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Original article
Cell-centred meta-analysis reveals baseline predictors of anti-TNFα non-response in biopsy and blood of patients with IBD
  1. Renaud Gaujoux1,2,
  2. Elina Starosvetsky1,
  3. Naama Maimon1,3,
  4. Francesco Vallania4,5,
  5. Haggai Bar-Yoseph3,
  6. Sigal Pressman3,
  7. Roni Weisshof3,
  8. Idan Goren6,7,
  9. Keren Rabinowitz7,8,
  10. Matti Waterman3,
  11. Henit Yanai6,7,8,
  12. Iris Dotan6,7,8,
  13. Edmond Sabo9,
  14. Yehuda Chowers1,3,
  15. Purvesh Khatri4,5,
  16. Shai S Shen-Orr1
  17. on behalf of the Israeli IBD research Network (IIRN)
  1. 1 Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
  2. 2 CytoReason
  3. 3 Department of Gastroenterology, Rambam Health Care Campus, Haifa, Israel
  4. 4 Division of Biomedical Informatics Research, Department of Medicine, Stanford University, Palo Alto, California, USA
  5. 5 Stanford Institute for Immunity Transplantation and Infection, Department of Medicine, Stanford University, Palo Alto, California, USA
  6. 6 Department of Gastroenterology and Liver Diseases, IBD Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
  7. 7 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
  8. 8 Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel
  9. 9 Department of Pathology, Rambam Health Care Campus, Haifa, Israel
  1. Correspondence to Yehuda Chowers, Division of Gastroenterology, Rambam Health Care Campus, Haifa, Israel; y_chowers{at}rambam.health.gov.il, Purvesh Khatri, Department of Medicine, Stanford University, Palo Alto, California, USA; pkhatri{at}stanford.edu and Shai S Shen-Orr, Faculty of Medicine, Technion, Haifa 32000, Israel; shenorr{at}technion.ac.il

Abstract

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.

  • Ibd
  • meta-analysis
  • gene expression
  • infliximab
  • tnf-alpha

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

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Footnotes

  • RG, ES and NM contributed equally.

  • YC, PK and SSS-O contributed equally.

  • Contributors RG, FV, ESt, NM,SP, PK, YC and SSS-O designed the research; RG, ESt, NM, FV and ESa analysed the data; ESt, NM, ESa and SP performed the experiments; HB-Y, SP, RW, IG, MW,KR, HY, ID, ESa and YC contributed to clinical part; RG, ESt, NM, FV, PK, YC and SSS-O wrote the manuscript.

  • Funding This work was supported by funding of the Helmsley Charitable Trust to YC, SSS-O and ID. PK is funded by the NIH’NIAID (grants U19AI109662, U 19AI057229, and U54I117925) and the Bill and Melinda Gates Foundation. FV by NIH K12 fellowship #5K12HL120001-02, RG was funded by the Lady Davis postdoctoral fellowship and by NIH’NIAID U19AI090019.

  • Competing interests YC declares Abbvie grant support, advisory and lecture fees, Janssen advisory and lecture fees, Takeda grant support and advisory and lecture fees, Pfizer advisory and lecture fees and Protalix Advisory fees. RG and ESt declares CytoReason equity and advisory fees. RG declares equity in CytoReason. SSO-O declares CytoReason equity and advisory fees and Takeda grant support.

  • Patient consent Obtained.

  • Ethics approval RAMBAM hospital IRB, Ichilov hospital IRB.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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