Disease exacerbation is common in inflammatory bowel disease patients treated wi

lNTRODUCTlON

Immune checkpoint inhibitor(ICI)monoclonal antibodies block surface receptors on leukocytes,triggering profound immune responses.Use of ICIs for cancer treatment is increasing;the number of Food and Drug Administration-approved indications is growing,with additional ICIs in development[1].Immune-related adverse events(irAEs)and disease exacerbations following ICIs have been documented for pre-existing inflammatory diseases and are typically managed with prompt steroids,immunomodulators,and/or tumor necrosis factor inhibitors[2,3].Thus,clinical benefit of ICIs for malignancy in patients with certain pre-existing conditions may be limited due to serious risks.

Gastrointestinal(GI)irAEs,including diarrhea and ICI-mediated colitis(IMC),are amongst the most common ICI-associated irAEs[4].In the general population treated with ICIs,the incidence of diarrhea was 12.1%-13.7% for anti-programmed cell death protein(PD)-1,30.2%-35.4% for anti-cytotoxic Tlymphocyte antigen 4(CTLA-4),and 9.1%-10.6% for combination ICIs,while the incidence of colitis was 0.7%-1.6% for anti-PD-1,5.7%-9.1% for anti-CTLA-4,and 13.6% for combination ICIs[1].Use of anti-CTLA-4 ICIs is considered to increase the risk of IMC[5,6].Recent reports suggest that the incidence of GI irAEs following ICI administration in patients with pre-existing inflammatory bowel disease(IBD)may be higher than the general population[7-9].While these studies provided insight into IBD exacerbation rates following ICI therapy in small cohorts at a limited number of study centers,data on patient comorbidities,medications,and baseline IBD activity were lacking and might affect irAE occurrence and recognition.Understanding the prevalence,detailed clinical characteristics and outcomes of ICIinduced IBD exacerbation in broader patient populations remains an ongoing challenge.We aimed to assess the clinical characteristics of IBD patients treated with ICIs at our previously unreported center and determine IBD exacerbation prevalence in this novel population.

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MATERlALS AND METHODS

We performed a retrospective cohort study of all IBD patients exposed to ICIs from 2000 through August 13,2020 at Stanford Healthcare using the Stanford Research Repository Tool database,as approved by the Stanford Institutional Review Board.Patients were screened by International Classification of Diseases codes(K50,CD;K51,ulcerative colitis;K52,other unspecified noninfective gastroenteritis and colitis;555,regional enteritis;556,other ulcerative colitis)and ICI(ipilimumab,nivolumab,pembrolizumab,atezolizumab,avelumab,durvalumab,or cemiplimab).Pre-existing IBD diagnosis and subsequent ICI administration were confirmed by chart review.All subjects with these inclusion criteria were reported.Patients whose IBD diagnosis did not predate ICI were excluded.Demographics,comorbidities,medications,disease phenotypes,and clinical outcomes were collected by chart review.The primary outcome was prevalence of IBD exacerbation following ICI,as defined by new onset bloody stool,rectal bleeding,diarrhea,and/or increased bowel movements.No patients with IBD exacerbations had documented GI infections following ICI use,as determined by GI polymerase chain reaction panel,toxin testing,and/or stool culture.One patient with IBD exacerbation had chronic hepatitis C virus infection,and another had a postoperative wound infection.Missing data is indicated in table footnotes.No data was imputed.Statistical analyses were performed in Microsoft Excel(16.43),GraphPad Prism(8.4.3)and R(3.3.2).

Four of seven patients with IBD exacerbations required GI-related hospitalization following ICI treatment,compared to none of 12 patients without exacerbations(57.1%0%;= 0.0090);two patients with exacerbations required GI surgery(Table 3).IBD medical therapy following ICI was not significantly different between patients with and without IBD exacerbations(Table 3).Importantly,no patients with IBD exacerbations had documented GI infections following ICI,consistent with exacerbation due to flare of underlying IBD.One patient who had an exacerbation after ICI underwent flexible sigmoidoscopy,demonstrating circumferential colitis from the anus to distal sigmoid colon,consistent with a flare of pre-existing left-sided UC.

RESULTS

Rubin SJS,Gubatan J and Habtezion A helped plan the study,interpret data,and draft the manuscript.Rubin SJS,Balabanis T,Gubatan J and Habtezion A interpreted data;Balabanis T collected data;all authors approved the final draft submitted.

All patients had controlled asymptomatic IBD when beginning ICI therapy,after which seven developed GI irAEs consistent with IBD exacerbation(Tables 2 and 3).Median length of ICI use was 12 mo(IQR,10)and 6.5 mo(IQR,9.3)in patients with and without exacerbations,respectively(= 0.3685;Table 3).Median follow-up time was 435 d(IQR,306)and 572 d(IQR,450)from beginning ICI therapy for patients with and without exacerbations,respectively(= 0.4824).Demographics,comorbidities,IBD characteristics(location,behavior,),and medications were evaluated and not associated with ICI-induced IBD exacerbation(Table 2).

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DlSCUSSlON

He gathered slowly, moving backwards4 and forwards through the bushes, but always keeping up with her. After a while, he came back to the path. She answered his questions - the children, her job, her parents - but always skirted round the main issue.

Patients with IBD exacerbations experienced more GI-related hospitalizations,half accompanied by surgery.There was no association between ICI type and IBD exacerbation.Although only three patients were on antibodies directed against CTLA-4,this is consistent with another recent report[9].We found no associations between IBD exacerbation and non-IBD medications,including proton pump inhibitors,3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors,antidiabetic agents,antihypertensive agents,and others analyzed(Table 2).

We conducted a retrospective cohort study of all IBD patients treated with ICIs for malignancy and Stanford Healthcare.

Our study adds to developing literature on ICIs in IBD,providing detailed data on prevalence of IBD exacerbation and outcomes in this vulnerable population.Importantly,while GI symptoms are common amongst IBD and cancer patients and could resemble GI irAEs,all patients had controlled asymptomatic IBD prior to ICI use,and no patients with subsequent IBD exacerbations had GI infections.Another strength of our study was inclusion of additional clinical characteristics,including medications,comorbidities,race,and ethnicity,relative to previous studies.Cohort size was limited due to the single-center nature of our study and the rarity of IBD preceding ICI therapy.

CONCLUSlON

In conclusion,our data highlight that relative to non-IBD patients,those with pre-existing IBD are a vulnerable population at increased risk of ICI-induced IBD flare.These findings demonstrate the importance of closely monitoring ICIs in the setting of IBD and the need for larger prospective studies to define factors associated with ICI-induced flare in IBD patients.

ARTlCLE HlGHLlGHTS

Research background

Colitis and diarrhea are immune-related adverse events associated with immune checkpoint inhibitor(ICI)therapy.

Research motivation

The risk of inflammatory bowel disease(IBD)exacerbation following ICI treatment of malignancy in these patients is poorly understood.

Research objectives

He longed to get to it, but how? neither road nor bridge was anywhere to be seen, yet the city drew him upwards26, and he felt that here at last was the country which he sought

Research methods

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Research results

The prevalence of IBD exacerbation amongst patients treated with ICI therapy for malignancy was 36.8%.Individuals with exacerbation of pre-existing IBD had more gastrointestinal-related hospitalizations.

Research conclusions

IBD exacerbation amongst patients treated with ICIs for malignancy was higher than reported rates of colitis and diarrhea in the general population treated with ICIs for malignancy.

Years ago, when I started looking for my first job, wise advisers urged, Barbara, be enthusiastic! Enthusiasm will take you further than any amount of experience.

Research perspectives

IBD patients are vulnerable to disease exacerbation when treated with ICIs for malignancy,and close monitoring should be implemented.Further studies will aim to better understand what factors modulate risk of IBD exacerbation in patients following ICI administration.

ACKNOWLEDGEMENTS

We thank Dr.Alexa R.Weingarden,MD,PhD for helpful discussions,critiques,and feedback on the study design and manuscript.

FOOTNOTES

Nineteen patients met inclusion criteria of pre-existing IBD and subsequent ICI therapy.Four had Crohn’s disease(CD),fourteen ulcerative colitis(UC),and one indeterminate IBD(Table 1).The median age of patients with CD was 63[interquartile range(IQR),4]and UC was 69(IQR,12.5).Patients were predominantly of male sex and white race.No patients had extraintestinal IBD manifestations nor pediatric onset IBD;the median age of onset was 56(IQR,0)for CD and 39.5(IQR,32.8)for UC.

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We aimed to understand clinical characteristics of IBD patients treated with ICIs for malignancy and their clinical outcomes.

the Stanford Medical Scholars Fellowship Program to Rubin SJS.

Recent reports suggest higher incidence of GI irAEs in patients with pre-existing IBD following ICI therapy(28%-41%)compared to the general population(diarrhea:9.1%-35.4%;colitis:0.7%-13.6%)[1,7-9].We observed GI irAEs consistent with IBD exacerbations in 36.8% of IBD patients treated with ICIs in a novel patient population,which parallels this emerging pattern.

The study is approved by the Stanford Institutional Review Board(57160).

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Because of the retrospective and anonymous character of this study,the need for informed consent was waived by the institutional review board.

All authors declare no conflicts of interest.

The full data underlying this article cannot be shared publicly due to privacy of the individuals that participated in the study.The de-identified data will be shared on reasonable request to the corresponding authors.

Authors have read the STROBE Statement-checklist of items,and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers.It is distributed in accordance with the Creative Commons Attribution NonCommercial(CC BYNC 4.0)license,which permits others to distribute,remix,adapt,build upon this work non-commercially,and license their derivative works on different terms,provided the original work is properly cited and the use is noncommercial.See:https://creativecommons.org/Licenses/by-nc/4.0/

United States

Samuel J S Rubin 0000-0001-7335-3868;Tatiana Balabanis 0000-0002-9475-6989;John Gubatan 0000- 0001-6037-2883;Aida Habtezion 0000-0002-4473-006X.

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