Immune checkpoint inhibitor mediated diarrhea and colitis, a commonly encountered toxicity from ICI therapy, ranges in the degree of severity and can result in cancer treatment interruption, morbidity, and mortality. [Schneider 2021; Wang 2018] Current recommendations for the management of ICI mediated diarrhea and colitis are based on CTCAE grading of symptoms and frequently involve the use of immunosuppressive therapy. [Schneider 2021; Haanen 2017; Puzanov 2017; Del Castillo 2016] In this study, we described 14 patients with ICI diarrhea and colitis who responded to the non-immunosuppressive therapies mesalamine and/or cholestyramine. Compared to those treated with immunosuppressive therapy, these patients were more likely to have received PD-1/L1 monotherapy, have delayed onset of symptoms and relatively lower inflammatory burden in the colon measured by fecal calprotectin, and more likely to resume ICI therapy, however there was no difference in CTCAE grade of diarrhea/colitis, histologic colitis or rates of hospitalization or recurrence of symptoms.
Although there was no significant difference in the CTCAE grade of diarrhea or colitis between these two treatment groups, the 14 cases treated with non-immunosuppressive therapy had fewer grade 3 diarrhea and no cases of grade 3 and 4 colitis. There were also no cases with ulceration, suggesting a lower inflammatory burden. The histologic findings varied among microscopic, chronic and acute colitis. Although 18% of the cases treated with immunosuppressive therapy had ulceration on endoscopy and higher rates of acute colitis, there was no significant difference in the endoscopic or histologic findings between the two groups. One would hypothesize that patients who may not require immunosuppressive therapy are more likely to have lower grade symptoms and lower grade inflammatory burden on colonoscopy evaluation such as absence of ulcer. However, this is not reflected from our findings likely due to the following reasons: 1) mesalamine and/or cholestyramine is not routinely used for immune mediated diarrhea and colitis, and these therapies were used at the discretion of physicians with initiation of steroids for grade 2 at the discretion of the physician; 2) there is poor correlation between clinical symptoms and endoscopic and/or histologic findings, therefore, individual parameter may not provide accurate measurement of severity of colitis; [Som 2019; Wang 2018] 3) this is a small sample size cohort, which added limitation to categorize patients into groups based on set criteria for each treatment. Notably, 9% of our cohort had no histologic colitis which is in line with other studies reporting that up to 15% of cases with ICI related gastrointestinal toxicity (diarrhea only) without objective colitis on histology. [Bellaguarda 2020] Nevertheless, we present a cohort of patients with histologic findings of colitis who had symptom resolution without immunosuppressive therapy, which suggests that there may be a subset of patients with ICI diarrhea and colitis who may not require immunosuppression for management.
Our findings re-demonstrated the lack of correlation between clinical symptoms of ICI diarrhea and colitis and endoscopy/histologic findings, which is in line with prior studies. [Bellaguarda 2020; Som 2019; Wang 2018] Given the range of ICI diarrhea and colitis clinical manifestations as well as the varying histologic findings, endoscopic evaluation is needed to improve the measurement accuracy on the severity and subtype of histologic colitis which may be important for choosing an appropriate therapy. In addition, non-invasive markers to monitor disease activity ought to be considered. Recent studies have shown calprotectin levels to be predictive of the inflammatory burden seen on endoscopic and histologic evaluation of ICI colitis at the time of diagnosis and after treatment. [Zou 2021] In our study, fecal calprotectin level at the time of ICI diarrhea and colitis diagnosis was significantly higher in those treated with immunosuppressive therapy (234 vs. 56, P = 0.012) however this association is limited by our sample size, varying histologic findings and study design. Larger prospective studies are needed to evaluate the utility of fecal calprotectin in ICI diarrhea and colitis and its association with histologic colitis.
In this study, the patients who responded to mesalamine and/or cholestyramine reflect similar reports of smaller case reports. This favorable response has been observed in patients with grade 1–3 diarrhea, grade 1–2 colitis and different histologic subtypes of ICI colitis including acute, chronic, and microscopic colitis as reported in our study. [Kubo 2017; Choi 2019; Abu-Seih 2018; Kikuchi 2019; Yamauchi 2018] The AGA has also endorsed mesalamine as a second line agent and trial of cholestyramine for diarrhea in conventional microscopic colitis, [Nguyen 2016] with success reported from the use of mesalamine and cholestyramine in the management of ICI induced microscopic colitis in case studies. [Ung 2000; Calabrese 2007] Given that mesalamine is an effective first line therapy for mild to moderate UC, prospective randomized studies are needed to evaluate the efficacy of these non-immunosuppressive treatment options for ICI colitis. [Rubin 2019; Nguyen 2016] In addition, other therapies such as pancreatic enzymes for ICI related diarrhea due to pancreatic exocrine insufficiency may also be considered in future studies.
Immunosuppressive therapy with systemic steroids and biologics such as infliximab are known to have significant side effects including the risk of infection. In our study, of the 14 cases treated with mesalamine and/or cholestyramine, there were no cases of infection during or within 30 days of therapy completion. However, this finding is limited by the small cohort, which does not provide a full representation of side effects associated with these drugs. On the contrary, of the 52 patients treated with steroid with or without infliximab, 21% had confirmed infection during therapy or within 30 days of completing steroid or biologic therapy. In comparison, an infection rate of 13–15% has been reported previously in patients treated with immunosuppressant after ICI therapy, while only 2% in those who did not receive additional immunosuppressive therapy. [Favara 2020; Del Castillo 2016] Furthermore, Wang et. al reported a rate of infection in patients treated with steroids for greater than 30 days for ICI diarrhea and colitis to be approximately 40% vs 26% for those on steroids for less than 30 days. [Abu-Sbeih 2018] These findings highlight the importance of minimizing immunosuppressive therapies when possible with a particular consideration to the length of steroids use, especially among those patients with no objective histologic colitis who generally had mild disease course. [Wang 2018] Furthermore, mesalamine and cholestyramine are generally well tolerated; patients may rarely experience headache, fever, rash, nausea, or vomiting, flatulence, constipation, with rare reports of hepatoxicity, pancreatitis, and interstitial nephritis related to mesalamine therapy. [Rubin 2019; Xie 2019; Barkun 2013] In the present study, there were no significant adverse events related to mesalamine and cholestyramine, however the small cohort of cases limits these findings. Nonetheless, given the favorable safety profile of mesalamine and cholestyramine, future studies may also consider evaluating the role of non-immunosuppressive therapy prophylactically to prevent severe diarrhea and colitis in at risk patients.
The risk associated with immunosuppressive therapy needs to be counterbalanced by the risk of worsening pathologic colitis progression that may be unresponsive to non-immunosuppressive therapy and delay cancer therapy. In our study, 11 of the 52 immunosuppressive cases had a delayed start of steroid treatment after persistent or worsening symptoms on non-immunosuppressive therapy. Eight of the 11 escalated to steroids within 3–5 days and three were over 10 days, which may have been related to insufficient communication to physicians. One case was associated with worsening of symptoms from grade 1 diarrhea and colitis on mesalamine ultimately requiring hospitalization within 30 days. Otherwise, there were no significant major adverse effects or impaired outcome from this delayed treatment transition compared to all cases that received immunosuppressive therapies. The optimal timing and duration of non-immunosuppressive trial before escalation needs further investigation.
There is a paucity of evidence determining when to resume ICI therapy and its safety in regard to the recurrence of potentially more severe irAEs. ICI diarrhea and colitis recurrence was reported in 34% of cases in a multi-center study, with risk factors including treatment resumption with a CTLA-4 agent, need for immunosuppressive therapy for the index episode of ICI diarrhea and colitis, and longer duration of symptoms. [Abu-Sbeih 2019] In comparison, of the 14 patients treated with non-immunosuppressive therapy in our cohort, the overall rate of recurrence was 36%, which is similar to those treated with immunosuppression. Our data also demonstrate that patients with recurring ICI diarrhea and colitis regardless of treatment had significantly better overall survival, which is comparable to Wang et al.’s findings. [Wang 2018; Zou 2020]] This association is presumably related to the prolonged effect of ICI that may provide better therapeutic benefit on cancer outcome while triggering long-lasting or recurrent irAE, however the pathogenicity for this association is unknown. [Som 2019]
The retrospective nature and small sample size of this study limits the power of our findings and conclusion. We were unable to measure cancer-related outcomes between those treated with non-immunosuppressive and those treated with immunosuppressive treatment given the study’s limited power. The limited cases treated with non-immunosuppressive therapy also limit our ability to effectively ascertain the side effect profile, complications and overall survival of this group. Furthermore, our sample size limits our ability to draw conclusions about which subtypes of ICI mediated histologic colitis may be more responsive to non-immunosuppressive therapy. We suspect that our data are also in part limited by the current practice patterns that are not inclusive of the use of mesalamine and cholestyramine for the treatment of ICI diarrhea and colitis. Given the aforementioned reason, the associations presented in this study are subject to bias related to patient selection for mesalamine and cholestyramine treatment. Despite these limitations, this study suggests that non-immunosuppressive therapy may have a therapeutic role in the management of mild ICI diarrhea and colitis. Lastly, in the present study we only comment on the therapeutic use of oral mesalamine formulations with lack of data on the topical options. Future prospective studies are also warranted to evaluate the different doses and routes of 5-ASA agents such as rectal administration given the different efficacies noted in the management of UC.