RT Journal Article SR Electronic T1 Cell-centred meta-analysis reveals baseline predictors of anti-TNFα non-response in biopsy and blood of patients with IBD JF Gut JO Gut FD BMJ Publishing Group Ltd and British Society of Gastroenterology SP 604 OP 614 DO 10.1136/gutjnl-2017-315494 VO 68 IS 4 A1 Renaud Gaujoux A1 Elina Starosvetsky A1 Naama Maimon A1 Francesco Vallania A1 Haggai Bar-Yoseph A1 Sigal Pressman A1 Roni Weisshof A1 Idan Goren A1 Keren Rabinowitz A1 Matti Waterman A1 Henit Yanai A1 Iris Dotan A1 Edmond Sabo A1 Yehuda Chowers A1 Purvesh Khatri A1 Shai S Shen-Orr A1 , YR 2019 UL http://gut.bmj.com/content/68/4/604.abstract AB Objective Although anti-tumour necrosis factor alpha (anti-TNFα) therapies represent a major breakthrough in IBD therapy, their cost–benefit ratio is hampered by an overall 30% non-response rate, adverse side effects and high costs. Thus, finding predictive biomarkers of non-response prior to commencing anti-TNFα therapy is of high value.Design We analysed publicly available whole-genome expression profiles of colon biopsies obtained from multiple cohorts of patients with IBD using a combined computational deconvolution—meta-analysis paradigm which allows to estimate immune cell contribution to the measured expression and capture differential regulatory programmes otherwise masked due to variation in cellular composition. Insights from this in silico approach were experimentally validated in biopsies and blood samples of three independent test cohorts.Results We found the proportion of plasma cells as a robust pretreatment biomarker of non-response to therapy, which we validated in two independent cohorts of immune-stained colon biopsies, where a plasma cellular score from inflamed biopsies was predictive of non-response with an area under the curve (AUC) of 82%. Meta-analysis of the cell proportion-adjusted gene expression data suggested that an increase in inflammatory macrophages in anti-TNFα non-responding individuals is associated with the upregulation of the triggering receptor expressed on myeloid cells 1 (TREM-1) and chemokine receptor type 2 (CCR2)-chemokine ligand 7 (CCL7) –axes. Blood gene expression analysis of an independent cohort, identified TREM-1 downregulation in non-responders at baseline, which was predictive of response with an AUC of 94%.Conclusions Our study proposes two clinically feasible assays, one in biopsy and one in blood, for predicting non-response to anti-TNFα therapy prior to initiation of treatment. Moreover, it suggests that mechanism-driven novel drugs for non-responders should be developed.