HLA-DQA1*05 Carriage Associated With Development of Anti-Drug Antibodies to Infliximab and Adalimumab in Patients With Crohn's Disease
Aleksejs Sazonovs, Nicholas A Kennedy, Loukas Moutsianas, Graham A Heap, Daniel L Rice, Mark Reppell, Claire M Bewshea, Neil Chanchlani, Gareth J Walker, Mandy H Perry, Timothy J McDonald, Charlie W Lees, J R Fraser Cummings, Miles Parkes, John C Mansfield, Peter M Irving, Jeffrey C Barrett, Dermot McGovern, James R Goodhand, Carl A Anderson, Tariq Ahmad, PANTS Consortium, Vinod Patel, Zia Mazhar, Rebecca Saich, Ben Colleypriest, Tony C Tham, Tariq H Iqbal, Vishal Kaushik, Senthil Murugesan, Salil Singh, Sean Weaver, Cathryn Preston, Assad Butt, Melissa 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, Andrew T Cole, Anurag Agrawal, Stephen Bridger, Julie Doherty, Sheldon C Cooper, Shanika de Silva, Craig Mowat, Phillip Mayhead, Charlie Lees, Gareth Jones, Tariq Ahmad, James W Hart, Daniel R Gaya, Richard K Russell, Lisa Gervais, Paul Dunckley, Tariq Mahmood, Paul J R Banim, Sunil Sonwalkar, Deb Ghosh, Rosemary H Phillips, Amer Azaz, Shaji Sebastian, Richard Shenderey, Lawrence Armstrong, Claire Bell, Radhakrishnan Hariraj, Helen Matthews, Hasnain Jafferbhoy, Christian P Selinger, Veena Zamvar, John S De Caestecker, Anne Willmott, Richard Miller, Palani Sathish Babu, Christos Tzivinikos, Stuart L Bloom, Guy Chung-Faye, Nicholas M Croft, John Me Fell, Marcus Harbord, Ailsa Hart, Ben Hope, Peter M Irving, James O Lindsay, Joel E Mawdsley, Alistair McNair, Kevin J Monahan, Charles D Murray, Timothy Orchard, Thankam Paul, Richard Pollok, Neil Shah, Sonia Bouri, Matt W Johnson, Anita Modi, Kasamu Dawa Kabiru, B K Baburajan, Bim Bhaduri, Andrew Adebayo Fagbemi, Scott Levison, Jimmy K Limdi, Gill Watts, Stephen Foley, Arvind Ramadas, George MacFaul, John Mansfield, Leonie Grellier, Mary-Anne Morris, Mark Tremelling, Chris Hawkey, Sian Kirkham, Charles Pj Charlton, Astor Rodrigues, Alison Simmons, Stephen J Lewis, Jonathon Snook, Mark Tighe, Patrick M Goggin, Aminda N De Silva, Simon Lal, Mark S Smith, Simon Panter, Fraser Cummings, Suranga Dharmisari, Martyn Carter, David Watts, Zahid Mahmood, Bruce McLain, Sandip Sen, Anna J Pigott, David Hobday, Emma Wesley, Richard Johnston, Cathryn Edwards, John Beckly, Deven Vani, Subramaniam Ramakrishnan, Rakesh Chaudhary, Nigel J Trudgill, Rachel Cooney, Andy Bell, Neeraj Prasad, John N Gordon, Matthew J Brookes, Andy Li, Stephen Gore, Aleksejs Sazonovs, Nicholas A Kennedy, Loukas Moutsianas, Graham A Heap, Daniel L Rice, Mark Reppell, Claire M Bewshea, Neil Chanchlani, Gareth J Walker, Mandy H Perry, Timothy J McDonald, Charlie W Lees, J R Fraser Cummings, Miles Parkes, John C Mansfield, Peter M Irving, Jeffrey C Barrett, Dermot McGovern, James R Goodhand, Carl A Anderson, Tariq Ahmad, PANTS Consortium, Vinod Patel, Zia Mazhar, Rebecca Saich, Ben Colleypriest, Tony C Tham, Tariq H Iqbal, Vishal Kaushik, Senthil Murugesan, Salil Singh, Sean Weaver, Cathryn Preston, Assad Butt, Melissa 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, Andrew T Cole, Anurag Agrawal, Stephen Bridger, Julie Doherty, Sheldon C Cooper, Shanika de Silva, Craig Mowat, Phillip Mayhead, Charlie Lees, Gareth Jones, Tariq Ahmad, James W Hart, Daniel R Gaya, Richard K Russell, Lisa Gervais, Paul Dunckley, Tariq Mahmood, Paul J R Banim, Sunil Sonwalkar, Deb Ghosh, Rosemary H Phillips, Amer Azaz, Shaji Sebastian, Richard Shenderey, Lawrence Armstrong, Claire Bell, Radhakrishnan Hariraj, Helen Matthews, Hasnain Jafferbhoy, Christian P Selinger, Veena Zamvar, John S De Caestecker, Anne Willmott, Richard Miller, Palani Sathish Babu, Christos Tzivinikos, Stuart L Bloom, Guy Chung-Faye, Nicholas M Croft, John Me Fell, Marcus Harbord, Ailsa Hart, Ben Hope, Peter M Irving, James O Lindsay, Joel E Mawdsley, Alistair McNair, Kevin J Monahan, Charles D Murray, Timothy Orchard, Thankam Paul, Richard Pollok, Neil Shah, Sonia Bouri, Matt W Johnson, Anita Modi, Kasamu Dawa Kabiru, B K Baburajan, Bim Bhaduri, Andrew Adebayo Fagbemi, Scott Levison, Jimmy K Limdi, Gill Watts, Stephen Foley, Arvind Ramadas, George MacFaul, John Mansfield, Leonie Grellier, Mary-Anne Morris, Mark Tremelling, Chris Hawkey, Sian Kirkham, Charles Pj Charlton, Astor Rodrigues, Alison Simmons, Stephen J Lewis, Jonathon Snook, Mark Tighe, Patrick M Goggin, Aminda N De Silva, Simon Lal, Mark S Smith, Simon Panter, Fraser Cummings, Suranga Dharmisari, Martyn Carter, David Watts, Zahid Mahmood, Bruce McLain, Sandip Sen, Anna J Pigott, David Hobday, Emma Wesley, Richard Johnston, Cathryn Edwards, John Beckly, Deven Vani, Subramaniam Ramakrishnan, Rakesh Chaudhary, Nigel J Trudgill, Rachel Cooney, Andy Bell, Neeraj Prasad, John N Gordon, Matthew J Brookes, Andy Li, Stephen Gore
Abstract
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.
Keywords: Drug Persistence; GWAS; Loss Of Response; PANTS.
Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.
Source: PubMed