J Crohns Colitis. 2024 Mar 1;18(3):431-445.doi: 10.1093/ecco-jcc/jjad166.

Benjamin Y H Bai ^1 2, Mark Reppell ³, Nizar Smaoui ³, Jeffrey F Waring ³, Valerie Pivorunas ³, Heath Guay ³, Simeng Lin ^4 5, Neil Chanchlani ^4 5, Claire Bewshea ⁵, James R Goodhand ^4 5, Nicholas A Kennedy ^4 5, Tariq Ahmad ^4 5, Carl A Anderson ¹; UK Inflammatory Bowel Disease Pharmacogenetics Study Group

Collaborators

UK Inflammatory Bowel Disease Pharmacogenetics Study Group: 

Vinod Patel, Zia Mazhar, Rebecca Saich, Ben Colleypriest, Tony C Tham, Tariq H Iqbal, Vishal Kaushik, Senthil Murugesan, Salil Singhi, 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 M E 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 P J 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

Author information

¹Genomics of Inflammation and Immunity Group, Wellcome Sanger Institute, Hinxton, UK.

²Postgraduate School of Life Sciences, University of Cambridge, Cambridge, UK.

³AbbVie Inc., Chicago, IL, USA.

⁴Department of Gastroenterology, Royal Devon University Healthcare NHS Foundation Trust, Exeter, UK.

⁵Exeter Inflammatory Bowel Disease and Pharmacogenetics Research Group, University of Exeter, Exeter, UK.

Abstract

Background and aims: Anti-tumour necrosis factor [anti-TNF] therapy is widely used for the treatment of inflammatory bowel disease, yet many patients are primary non-responders, failing to respond to induction therapy. We aimed to identify blood gene expression differences between primary responders and primary non-responders to anti-TNF monoclonal antibodies [infliximab and adalimumab], and to predict response status from blood gene expression and clinical data.

Methods: The Personalised Anti-TNF Therapy in Crohn's Disease [PANTS] study is a UK-wide prospective observational cohort study of anti-TNF therapy outcome in anti-TNF-naive Crohn's disease patients [ClinicalTrials.gov identifier: NCT03088449]. Blood gene expression in 324 unique patients was measured by RNA-sequencing at baseline [week 0], and at weeks 14, 30, and 54 after treatment initiation [total sample size = 814].

Results: After adjusting for clinical covariates and estimated blood cell composition, baseline expression of major histocompatibility complex, antigen presentation, myeloid cell enriched receptor, and other innate immune gene modules was significantly higher in anti-TNF responders vs non-responders. Expression changes from baseline to week 14 were generally of consistent direction but greater magnitude [i.e. amplified] in responders, but interferon-related genes were upregulated uniquely in non-responders. Expression differences between responders and non-responders observed at week 14 were maintained at weeks 30 and 54. Prediction of response status from baseline clinical data, cell composition, and module expression was poor.

Conclusions: Baseline gene module expression was associated with primary response to anti-TNF therapy in PANTS patients. However, these baseline expression differences did not predict response with sufficient sensitivity for clinical use.