Baseline Expression of Immune Gene Modules in Blood is Associated With Primary Response to Anti-TNF Therapy in Crohn’s Disease Patients

Benjamin Y H Bai, Mark Reppell, Nizar Smaoui, Jeffrey F. Waring, Valerie Pivorunas, Heath Guay, Simeng Lin, Neil Chanchlani, Claire Bewshea, James R Goodhand, Nicholas A Kennedy, Tariq Ahmad, Carl A Anderson (Lead / Corresponding author), , Vinod Patel (Contributing member), Zia Mazhar (Contributing member), Rebecca Saich (Contributing member), Ben Colleypriest (Contributing member), Tony C Tham (Contributing member), Tariq H Iqbal (Contributing member)Vishal Kaushik (Contributing member), Senthil Murugesan (Contributing member), Salil Singhi (Contributing member), Sean Weaver (Contributing member), Cathryn Preston (Contributing member), Assad Butt (Contributing member), Melissa Smith (Contributing member), Dharamveer Basude (Contributing member), Amanda Beale (Contributing member), Sarah Langlands (Contributing member), Natalie Direkze (Contributing member), Miles Parkes (Contributing member), Franco Torrente (Contributing member), Juan De La Revella Negro (Contributing member), Chris Ewen MacDonald (Contributing member), Stephen M. Evans, Anton V.J. Gunasekera (Contributing member), Alka Thakur (Contributing member), David Elphick (Contributing member), Achuth Shenoy (Contributing member), Chuka U Nwokolo (Contributing member), Anjan Dhar (Contributing member), Andrew T Cole (Contributing member), Anurag Agrawal (Contributing member), Stephen Bridger (Contributing member), Julie Doherty (Contributing member), Sheldon C Cooper (Contributing member), Shanika de Silva (Contributing member), Craig Mowat, Phillip Mayhead (Contributing member), Charlie Lees (Contributing member)

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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.

Original languageEnglish
Pages (from-to)431-445
Number of pages15
JournalJournal of Crohn's and Colitis
Volume18
Issue number3
Early online date30 Sept 2023
DOIs
Publication statusPublished - Mar 2024

Keywords

  • Anti-TNF
  • Crohn’s disease
  • transcriptomic biomarkers

ASJC Scopus subject areas

  • General Medicine

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