Baseline Expression of Immune Gene Modules in Blood is Associated With Primary Response to Anti-TNF Therapy in Crohn’s Disease Patients
Authors: Bai Benjamin Y H , Reppell Mark , Smaoui Nizar , Waring Jeffrey F , Pivorunas Valerie , Guay Heath , Lin Simeng , Chanchlani Neil , Bewshea Claire , Goodhand James R , Kennedy Nicholas A , Ahmad Tariq , Anderson Carl A ,   UK Inflammatory Bowel Disease Pharmacogenetics Study Group, Patel Vinod , Mazhar Zia , Saich Rebecca , Colleypriest Ben , Tham Tony C , Iqbal Tariq H , Kaushik Vishal , Murugesan Senthil , Singhi Salil , Weaver Sean , Preston Cathryn , Butt Assad , Smith Melissa , Basude Dharamveer , Beale Amanda , Langlands Sarah , Direkze Natalie , Parkes Miles , Torrente Franco , De La Revella Negro Juan , MacDonald Chris Ewen , Evans Stephen M , Gunasekera Anton V J , Thakur Alka , Elphick David , Shenoy Achuth , Nwokolo Chuka U , Dhar Anjan , Cole Andrew T , Agrawal Anurag , Bridger Stephen , Doherty Julie , Cooper Sheldon C , de Silva Shanika , Mowat Craig , Mayhead Phillip , Lees Charlie , Jones Gareth , Ahmad Tariq , Hart James W , Gaya Daniel R , Russell Richard K , Gervais Lisa , Dunckley Paul , Mahmood Tariq , Banim Paul J R , Sonwalkar Sunil , Ghosh Deb , Phillips Rosemary H , Azaz Amer , Sebastian Shaji , Shenderey Richard , Armstrong Lawrence , Bell Claire , Hariraj Radhakrishnan , Matthews Helen , Jafferbhoy Hasnain , Selinger Christian P , Zamvar Veena , De Caestecker John S , Willmott Anne , Miller Richard , Babu Palani Sathish , Tzivinikos Christos , Bloom Stuart L , Chung-Faye Guy , Croft Nicholas M , Fell John M E , Harbord Marcus , Hart Ailsa , Hope Ben , Irving Peter M , Lindsay James O , Mawdsley Joel E , McNair Alistair , Monahan Kevin J , Murray Charles D , Orchard Timothy , Paul Thankam , Pollok Richard , Shah Neil , Bouri Sonia , Johnson Matt W , Modi Anita , Kabiru Kasamu Dawa , Baburajan B K , Bhaduri Bim , Fagbemi Andrew Adebayo , Levison Scott , Limdi Jimmy K , Watts Gill , Foley Stephen , Ramadas Arvind , MacFaul George , Mansfield John , Grellier Leonie , Morris Mary-Anne , Tremelling Mark , Hawkey Chris , Kirkham Sian , Charlton Charles P J , Rodrigues Astor , Simmons Alison , Lewis Stephen J , Snook Jonathon , Tighe Mark , Goggin Patrick M , De Silva Aminda N , Lal Simon , Smith Mark S , Panter Simon , Cummings Fraser , Dharmisari Suranga , Carter Martyn , Watts David , Mahmood Zahid , McLain Bruce , Sen Sandip , Pigott Anna J , Hobday David , Wesley Emma , Johnston Richard , Edwards Cathryn , Beckly John , Vani Deven , Ramakrishnan Subramaniam , Chaudhary Rakesh , Trudgill Nigel J , Cooney Rachel , Bell Andy , Prasad Neeraj , Gordon John N , Brookes Matthew J , Li Andy , Gore Stephen 
Published: September 2023

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.