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Original research
Biopsy and blood-based molecular biomarker of inflammation in IBD
  1. Carmen Argmann1,
  2. Ruixue Hou2,
  3. Ryan C Ungaro3,
  4. Haritz Irizar1,
  5. Zainab Al-Taie1,2,
  6. Ruiqi Huang2,
  7. Roman Kosoy1,
  8. Swati Venkat4,
  9. Won-Min Song1,
  10. Antonio F Di'Narzo1,5,
  11. Bojan Losic1,
  12. Ke Hao1,5,
  13. Lauren Peters1,
  14. Phillip H Comella1,
  15. Gabrielle Wei1,
  16. Ashish Atreja3,
  17. Milind Mahajan1,5,
  18. Alina Iuga6,
  19. Prerak T Desai4,
  20. Patrick Branigan4,
  21. Aleksandar Stojmirovic4,
  22. Jacqueline Perrigoue4,
  23. Carrie Brodmerkel4,
  24. Mark Curran4,
  25. Joshua R Friedman4,
  26. Amy Hart4,
  27. Esi Lamousé-Smith4,
  28. Jan Wehkamp4,
  29. Saurabh Mehandru3,
  30. Eric E Schadt1,5,
  31. Bruce E Sands3,
  32. Marla C Dubinsky3,
  33. Jean-Frederic Colombel3,
  34. Andrew Kasarskis1,5,
  35. Mayte Suárez-Fariñas1,2
  1. 1Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA
  2. 2Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, New York, USA
  3. 3The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
  4. 4Janssen R&D, Spring House, Pennsylvania, USA
  5. 5Sema4, Stamford, Connecticut, USA
  6. 6Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  1. Correspondence to Dr Carmen Argmann, Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA; carmen.argmann{at}mssm.edu; Dr Mayte Suárez-Fariñas; mayte.suarezfarinas{at}mssm.edu

Abstract

Objective IBD therapies and treatments are evolving to deeper levels of remission. Molecular measures of disease may augment current endpoints including the potential for less invasive assessments.

Design Transcriptome analysis on 712 endoscopically defined inflamed (Inf) and 1778 non-inflamed (Non-Inf) intestinal biopsies (n=498 Crohn’s disease, n=421 UC and 243 controls) in the Mount Sinai Crohn’s and Colitis Registry were used to identify genes differentially expressed between Inf and Non-Inf biopsies and to generate a molecular inflammation score (bMIS) via gene set variance analysis. A circulating MIS (cirMIS) score, reflecting intestinal molecular inflammation, was generated using blood transcriptome data. bMIS/cirMIS was validated as indicators of intestinal inflammation in four independent IBD cohorts.

Results bMIS/cirMIS was strongly associated with clinical, endoscopic and histological disease activity indices. Patients with the same histologic score of inflammation had variable bMIS scores, indicating that bMIS describes a deeper range of inflammation. In available clinical trial data sets, both scores were responsive to IBD treatment. Despite similar baseline endoscopic and histologic activity, UC patients with lower baseline bMIS levels were more likely treatment responders compared with those with higher levels. Finally, among patients with UC in endoscopic and histologic remission, those with lower bMIS levels were less likely to have a disease flare over time.

Conclusion Transcriptionally based scores provide an alternative objective and deeper quantification of intestinal inflammation, which could augment current clinical assessments used for disease monitoring and have potential for predicting therapeutic response and patients at higher risk of disease flares.

  • IBD
  • MOLECULAR PATHOLOGY
  • MOLECULAR MECHANISMS
  • STATISTICS
  • IBD CLINICAL

Data availability statement

Data are available in a public, open access repository. Data are available upon reasonable request. RNA-seq and meta-data are available on GEO under the follwing accession numbers GSE186507, GSE193677, GSE206285, GSE207465.

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Data availability statement

Data are available in a public, open access repository. Data are available upon reasonable request. RNA-seq and meta-data are available on GEO under the follwing accession numbers GSE186507, GSE193677, GSE206285, GSE207465.

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Footnotes

  • CA and RH are joint first authors.

  • MCD, J-FC, AK and MS-F are joint senior authors.

  • Contributors RHo ZA-T and RHu performed statistical analysis for most of the paper with additional analysis by SV, CA and MS-F. Data generation or preparation was performed by HI, RK, AFDN, BL, KH, MM, AA, AI, GW, WS, LP, PHC and AS. RHo and HI were responsible for preprocessing, QC of RNA-seq data as well as depositing into the public repository. CA and MS-F interpreted results, wrote the manuscript and supervised analysis. RU, AA, SM, MD, BS, SM and J-FC provided patient samples and intellectual input. CA, ES, MC, CB, JP, AS, JRF, AH, AK, MC, J-FC and MS-F were involved in the study concept and design. All authors critically revised the manuscript. J-FC, AK, MS-F share senior co-authorships. CA, RHo, RU and HI share first co-authorships. MS-F and CA are guarantors of this study and accept responsibility for the overall content.

  • Funding This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. All sample processing was provided by Human Immune Monitoring Center at Icahn School of Medicine at Mount Sinai. The sampling of the Inflammatory Bowel Disease cohort was jointly designed as part of the research alliance between Janssen Biotech, Inc. and The Icahn School of Medicine at Mount Sinai. Beyond this exception, no other funders had a role in analysis design and interpretation.

  • Competing interests Mount Sinai co-authors (from Genetics and Genomics, Icahn Institute for Data Science and Genomic Technology, Population Health Science and Policy, Division of Gastroenterology, Pediatric GI and Hepatology, Susan and Leonard Feinstein IBD Clinical Center at Icahn School of Medicine at Mount Sinai) were partially funded as part of research alliance between Janssen Biotech and The Icahn School of Medicine at Mount Sinai. SV, PTD, PB, AS, JP, CB, MC, EL-S and JW are employees at Janssen Biotech, Inc. Joshua R. Friedman is a former employee at Janssen Biotech, Inc. KH, MM, AK, AD and ES are employees at Sema4. BS, J-FC and MCD are consultants for Janssen. MCD is an advisory board member of Janssen.

    RCU has served as an advisory board member or consultant for AbbVie, Bristol Myers Squibb, Janssen, Pfizer, and Takeda; research support from AbbVie, Boehringer Ingelheim, Eli Lilly, and Pfizer.

    B.E.S. discloses the following: consulting fees from 4D Pharma, Abbvie, Allergan, Amgen, Arena Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Boston Pharmaceuticals, Capella Biosciences, Celgene, Celltrion Healthcare, EnGene, Ferring, Genentech, Gilead, Hoffmann-La Roche, Immunic, Ironwood Pharmaceuticals, Janssen, Lilly, Lyndra, MedImmune, Morphic Therapeutic, Oppilan Pharma, OSE Immunotherapeutics, Otsuka, Palatin Technologies, Pfizer, Progenity, Prometheus Laboratories, Redhill Biopharma, Rheos Medicines, Seres Therapeutics, Shire, Synergy Pharmaceuticals, Takeda, Target PharmaSolutions, Theravance Biopharma R&D, TiGenix, and Vivelix Pharmaceuticals; honoraria for speaking in CME programs from Takeda, Janssen, Lilly, Gilead, Pfizer, and Genetech; and research funding from Celgene, Pfizer, Takeda, Theravance Biopharma R&D, and Janssen.

    M.C.D. discloses consulting fees from Abbvie, Allergan, Amgen, Arena Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Celgene, Ferring, Genentech, Gilead, Hoffmann-La Roche, Janssen, Pfizer, Prometheus Biosciences, Takeda, and Target PharmaSolutions and research funding from Abbvie, Janssen, Pfizer, and Prometheus Biosciences Takeda.

    J-F.C. reports: receiving research grants from AbbVie, Janssen Pharmaceuticals, and Takeda; receiving payment for lectures from AbbVie, Amgen, Allergan, Inc., Ferring Pharmaceuticals, Shire, and Takeda; receiving consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Celgene Corporation, Eli Lilly, Ferring Pharmaceuticals, Galmed Research, Glaxo Smith Kline, Geneva, Iterative Scopes, Janssen Pharmaceuticals, Kaleido Biosciences, Landos, Otsuka, Pfizer, Prometheus, Sanofi, Takeda, and TiGenix; and holding stock options in Intestinal Biotech Development.

    S.M. has received investigator-initiated grant funding from Takeda Pharma and Genentech and has served as consultant or paid speaker for Takeda Pharma, Genentech, Morphic, and Glaxo Smith Kline. RCU supported by an NIH K23 Career Development Award (K23KD111995-01A1). CA, LP, PHC, GW and ES were supported in part by The Leona M. and Harry B. Helmsley Charitable Trust and LP, ES, CA and PHC also by an RC2 DK122532/DK/NIDDK NIH.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

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

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