Longitudinal multi-omics analysis identifies early blood-based predictors of anti-TNF therapy response in inflammatory bowel disease
Authors: Mishra Neha , Aden Konrad , Blase Johanna I. , Baran Nathan , Bordoni Dora , Tran Florian , Conrad Claudio , Avalos Diana , Jaeckel Charlot , Scherer Michael , Sørensen Signe B. , Overgaard Silja H. , Schulte Berenice , Nikolaus Susanna , Rey Guillaume , Gasparoni Gilles , Lyons Paul A. , Schultze Joachim L. , Walter Jörn , Andersen Vibeke ,   SYSCID Consortium, Banos Aggelos , Bertsias George , Beyer Marc , Boumpas Dimitrios , Finckh Axel , Franke Andre , Georges Michel , Gu Wei , Häsler Robert , Jawhara Mohamad , Kenyon Amy , Kratsch Christina , Krause Roland , Lauc Gordan , Mangino Massimo , Natoli Gioacchino , Ostaszewski Marek , Pezer Marija , Raes Jeroen , Rahmouni Souad , Ramos-Pamplona Marilou , Reiz Benedikt , Rosati Elisa , Sanoudou Despina , Satagopam Venkata , Schneider Reinhard , Schulte-Schrepping Jonas , Sidiropoulos Prodromos , Smith Kenneth G. C. , Spector Timothy , Vandeputte Doris , Vieira-Silva Sara , Vojta Aleksandar , Warnat-Herresthal Stefanie , Zoldoš Vlatka , Dermitzakis Emmanouil T. , Schreiber Stefan , Rosenstiel Philip 
Published: September 2022

Abstract
Background and aims
Treatment with tumor necrosis factor α (TNFα) antagonists in IBD patients suffers from primary non-response rates of up to 40%. Biomarkers for early prediction of therapy success are missing. We investigated the dynamics of gene expression and DNA methylation in blood samples of IBD patients treated with the TNF antagonist infliximab and analyzed the predictive potential regarding therapy outcome.

Methods
We performed a longitudinal, blood-based multi-omics study in two prospective IBD patient cohorts receiving first-time infliximab therapy (discovery: 14 patients, replication: 23 patients). Samples were collected at up to 7 time points (from baseline to 14 weeks after therapy induction). RNA-sequencing and genome-wide DNA methylation data were analyzed and correlated with clinical remission at week 14 as a primary endpoint.

Results
We found no consistent ex ante predictive signature across the two cohorts. Longitudinally upregulated transcripts in the non-remitter group comprised TH2- and eosinophil-related genes including ALOX15, FCER1A, and OLIG2. Network construction identified transcript modules that were coherently expressed at baseline and in non-remitting patients but were disrupted at early time points in remitting patients. These modules reflected processes such as interferon signaling, erythropoiesis, and platelet aggregation. DNA methylation analysis identified remission-specific temporal changes, which partially overlapped with transcriptomic signals. Machine learning approaches identified features from differentially expressed genes cis-linked to DNA methylation changes at week 2 as a robust predictor of therapy outcome at week 14, which was validated in a publicly available dataset of 20 infliximab-treated CD patients.

Conclusions
Integrative multi-omics analysis reveals early shifts of gene expression and DNA methylation as predictors for efficient response to anti-TNF treatment. Lack of such signatures might be used to identify patients with IBD unlikely to benefit from TNF antagonists at an early time point.