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CLINICAL COURSE AND IMPACT OF IMMUNE-CHECKPOINT INHIBITOR COLITIS RESEMBLING MICROSCOPIC COLITIS

: Background/Aims: Microscopic colitis is suspected to result from increased immune activity in gut mucosa. Immune checkpoint inhibitors treat cancer by activating the immune system, and further investigation is needed regarding their role in the development of microscopic colitis. Methods: A retrospective case series investigated cases of endoscopically and histologically confirmed microscopic colitis developing after administration of immune checkpoint inhibitors. Clinical notes and medication administration records were reviewed for demographics, symptom duration and treatment response. Results: Nineteen cases of de novo microscopic colitis were identified, with 95% of cases requiring steroid treatment, 53% presenting with hospitalization, and colitis-related mortality in one individual. Symptom onset occurred a median of 160 days after initiation of immune checkpoint inhibitor therapy and 53 days after their most recent dose of therapy. Patients had a median of 125 days of symptoms, and immune checkpoint inhibitor therapy was held in 70% of individuals due for treatment. Discussion/Conclusions: Microscopic colitis can develop after immune checkpoint inhibitor administration, and presents with severe symptoms, often requiring hospitalization and steroid treatment. In certain individuals this can require a prolonged treatment course of steroid therapy or immunomodulators. Individuals developing diarrhea after immune checkpoint inhibitor therapy warrant thorough workup including endoscopy and rapid treatment initiation given the disease severity observed in this series. Lay Summary: We describe the development and disease course of microscopic colitis, a previously considered benign disease, arising in patients receiving immune checkpoint inhibitor therapy for cancer. This complication has a prolonged disease duration and frequently results in hospitalization. Results: A total of 19 cases of patients diagnosed with de-novo MC post-ICI therapy was identified. Sixteen patients (84%) had lymphocytic colitis and three (16%) had collagenous colitis. Eleven patients (58%) were diagnosed by colonoscopy and eight (42%) by flexible sigmoidoscopy. Eight patients (42%) underwent colorectal cancer screening colonoscopies prior to symptom onset, and none of the colonoscopies had evidence of macroscopic colitis. None of the prior colonoscopies contained random biopsies to assess for microscopic colitis.Two patients were current smokers (11%). ICI colitis cohort

A c c e p t e d M a n u s c r i p t  Background/Aims: Microscopic colitis is suspected to result from increased immune activity in gut mucosa. Immune checkpoint inhibitors treat cancer by activating the immune system, and further investigation is needed regarding their role in the development of microscopic colitis.
Methods: A retrospective case series investigated cases of endoscopically and histologically confirmed microscopic colitis developing after administration of immune checkpoint inhibitors. Clinical notes and medication administration records were reviewed for demographics, symptom duration and treatment response.
Results: Nineteen cases of de novo microscopic colitis were identified, with 95% of cases requiring steroid treatment, 53% presenting with hospitalization, and colitis-    Pembrolizumab (47%) and nivolumab (26%) monotherapies were the most frequent ICI used, and 21% of cases received multiple ICIs. The most common ICI combination was nivolumab and pembrolizumab (n=2, 11%). A total of 53% of cases were hospitalized at the time of MC diagnosis. ICI therapy was held due to colitis in 70% of the cohort who had yet to complete ICI treatment course for their malignancy.
The most common malignancy prompting ICI treatment was melanoma (n=10), followed by non-small cell lung carcinoma (n=4).  Steroid-free remission was achieved in 13 patients (68%), while 3 (16%) were still steroid-dependent 6 months following onset of MC. One patient died due to electrolyte abnormalities from colitis. Another patient died two months after diagnosis with failure to thrive secondary to ICI-induced enteritis.
Additional ICI toxicities were identified in 5 individuals in this cohort. They included pneumonitis, pancreatitis, hypophysitis, thyroiditis, and peripheral motor neuropathy.
All the toxicities were CTCAE grade 2 except for the peripheral motor neuropathy which was CTCAE grade 3.

Discussion:
We describe the largest series of patients diagnosed clinically with ICIinduced colitis with the histologic appearance of MC and make a novel observation that these patients have severe symptoms often requiring hospitalization. Of the 19 individuals who developed MC, 95% required steroids, 58% had severe colitis with CTCAE grading of diarrhea of three or greater, 53% required hospitalization, one individual died from enteritis, and one individual died from complications related to colitis. The overall colitis-associated mortality rate in our cohort was 5%. In addition, 26% of this cohort suffered additional ICI toxicities. The small size of this subgroup limits our analysis for predisposing factors. Future studies are needed to better understand the risk factors for ICI toxicity.
While ICI-induced diarrhea and colitis has been extensively documented, de-novo MC has not been well described. [5] The diagnosis of MC differs from classically A c c e p t e d M a n u s c r i p t defined ICI-induced colitis, both endoscopically and histologically. Findings in acute colitis will show a diffuse inflammatory infiltrate with alteration of normal tissue as evidenced by neutrophilic abscesses, cellular apoptosis, and crypt destruction ( Figure 1A). However, this differs from the thickened collagen band seen in collagenous colitis ( Figure 1B) or the pure increase in intraepithelial lymphocyte ratio ( Figure 1C) seen with MC. In addition, the mucosa is typically endoscopically normal in appearance in patients with MC. In contrast, patients with ICI-induced colitis often have endoscopically confirmed inflammation characterized by erythema, friability, and ulceration. Our study shows that ICI-induced MC appears more severe than traditional MC in several respects. First, the disease presentation is more severe.
Traditional MC has a much lower rate of hospitalization at the time of diagnosis, with a 7% rate seen in a recent cohort study of MC. [6] ICI-induced MC also appears more refractory to treatment. This cohort's median time to symptom remission was 125 days, even with 63% of individuals receiving budesonide, while previous studies describe improvement in 10-30 days in patients with MC treated with budesonide. [7] This slower response may be due to the immune system activation after ICI administration making traditional treatments less effective. In addition, our cohort found a relatively equal distribution between males and females, whereas previous reviews have found a significant female dominance. [8] There were some similarities in our cohort to classically defined MC. The cohort study by Loreau et al., 2019 also found a diagnostic delay of 8 weeks, which is similar to our cohort. [6] However, in our patients, treatment was often initiated prior to endoscopic diagnosis, likely due to closer observation from their oncologists.
While these patients were all diagnosed clinically and on histologic analysis with MC, their disease perhaps represents an intermediary between ICI-induced colitis more A c c e p t e d M a n u s c r i p t generally and MC. The histologic diagnosis of MC relies on the presence of >20 intraepithelial lymphocytes per 100 epithelial cells seen on colonic biopsies. ICIinduced colitis typically has a patchier lymphocytic infiltrate that would not meet the criteria for MC. [9] Given the lack of a respective control group we cannot draw any conclusions as to which risk factors predispose this population to developing microscopic colitis in response to immune checkpoint inhibitors. Previous studies (Hughes et al., 2019) identified that patients experiencing MC trended towards exposure to a single agent PD-L1 compared to individuals developing classical acute colitis, although this did not reach statistical significance. [7] Additional factors that may predispose individuals to developing a MC in response to ICI therapy include the relatively low percentage of current and former smokers in our population.
Regardless, these patients all presented with a diagnosis of MC distinct from classically defined ICI-colitis due to both their clinical and histologic appearance.

Conclusion:
In summary, we describe a case series of patients developing de novo MC after initiation of ICI therapy that appears more severe than classically described MC. These individuals often present with severe diarrhea requiring hospitalization.
Individuals on ICI therapy presenting with symptoms of colitis warrant further diagnostic workup regardless of endoscopic findings including biopsies and prompt therapy given the disease course seen in this cohort. Further studies with larger sample size and prospective design are warranted to confirm our observations.