walker,Mandy H Perry,Colin N.A. Palmer,Charlie W Lees,Fraser Cummings,Miles Parkes,John C. Mansfield,Peter Irving,Jeffrey C. Barrett,Dermot P. McGovern,James Goodhand,Carl A. Anderson,Tariq Ahmad,Vinod Patel,Zia Mazhar,Rebecca Saich,Ben Colleypriest,Tristan Tham,Tariq Iqbal,Vishal Kaushik,Senthil V. Murugesan,Salil Singh,Sean Weaver,Cathryn Preston,Assad Butt,Melissa A. Smith,Dharamveer Basude,Amanda Beale,Sarah Langlands,Natalie Direkze,Miles Parkes,Franco Torrente,Juan De La Revella Negro,Chris Ewen MacDonald,Stephen M. Evans,Anton V J Gunasekera,Alka Thakur,David Elphick,Achuth Shenoy,Chuka U. Nwokolo,Anjan Dhar,A.T. Cole,Anurag K. Agrawal,Stephen Bridger,Julie Doherty,Sheldon C. Cooper,Shanika de Silva,Craig Mowat,Phillip Mayhead,Charlie W. Lees,Gareth Jones,Tariq Ahmad,J. W. Hart,Daniel R. Gaya,Richard K. Russell,Lisa Gervais,Paul Dunckley,Tariq Mahmood,Paul Banim,Sunil Sonwalkar,Deb Ghosh,Rosemary Phillips,Amer Azaz,Shaji Sebastian,Richard Shenderey,Lawrence Armstrong,Catherine D. Bell,Radhakrishnan Hariraj,Helen Matthews,Hasnain Jafferbhoy,Christian P. Selinger,Vipin Zamvar,John S. de Caestecker,Anne Willmott,R. Drew Miller,Palani Sathish Babu,Christos Tzivinikos,Stuart Bloom,Guy Carrault,Nicholas M. Croft,John Fell,Marcus Harbord,Ailsa Hart,Ben Hope,Peter M. Irving,James O. Lindsay,Joel Mawdsley,Alistair McNair,Kevin Monahan,Charles Murray,Timothy R. Orchard,Thankam Paul,Richard Pollok,Neil Shah,Sonia Bouri,Matt Johnson,Anita Modi,Kasamu Dawa Kabiru,Bijay Baburajan,Bim Bhaduri,Andrew Fagbemi,Scott Levison,Jimmy K. Limdi,Gill Watts,Stephen Foley,Arvind Ramadas,George MacFaul,John C. Mansfield,Leonie Grellier,Mary-Anne Morris,Mark Tremelling,Chris J. Hawkey,Sian Kirkham,C. P. J. Charlton,Astor Rodrigues,Alison Simmons,Stephen J. Lewis,Jonathon Snook,Mark Tighe,Patrick Goggin,Aminda N. De Silva,Simon Lal,Mark Smith,Simon Panter,Fraser Cummings,Suranga Dharmisari,Martyn Carter,David Watts,Zahid Mahmood,B McLain,Sandip Sen,Anna Pigott,David Hobday,Emma Wesley,Richard L. Johnston,Cathryn Edwards,John Beckly,Deven Vani,Subramaniam Ramakrishnan,Rakesh Chaudhary,Nigel Trudgill,Rachel Cooney,A.J. Bell,Neeraj Prasad,J Gordon,Matthew Brookes,Andy Li,Stephen Gore
摘要
Background & AimsAnti–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.MethodsWe 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.ResultsThe 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).ConclusionsIn 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. 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. 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. 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). 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.