Nivolumab-induced immune-mediated colitis: an ulcerative colitis look-alike—report of new cases and review of the literature

  • Fiorella Cañete
  • Míriam Mañosa
  • Triana Lobatón
  • Francisco Mesonero
  • Iago Rodríguez-Lago
  • Eduard Cabré
  • José L. Cabriada
  • Antonio López-Sanromán
  • Eugeni DomènechEmail author
Original Article



Nivolumab, a monoclonal antibody-targeting programmed cell death protein-1, is being increasingly used for the treatment of some advanced neoplasms. Several of its adverse effects are a result of the upregulation of T cells, with colitis as one of the most severe, and a challenging differential diagnosis with ulcerative colitis. However, few real-life clinical practice cases have been reported beyond trials. Our aim was to report a series of new cases, reviewing previously communicated endoscopic-proven nivolumab-induced colitis.


All patients treated with nivolumab in three university centers were identified and those who developed immune-mediated colitis (defined as the presence of diarrhea and evidence of colitis demonstrated by colonoscopy) were described. Additionally, a review of case reports of nivolumab-induced colitis reported in the literature up to March 2018 was performed.


Six new cases of nivolumab-induced colitis and 13 previously reported cases out of randomized clinical trials are described. Colonoscopy showed a mucosal pattern mimicking ulcerative colitis in a large proportion of patients. Clostridium difficile superinfection was observed in two out of 19 cases. All but three patients definitively discontinued nivolumab therapy. Most patients were initially managed with oral or intravenous corticosteroids, but five of them required rescue therapy with infliximab.


Nivolumab-induced colitis may mimic ulcerative colitis. Steroid therapy (oral or intravenously) is often efficient, but one-fourth of patients need rescue therapy with anti-TNF. Intestinal superinfection with Clostridium difficile or cytomegalovirus should be ruled out before starting immunosuppressive therapy.


Immune-mediated colitis Nivolumab Corticosteroids Colonoscopy Pathology 



FC received a research grant from the Societat Catalana de Digestologia.

Compliance with ethical standards

The study was approved by the local Ethics Committee of the coordinating center (Hospital Universitari Germans Trias I Pujol).

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Abdel-Rahman O, ElHalawani H, Fouad M (2015) Risk of gastrointestinal complications in cancer patients treated with immune checkpoint inhibitors: a meta-analysis. Immunotherapy 7:1213–1227CrossRefGoogle Scholar
  2. 2.
    Pollack MH, Betof A, Dearden H, Rapazzo K, Valentine I, Brohl AS, Ancell KK, Long GV, Menzies AM, Eroglu Z, Johnson DB, Shoushtari AN (2018) Safety of resuming anti-PD-1 in patients with immune-related adverse events (irAEs) during combined anti-CTLA-4 and anti-PD1 in metastatic melanoma. Ann Oncol 29:250–255CrossRefGoogle Scholar
  3. 3.
    Ishida Y, Agata Y, Shibahara K, Honjo T (1992) Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 11:3887–3895CrossRefGoogle Scholar
  4. 4.
    Cramer P, Bresalier RS (2017) Gastrointestinal and hepatic complications of immune checkpoints inhibitors. Curr Gastroenterol Rep 19:3CrossRefGoogle Scholar
  5. 5.
    Buchbinder EI, Desai A (2016) CTLA-4 and PD-1 pathways: similarities, differences and implications of their inhibition. Am J Clin Oncol 39:98–106CrossRefGoogle Scholar
  6. 6.
    Wei W, Zhibin L (2017) Risk of gastrointestinal toxicities with PD-1 inhibitors in cancer patients. A meta-analysis of randomized clinical trials. Medicine (Baltimore) 96:e8931CrossRefGoogle Scholar
  7. 7.
    Collins M, Michot JM, Danlos FX et al (2017) Inflammatory gastrointestinal diseases associated with PD-1 blockade antibodies. Ann Oncol 18:2860–2865CrossRefGoogle Scholar
  8. 8.
    Coutzac C, Adam J, Soularue E, Collins M, Racine A, Mussini C, Boselli L, Kamsukom N, Mateus C, Charrier M, Cassard L, Planchard D, Ribrag V, Fizazi K, Loriot Y, Lepage P, Scoazec JY, Robert C, Carbonnel F, Chaput N (2017) Colon immune-related adverse events: anti-CTLA-4 and anti-PD-1 blockage induce distinct immunopathological entities. J Crohns Colitis 11:1238–1246CrossRefGoogle Scholar
  9. 9.
    Wang DY, Ye F, Zhao S, Johnson DB (2017) Incidence of immune checkpoint inhibitor-related colitis in solid tumor patients: a systematic review and meta-analysis. Oncoimmunology 6:e1344805CrossRefGoogle Scholar
  10. 10.
    Abdel-Wahab N, Shah M, Suarez-Almazor ME (2016) Adverse events associated with immune checkpoint blockade in patients with cancer: a systematic review of case reports. PLoS One 11:e0160221CrossRefGoogle Scholar
  11. 11.
    Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. U.S. Department of Health and Human Services; National Institutes of Health; National Cancer Institute; Accessed November 2017, at
  12. 12.
    Berggvist V, Hertervig E, Gedeon P et al (2017) Vedolizumab treatment for immune checkpoint inhibitor-induces enterocolitis. Cancer Immunol Immunother 66:581–592CrossRefGoogle Scholar
  13. 13.
    Gondal B, Patel P, Gallan A et al (2016) Immune-mediated colitis with novel immunotherapy: PD-1 inhibitor associated gastrointestinal toxicity. Acta Gastroenterol Belg 79:379–381Google Scholar
  14. 14.
    Fujii Y, Nishikawa Y, Nomura M et al (2017) Readministration of nivolumab after persistent immune-related colitis in a patient with recurrent melanoma. Intern Med: published online Dec 21.
  15. 15.
    Gonzalez RS, Salaria SN, Bohannon CD, Huber AR, Feely MM, Shi C (2017) PD-1 inhibitor gastroenterocolitis: case series and appraisal of ‘immunomodulatory gastroenterocolitis’. Histopathology 70:558–567CrossRefGoogle Scholar
  16. 16.
    Kubo K, Kato M, Mabe K (2017) Nivolumab-associated colitis mimicking ulcerative colitis. Clin Gastroenterol Hepatol 15:A35–A36CrossRefGoogle Scholar
  17. 17.
    Yanai S, Nakamura S, Matsumoto T (2017) Nivolumab-induced colitis treated by infliximab. Clin Gastroenterol Hepatol 15:e80–e81CrossRefGoogle Scholar
  18. 18.
    Iyoda T, Kurita N, Takada A et al (2018) Resolution of infliximab-refractory nivolumab-induced acute severe enterocolitis after cyclosporine treatment in a patient with non-small cell lung cancer. Am J Case Rep 27:360–364CrossRefGoogle Scholar
  19. 19.
    Yasuda Y, Urata Y, Tohnai R et al (2017) Immune-related colitis induced by the long-term use of nivolumab in a patient with non-small cell lung cancer. Intern Med: published online Dec 27.
  20. 20.
    Nishijima TF, Shachar SS, Nyrop KA, Muss HB (2017) Safety and tolerability of PD-1/PD-L1 inhibitors compared with chemotherapy in patients with advanced cancer: a meta-analysis. Oncologist 22:470–479CrossRefGoogle Scholar
  21. 21.
    Wang Y, Abu-Sbeih H, Mao E, Ali N, Qiao W, Trinh VA, Zobniw C, Johnson DH, Samdani R, Lum P, Shuttlesworth G, Blechacz B, Bresalier R, Miller E, Thirumurthi S, Richards D, Raju G, Stroehlein J, Diab A (2018) Endoscopic and histologic features of immune checkpoint inhibitor-related colitis. Inflamm Bowel Dis 24:1695–1705CrossRefGoogle Scholar
  22. 22.
    Postow MA (2015) Managing immune checkpoint-blocking antibody side effects. Am Soc Clin Oncol Educ Book 35:76–83CrossRefGoogle Scholar
  23. 23.
    Samaan MA, Pavlidis P, Papa S, Powell N, Irving PM (2018) Gastrointestinal toxicity of immune checkpoint inhibitors: from mechanisms to management. Nat Rev Gastroenterol Hepatol 15:222–234Google Scholar
  24. 24.
    Adler BL, Pezhouh MK, Kim A et al (2018) Histopathological and immunophenotypic features of ipilimumab-associated colitis compared to ulcerative colitis. J Intern Med: published online Feb 21.
  25. 25.
    Villadolid J, Amin A (2015) Immune checkpoint inhibitors in clinical practice: update on management of immune-related toxicities. Transl Lung Cancer Resp 4:560–575Google Scholar
  26. 26.
    Li M, Pan Q, Peppelenbosch MP (2017) Should nivolumab-induced colitis be treated by infliximab? Clin Gastroenterol Hepatol 15:1637CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Fiorella Cañete
    • 1
    • 2
    • 3
  • Míriam Mañosa
    • 1
    • 2
  • Triana Lobatón
    • 1
  • Francisco Mesonero
    • 4
  • Iago Rodríguez-Lago
    • 5
  • Eduard Cabré
    • 1
    • 2
  • José L. Cabriada
    • 5
  • Antonio López-Sanromán
    • 2
    • 4
  • Eugeni Domènech
    • 1
    • 2
    Email author
  1. 1.Gastroenterology DepartmentHospital Universitari Germans Trias i PujolBadalonaSpain
  2. 2.Centro de Investigaciones Biomédicas en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD)MadridSpain
  3. 3.Universitat Autònoma de BarcelonaBarcelonaSpain
  4. 4.Gastroenterology DepartmentHospital Ramón y CajalMadridSpain
  5. 5.Gastroenterology DepartmentHospital de GaldakaoGaldakaoSpain

Personalised recommendations