Immune-mediated diarrhea and colitis with normal biochemical, endoscopic and histologic findings: a retrospective study

Malek Shatila; Sharada Wali; Carolina Colli Cruz; Kei Takigawa; Andres Caleb Urias Rivera; Kian Abdul-Baki; Tanvi Gupta; Elliot Baerman; Linfeng Lu; Irene Jeong-Ah Lee; Raakhi Menon; Hamza Salim; Andrew Sullivan; Varun Vemulapalli; Cristina Natha; Ayesha Khan; Krishnavathana Varatharajalu; Stephane Champiat; Kerry L. Reynolds; Lucy B. Kennedy; Katy Tsai; Anusha Shirwaiker Thomas; Yinghong Wang

Authors Malek Shatila, Sharada Wali, Carolina Colli Cruz, Kei Takigawa, Andres Caleb Urias Rivera, Kian Abdul-Baki, Tanvi Gupta, Elliot Baerman, Linfeng Lu, Irene Jeong-Ah Lee, Raakhi Menon, Hamza Salim, Andrew Sullivan, Varun Vemulapalli, Cristina Natha, Ayesha Khan, Krishnavathana Varatharajalu, Stephane Champiat, Kerry L. Reynolds, Lucy B. Kennedy, Katy Tsai, Anusha Shirwaiker Thomas, Yinghong Wang.

Abstract

Background Immune-mediated diarrhea and colitis (IMDC) due to checkpoint inhibition infrequently presents with normal stool biomarkers and no endoscopic or histologic evidence of inflammation. Little is known about the treatment needs and outcomes of this subset of patients. We aimed to describe this entity and clarify the role of immunosuppressive treatments in its management.

Method This was a single-center, retrospective study of patients treated with immune checkpoint inhibitors who developed clinical symptoms of IMDC, with no evidence of inflammation based on fecal calprotectin or endoscopic/histologic evaluation, between January 2010 and February 2024.

Results Of 1151 patients with IMDC, 131 (11.4%) had no evidence of inflammation. These patients more frequently had PD-1/L1 agent exposure (P=0.019) and presented with less severe diarrhea than patients with evidence of inflammation (P<0.001). This group had a lower rate of hospitalization (P=0.003). Around 40% of patients with no evidence of inflammation required immunosuppressive treatment. There was no difference in clinical symptoms or severity between patients requiring immunosuppression and those who did not.

Conclusions Our study is the first to explore IMDC with no elevations in calprotectin and normal endoscopic/histologic findings. We found that PD-1/PD-L1 inhibition may predispose patients to developing this form of IMDC, which is associated with a lower severity of diarrhea, fewer hospitalizations and lower recurrence rates. Many patients still require immunosuppressive treatment, and a small subset later develop colonic inflammation. Future studies are needed to further elucidate the treatment needs and outcomes of this patient population.

Keywords Immune-mediated diarrhea and colitis, immunotherapy, infliximab, vedolizumab

Ann Gastroenterol 2026; 39 (1): 79-87