We appreciate the discussion raised by Nicolaides et al [1], regarding our study on suspected immune-mediated diarrhea and colitis (IMDC) without evidence of inflammation [2]. We acknowledge the limitations inherent to our study’s retrospective design and welcome the opportunity to clarify these issues.
The incidence of immune checkpoint inhibitor (ICI) enteritis is estimated at 0.1-0.5% [3] making it rare. Our study relied on colonoscopic evaluation with terminal ileal biopsy and fecal calprotectin (FC) to assess inflammation. FC has a high sensitivity and specificity for detecting endoscopic inflammation [4], including small bowel lesions [5]. It is therefore unlikely that a significant number of patients would have ICI-enteritis. Current guidelines do recommend esophagogastroduodenoscopy in cases with negative colonoscopy if there is clinical suspicion however [6].
One of the main limitations of our study was the inconsistency in the testing of included patients. Ideally, our sample would have both baseline and follow-up biomarker and endoscopic data to evaluate for inflammation. In clinical practice, this is difficult to achieve. For this reason, we grouped patients based on the information available.
The role of imaging in IMDC is currently limited; abdominal computed tomography has low sensitivity and negative predictive value for diagnosing IMDC [7]. Intestinal ultrasound (IUS) is a cost-effective alternative that is seeing increasing use in inflammatory bowel disease [8]. Only 3 studies have reported its use in IMDC, proving it effective at assessing endoscopic inflammation and therapeutic response [9-11]. More evidence supporting its use is needed before it can be incorporated into future guidelines.
To conclude, further studies will be important to determine the need for systemic immunosuppression and biologic agents for this disease. IUS is a readily available tool with a potential role in evaluating IMDC. However, more data on its use will be needed before recommendations can be made regarding its applications.
Biography
Wayne State University, Detroit, MI; The University of Texas MD Anderson Cancer Center, Houston, TX
Footnotes
Conflict of Interest: None
References
- 1.Nicolaides S, Ardalan Z, Boussioutas A. Immune-mediated diarrhea with normal investigations: the importance of diagnostic stratification and small-bowel assessment. Ann Gastroenterol. 2026;39:495–496. doi: 10.20524/aog.2026.1071. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Shatila M, Wali S, Cruz CC, et al. Immune-mediated diarrhea and colitis with normal biochemical, endoscopic and histologic findings: a retrospective study. Ann Gastroenterol. 2026;39:79–87. doi: 10.20524/aog.2026.1028. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Wali S, Patel RS, Santos MJMN, et al. Isolated immune-mediated enteritis in patients treated with immune checkpoint inhibitor therapy. Ann Gastroenterol. 2026;39:262–269. doi: 10.20524/aog.2026.1032. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Zou F, Wang X, Glitza Oliva IC, et al. Fecal calprotectin concentration to assess endoscopic and histologic remission in patients with cancer with immune-mediated diarrhea and colitis. J Immunother Cancer. 2021;9:e002058. doi: 10.1136/jitc-2020-002058. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Romero-Mascarell C, Fernández-Esparrach G, Rodríguez-De Miguel C, et al. Fecal calprotectin for small bowel Crohn's disease: is it a cutoff issue? Diagnostics (Basel) 2022;12:2226. doi: 10.3390/diagnostics12092226. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Dougan M, Wang Y, Rubio-Tapia A, Lim JK. AGA clinical practice update on diagnosis and management of immune checkpoint inhibitor colitis and hepatitis: expert review. Gastroenterology. 2021;160:1384–1393. doi: 10.1053/j.gastro.2020.08.063. [DOI] [PubMed] [Google Scholar]
- 7.Ibarra Rovira J, Thirumurthi S, Taggart M, et al. Role of abdominal and pelvic CT scans in diagnosis of patients with immunotherapy-induced colitis. J Immunother Precis Oncol. 2022;5:32–36. doi: 10.36401/JIPO-21-21. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Chavannes M, Dolinger MT, Cohen-Mekelburg S, Abraham B. AGA clinical practice update on the role of intestinal ultrasound in inflammatory bowel disease: commentary. Clin Gastroenterol Hepatol. 2024;22:1790–1795. doi: 10.1016/j.cgh.2024.04.039. [DOI] [PubMed] [Google Scholar]
- 9.Sakurai K, Katsurada T, Nishida M, et al. Characteristics and usefulness of transabdominal ultrasonography in immune-mediated colitis. Intest Res. 2023;21:126–136. doi: 10.5217/ir.2021.00166. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Mei R, Pepe E, Oh DY, Tsai KK, Chugh R, Kattah MG. Symptomatic and sonographic improvement of immune checkpoint inhibitor enterocolitis with risankizumab. Inflamm Bowel Dis. 2025;31:1182–1183. doi: 10.1093/ibd/izae259. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Omotehara S, Nishida M, Nagashima K, et al. Immune checkpoint inhibitor-induced colitis successfully followed up by ultrasonography. SN Compr Clin Med. 2020;2:215–221. [Google Scholar]