Immune checkpoint inhibitor–related luminal GI adverse events

Journal Pre-proof “Immune checkpoint inhibitor-related luminal GI adverse events” Paul T. Kröner, MD, MSc, Kabir Mody, MD, Francis A. Farraye, MD, MSc PII:

S0016-5107(19)32242-4

DOI:

https://doi.org/10.1016/j.gie.2019.09.009

Reference:

YMGE 11750

To appear in:

Gastrointestinal Endoscopy

Received Date: 12 July 2019 Accepted Date: 8 September 2019

Please cite this article as: Kröner PT, Mody K, Farraye FA, “Immune checkpoint inhibitor-related luminal GI adverse events”, Gastrointestinal Endoscopy (2019), doi: https://doi.org/10.1016/j.gie.2019.09.009. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Copyright © 2019 by the American Society for Gastrointestinal Endoscopy

“Immune checkpoint inhibitor-related luminal GI adverse events”

Paul T. Kröner, MD, MSc1; Kabir Mody, MD2; Francis A. Farraye, MD, MSc1 1

2

Division of Gastroenterology and Hepatology, Division of Hematology/Oncology, Mayo Clinic, Florida.

Short title: Checkpoint inhibitor luminal gastrointestinal adverse events

Correspondence to: Paul T. Kröner, MD, MSc Department of Gastroenterology and Hepatology Mayo Clinic Florida 4500 San Pablo Road South Jacksonville, FL 32224, USA Tel: +1 904-953-6970

Keywords: Immune Checkpoint Inhibitors, Luminal Gastrointestinal Adverse Events

Abstract The early promising results of immune checkpoint inhibitors use in the treatment of selected malignancies has ushered a new era in research of cancer and development of treatment options. With the increasing use of this class of medications, a wide array of adverse events are becoming evident, many of which will be encountered by the gastroenterologist. The second most common adverse events associated with the immune checkpoint inhibitors involve the gastrointestinal tract and include diarrhea and colitis. These are experienced by up to 50% of patients on these agents. The severity of these events varies greatly and may range from mild to fatal. Therefore, the importance for the gastroenterologist to be aware of the spectrum of potential gastrointestinal adverse events cannot be understated. For this review we conducted an extensive literature search and compiled all relevant information pertaining to the luminal gastrointestinal tract. The presentation, approach to the patient with luminal gastrointestinal adverse reactions, risk stratification, management, challenging populations, endoscopic considerations and findings, and histologic findings are all discussed in this review.

Introduction In recent years, immunotherapy has emerged as an effective strategy for the treatment of many malignancies. The concept of using a patient’s own immune system to fight cancer was first envisioned by Dr. William Coley when a mixture of attenuated bacteria was injected into patients in order to elicit an immune-mediated response against sarcoma.1,2 Substantial progress has only been achieved in recent years, with immunotherapies eliciting clear efficacy in clinical trials and gaining FDA approval for routine use across cancer types, including malignancies of the gastrointestinal tract (see Figure, Appendix). One such class of immunotherapies are immune checkpoint inhibitors (ICI). Immune checkpoints are the immune system’s own natural mechanism used to dampen the immune response and prevent autoimmunity. Tumor cells exploit this tool, expressing immune checkpoint proteins (eg, programmed cell death [PD]-1, PD-L1, cytotoxic T lymphocyte-associated antigen [CTLA]-4), to enable escape from immune system. These allow tumor cell interaction with T-cells, rendering them incapable of killing. Hence, these immune checkpoint proteins are therapeutic targets. The first ICI to be approved was ipilimumab in 2011 (Yervoy, Bristol-Myers Squibb), an anti-CTLA-4 antibody.3 It was initially approved for the treatment of unresectable metastatic melanoma and has since also demonstrated efficacy in and been approved for renal cell carcinoma and microsatellite instability-high cancers. Pembrolizumab, approved in 2014 (Keytruda, Merck & Co) and nivolumab, approved in 2014 (Opdivo, Bristol-Myers Squibb) are the first 2 FDA-approved drugs blocking the interaction between the immune checkpoint PD-1 (expressed by T-cells) and its ligands PD-L1 and PD-L2 (expressed by tumor and myeloid cells). These drugs have also demonstrated significant activity and been approved for use in several cancer types.

Immune-related adverse reactions The occurrence of immune-related adverse events (irAE) with immune checkpoint inhibitor (ICI) use ranges from 15% to 90% in the reported literature.1 Anti-CTLA-4 agents have been associated with allgrade irAE from 61% to 79%, of which 17% to 31% were reported as severe.2 The occurrence of these irAE have been noted to be dose-dependent, with higher doses being associated with an increased risk of irAE.3 In comparison, anti-PD-1 and anti-PD-L1 agents have associated irAE of 27% (6% of all patients exposed have severe adverse events).4 In contrast to Anti-CTLA-4 agents, anti-PD-1 and anti-PD-L1 agents do not seem to exhibit a dose-dependent association with irAE. Occurrence of irAE not only varies depending on class of agent used, but also if agents are simultaneously used. The rates of fatal irAE also vary by agent class, with anti-PD-1 having rates of 0.36%, anti-PD-L1 0.38%, anti-CTLA-4 1.08%, and combination regimens 1.23%.5 The etiologies of fatalities vary with the different medication classes used. Although the majority of fatalities in patients on anti-CTLA-4 agents were related to colitis, fatalities associated with anti-PD-1/PD-L1 were primarily related to pneumonitis (35%), myocarditis (25%, with a fatality rate of 39.7%) and hepatitis (22%). In combination regimens, colitis was the most common fatal adverse event (37%).5 The use of monotherapy is associated with a lesser recurrence of adverse reactions, compared to combination immunotherapy. The occurrence of severe irAE has been reported in an excess of 60% of patients receiving combination therapy (eg, anti-PD1+anti-CTLA-4).6 This is also reflected in the fact that patients undergoing combination therapy who experience irAE are more likely to discontinue treatment, compared to monotherapy alone (39% versus 12%-16%).7 A relationship between tumor type and development of irAE has also been suggested. For example, patients with melanoma experience higher occurrence of dermatologic and gastrointestinal adverse events when compared to cases of non-small cell lung cancer.8,9 It is worth noting that although dataare conflicting, an inverse relationship between development of irAE and treatment response has been noted in some studies. One meta-analysis by Teulings et al noted clear survival improvement in patients with stage III to IV melanoma who developed vitiligo.10 Other patients who experienced rheumatologic (ie, inflammatory arthritis), and gastrointestinal (ie, diarrhea) irAE have also been noted to have improved rates of tumor response rates and survival, although this subject warrants more robust supportive data.10-13 The most commonly associated irAE for ICI in general are dermatologic (in 44% to 68%, with less than 5% of all patients exposed to ICI experiencing severe reactions), followed by gastrointestinal (35% to 50%, with 11% of the total number of patients exposed experiencing severe adverse events), hepatic (5% to 10%, with an average of 5% of patients developing severe adverse events), and endocrine (up to 6%, with less than 5% of the total number of patients experiencing severe adverse events).2,14 This review will cover the gastrointestinal irAE.

Gastrointestinal Adverse Reactions Gastrointestinal adverse reactions are the second most common irAE. Immunotherapy-related adverse events are the leading cause for discontinuation of therapy with checkpoint inhibitors, with associated discontinuation rates of 0.5% to 13%.15,16 The occurrence of irAE can happen at any point in time after initiation of treatment, during the corticosteroid tapering period, or even after treatment has been discontinued.17 The onset of gastrointestinal symptoms usually occurs after 6 to 8 weeks of initiation of ICI, but can also occur several months after initiating ICI therapy and even after treatment discontinuation.18-22 Gastrointestinal involvement can occur at any location including the esophagus, stomach, small bowel, colon, liver, and pancreas. Gastrointestinal involvement of the liver and pancreas is beyond the scope of this article and will not be discussed. The reader is referred to the National Comprehensive Cancer Network (NCCN) guideline on these topics.1 Endoscopic findings due to gastrointestinal involvement may occur throughout the gastrointestinal tract from upper involvement with oral aphthous ulcers, esophagitis, gastritis, to more distal involvement with enteritis, and colitis.23 Patients may present with abdominal pain, increased bowel frequency, diarrhea, and urgency. Symptom severity does not correlate to the degree of colitis as evaluated on endoscopy and histology.18 The medication class most commonly associated with gastrointestinal irAE are anti-CTLA-4, with diarrhea being reported in 33% to 50% (8% of total number of patients exposed developing severe diarrhea) of patients, whereas colitis may occur in up to 7% to 22% (7% of total number of patients exposed developing severe colitis) of patients.23,24 The use of anti-PD-1 or anti-PD-L1 monotherapy was associated with the lowest occurrence of significant irAE, with 1.3% of patients developing unspecified colitis, 0.9% developing severe colitis, and 1.2% developing significant diarrhea.25 The highest occurrence of severe gastrointestinal irAE is in patients on combination therapy of anti-PD1/PD-L1 agents with anti-CTLA-4 therapy, with 14% of patients developing colitis, 9% severe colitis, and 32.7% diarrhea.26,27

Approach to the patient on ICI with gastrointestinal symptoms In evaluating patients with suspected irAE, prompt identification is of paramount importance. Timely identification can result in earlier treatment and a decrease in rates of progression to more severe disease. The grading of the adverse event is based on the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) classification, which classifies diarrhea and colitis into Grades 1 to 5, depending on the severity.1,16 When assessing the degree of diarrhea in a patient with suspected irAE, obtaining a comprehensive history and physical examination is the first step. The clinician should inquire about the patient's usual bowel habits or presence of abdominal pain before starting immunotherapy, along with changes in the bowel habits while on the medication. Associated gastrointestinal symptoms such as dysphagia, nausea, vomiting and weight loss should also be elicited. It is not only critical to consider the patient's current

immunotherapy regimen, but also other comorbidities that might be contributing to the symptoms, such as concomitant infections or electrolyte abnormalities, among others. In addition to providing supportive measures, all patients presenting with moderate to severe diarrhea who are currently on ICI should undergo comprehensive testing. Obtaining stool and/or serum studies to rule out infectious etiologies, as well as laboratory studies including complete blood counts, comprehensive metabolic panel, antinuclear antibodies, thyroid-stimulating hormone, erythrocyte sedimentation rate, C-reactive protein, and HIV should be obtained when appropriate. In addition, it is the authors’ opinion that clinicians can consider performing testing for viral hepatitis and tuberculosis in preparation for possible later administration of biologic agents. Abdominal imaging, (ie, computed tomography [CT]) is usually obtained to rule out local adverse events. Early consultation with a gastroenterologist for assessment and consideration of diagnostic sigmoidoscopy, colonoscopy or upper endoscopy is appropriate.1,16 Some experts recommend to test for fecal lactoferrin to assist in stratifying patients for the need of more timely endoscopic intervention, as well as testing for fecal calprotectin to monitor disease activity (ie, before, during and after treatment).26,27 Anti-CTLA-4 agents should be permanently discontinued if the irAE were life-threatening. In general, it is also recommended that if toxicity recurs with a re-challenge, permanent discontinuation of that class of ICI is appropriate. If serious irAE (Grades 3 to 4) occur with one class of medications, the oncologist may consider switching to a different class of ICI once toxicity episode has resolved.1

Management of toxicity As stated above, in all cases of irAE, the first and most important step is to consider the diagnosis and then perform appropriate testing to confirm or exclude the diagnosis. Once a diagnosis is made, the treatment will depend on the severity of the event using the CTCAE described above. This will determine the need for conservative management, immune suppressive therapy or modification of the ICI regimen. Table 1 Grading Grade 1

Grade 2

Signs and/or Symptoms Increase of stool frequency <4/day over baseline Mild increase in ostomy output No symptoms of colitis Radiographic or histologic findings of colitis Increase of stool frequency 4-6/day over baseline Moderate increase in ostomy output Abdominal pain Fever Hematochezia

Treatment Considerations * Symptomatic management Loperamide, diphenoxylate/atropine* Budesonide EC* Symptomatic management Measure fecal calprotectin/lactoferrin Prednisone 1mg/kg/day Gastroenterology consult Consider EGD/colonoscopy Hold anti-PD-1/PD-L1 temporarily Permanently discontinue anti-CTLA-4

Grade 3

Increase of stool frequency ≥7/day over baseline Severe increase in ostomy output Significant abdominal pain or peritoneal signs Fever Ileus

Hospitalization IV fluid hydration, electrolyte repletion Prednisone 2mg/kg/day* Consider IV methylprednisolone Consider infliximab if steroid non-responsive*¶ Gastroenterology consult Consider EGD/colonoscopy Hold anti-PD-1/PD-L1 temporarily Permanently discontinue anti-CTLA-4

Grade 4

Development of life-threatening event Toxic megacolon Bowel ischemia or necrosis Perforation

Hospitalization IV methylprednisolone 2mg/kg/day* Consider infliximab if steroid non-responsive* ¶ Consider EGD/colonoscopyⱡ Surgical consultation† Permanently discontinue all agents

Grade 5 Death *Once infection ruled out. ¶

Vedolizumab can be considered in cases where infliximab is contraindicated, or if patients did not respond to infliximab. ⱡ Once perforation and toxic megacolon have been ruled out † For cases of bowel perforaƟon, ischemia, necrosis or toxic megacolon EGD, esophagogastroduodenoscopy; IV, intravenous

General management Patients with Grade 1 diarrhea should be treated conservatively. Adequate hydration and symptomatic management with anti-motility agents such as loperamide or diphenoxylate/atropine is recommended.1,16 Stool examination to rule out infectious pathogens should be considered when appropriate. For Grade 1 diarrhea, budesonide EC has been described as effective in reducing symptoms.28 For patients with Grade 2 events, after having ruled out infectious etiologies, starting immunosuppression with systemic corticosteroids is advised at a dose equivalent to prednisone 1 mg/kg/day. Current consensus recommends doubling the prednisone dose to 2 mg/kg/day if the diarrhea has not improved within the first 72 hours after the initial prednisone dose.1,16 Abdominal CT scan can show distinct patterns of isolated segmental rectosigmoid colitis without diverticulosis, segmental colitis with diverticulitis, terminal ileitis and diffuse colitis.29,30 Typical findings on CT include mesenteric vasculature engorgement (83%), bowel wall thickening (75%), colonic dilation with fluid levels (25%), and fat stranding (16%) (Figure 1).29 If not performed yet, flexible sigmoidoscopy or colonoscopy depending on disease distribution is appropriate to confirm the diagnosis, assess disease

severity and ultimately guide appropriate treatment. A dedicated section to the importance of endoscopy and endoscopic considerations is provided below.

It is advisable that patients with grade 3 or 4 irAE be admitted to the hospital not only for supportive management, but for urgent evaluation and treatment. Aggressive intravenous fluid resuscitation and management of electrolyte imbalances is usually required. In addition to ruling out infectious etiologies and obtaining laboratory studies as an inpatient with grade 2 diarrhea, abdominal CT and diagnostic endoscopy should be strongly considered.1 Intravenous methylprednisolone at doses of 1 to 2 mg/kg/day should be administered until clinical improvement is observed. Thereafter, it is recommended that the patient be switched to an oral prednisone taper over at least 4 to 6 weeks.1 In cases of anti-CTLA-4-related grade 3 toxicity, it is recommended to immediately and permanently discontinue the medication. These patients can be considered for anti-PD-1/PD-L1 agents once the irAE has resolved.24,31 For patients with Grade 4 toxicity, IV methylprednisolone is recommended until symptoms decrease to Grade 1. Systemic corticosteroids should then be tapered over 4 to 6 weeks. If no improvement is noted at 72 hours of starting therapy, infliximab may be considered. In these cases; it is recommended to permanently discontinue the offending agent.1 Vedolizumab can be considered in cases where infliximab has not been effective or if the use of infliximab is contraindicated.1 It is hypothesized that the intestinal microbiome may play a significant role in the development irAE.32,33 Studies have not only shown an association between particular phyla of bacteria and decreased propensity to develop anti-CTLA-4-induced colitis, but have also shown a blunted response to immunotherapy in patients who had been previously treated with antibiotics.34,35 Convincing evidence to support the use of fecal microbiota transplantation (FMT) is lacking. However, in one small case series (two patients with ICI-related colitis refractory to steroids, infliximab and vedolizumab), one patient underwent FMT and was reported to improve clinically, whereas the second patient had short-term clinical improvement, requiring a second dose of FMT that was associated with complete symptom resolution.36 Fecal transplantation has been suggested as a potential treatment option for patients with refractory immune-mediated colitis. However, at present, available evidence comes only from case series and therefore prospective trials are required to confirm these observations.37,38 In cases of irAE, the decision to re-challenge a patient with ICI should be performed in concert with medical oncology. Current National Comprehensive Cancer Network guidelines have separate recommendations for anti-PD-1/PD-L1 agents and anti-CTLA-4 agents. For anti-PD-1/PD-L1 agents, when grade 2 to 3 colitis occurred, consider resuming ICI after symptoms have resolved to grade 1 or less. Systemic corticosteroids are usually completely tapered before attempting for resume ICI. In the event that the patient cannot be tapered off steroids, consider restarting ICI once the patient is on 10 mg of prednisone daily or less.

In cases of severe abdominal pain, toxic megacolon, or bowel perforation, urgent surgical consultation is warranted.

Immunosuppression Considerations Systemic steroids are the cornerstone of treatment for high-grade adverse reactions (Grades 2 to 4). Initial treatment with systemic steroids has a reported treatment response a 40% to 60%.16,18 Although it has been hypothesized that because steroids have the polar opposite effect on the immune system when compared to immunotherapy, the administration of immune suppressing medications such as systemic steroids or infliximab after the onset of irAE has not been shown to interfere with overall response rates, anti-tumor efficacy or survival of patients treated with ICI. 15,39-41 However, pre-existing corticosteroid use, equivalent to 10 mg of daily prednisone was associated with poorer outcomes in patients treated with anti-PD-L1 agents.42 Once steroids are used, enough time should be allowed for the irAE to resolve and avoid recurrences. Thereafter, a slow steroid taper over 4 to 6 weeks should be considered.1 Restarting ICI therapy should be cautiously considered when symptoms from the irAE have markedly improved to at least grade 1. In cases of severe adverse reactions, or if the event is not responsive to systemic corticosteroids within the first 72 hours, the use of additional immunosuppressive therapy may be warranted.1 For cases of immune-mediated colitis initiation of infliximab, if an irAE is steroid-refractory at 72 hours, can be considered. Usually, a single dose of infliximab is administered. However, subsequent doses can be considered after two weeks as well.18,43 Infliximab has also been associated with faster symptom resolution compared to corticosteroids in patients with ICI-related colitis.43 Vedolizumab has also been described as a potential agent useful in treating ICI-related colitis.44 Vedolizumab, like infliximab, can be considered in cases of steroid dependent or steroid refractory colitis, as well as in cases of infliximab-resistant disease.45 The proposed advantage of vedolizumab is that its gut-selective mechanism of action avoids systemic immunosuppression without altering tumor responses to chemotherapy.1 Other nonsteroidal immunosuppressants have been used in treating irAE from ICI. The use of mycophenolate in combination with steroids in small case series has been shown to hasten the improvement of high-grade colitis to normal bowel habit and reduce the incidence of colitis flares.46 Antimetabolites such as tacrolimus and cyclosporine have been used in steroid-refractory cases of ICIrelated hepatitis.47 Other medications, such as rituximab, tocilizumab, cyclophosphamide, methotrexate and rheumatic agents are also used for other non-gastrointestinal immune checkpoint inhibitor adverse reactions, and their use has not been evaluated in cases of ICI-related colitis.48-51 Larger studies are necessary to assess the usefulness of these agents in ICI-related colitis. In general, steroids should be considered to be used for the shortest time possible. A study by Wang et al found that long-term steroid monotherapy was associated with increased risk of infection as compared to short term steroids and concomitant infliximab.11 This suggests that earlier use of steroidsparing regimens may be associated with improved outcomes.

Considering immunosuppressive therapies, long-term adverse reactions should be anticipated. Patients on long-term systemic corticosteroid treatment are at risk of developing steroid-induced hyperglycemia, gastritis, or opportunistic infections, and osteoporosis, among others.52,53 Therefore, the management of patients on long-term corticosteroid treatment should be done in concert with medical oncology, endocrinology, gastroenterology and infectious disease specialists. According to the NCCN guidelines for management of immunotherapy-related toxicities, patients on long-term corticosteroids should have frequent serum glucose measurements, receive proton pump inhibitors or H2 antagonists, and receive vitamin-D/calcium supplementation. Furthermore, it is recommended that patients taking 20 mg or more of prednisone daily for more than 4 weeks should receive Pneumocystis jiroveci prophylaxis and, if taking these doses for more than 6 weeks, should also receive fungal infection prophylaxis with fluconazole and consider herpes zoster prophylaxis with vaccination.1 Although there are no trials comparing live-attenuated and the adjuvanted recombinant vaccines, the latter has shown increased immunogenic response and theoretically does not pose a risk to immunocompromised patients.54 As stated above, in patients in whom infliximab use is being considered, reactivation of viral hepatitis or tuberculosis may occur.55-57 Therefore, the current NCCN guidelines recommend serologic testing for hepatitis B, hepatitis C and tuberculosis preceding the start of anti-TNF alpha therapy. Nevertheless, the NCCN guidelines state that tuberculosis testing should not delay the administration of the medication in urgent, life-threatening situations.1 Alternatively, it is the opinion of the authors that these tests could potentially be performed as part of the initial evaluation of patients with ICI-related colitis, in preparation for possible administration of infliximab or vedolizumab.

Challenging populations In addressing irAE, several patient populations remain a challenge to treat. Patients with autoimmune conditions may theoretically experience reactivation or flare of their underlying condition. The treatment of these patients should be provided in concert with all relevant specialists (eg, gastroenterologists, oncologists, rheumatologists, and endocrinologists, among others). Data from smaller studies suggests that patients with underlying autoimmune diseases that experience a flare in the setting of ICI use can be successfully managed with immunosuppressive therapy.58,59 Johnson et al60 showed that in patients with underlying autoimmune conditions including inflammatory bowel disease (IBD), rheumatoid arthritis, psoriasis, and systemic lupus erythematosus, among others, 27% of those receiving therapy with anti-CTLA-4 agents experienced a flare of the disease which was successfully treated with immunosuppressants. Although the decision of restarting ICI in patients with a prior irAE must be taken in concert with the multidisciplinary care team, it is worth noting that 18% of patients that restarted anti-PD-1 after being held for an irAE had recurrence of the same irAE whereas 21% experienced a new irAE.61 Patients with underlying IBD are of particular interest, as colitis secondary to ICI use may be lifethreatening. Colitis secondary to ICI can be clinically indistinguishable from an IBD flare. The histological characteristic that favors ICI-related colitis is acute inflammation.62 Because patients with underlying

autoimmune conditions are usually excluded from clinical trials, evidence of ICI-induced colitis is limited to case series. In one case series, Johnson et al report that 2 out of 6 patients (33%) with IBD experienced a flare while on ICI.60 One patient was successfully treated with infliximab, whereas the other patient was treated with methylprednisolone. Another case series by Kähler et al63 also showed occurrence of ICI-related colitis in 1 out of 3 patients receiving ipilimumab. Patients who have received an organ transplant also represent a clinical challenge as, in theory, immunotherapy may heighten the immune response and increase the risk of rejection. Data of this patient population are scant because this patient population is also typically excluded from the ICI clinical trials. Therefore, current evidence is based on case reports.64-66 There are reports of safe use of anti-CTLA-4 agents in liver or kidney transplant recipients, but there is also evidence in the literature of graft rejection in patients treated with immunotherapy.67

Endoscopic assessment The use of endoscopy is an invaluable tool in the assessment and diagnosis of gastrointestinal irAE. It allows for direct visual inspection of gastrointestinal lesions that may be suggestive of irAE and enables obtaining tissue biopsies to confirm the diagnosis. Currently, endoscopic testing is considered for patients with Grade 2 irAE or above. Endoscopic examination can also be strongly considered in patients with steroid-refractory disease, as ulcerations in the colon are more prevalent in cases of steroidrefractory disease.18,68,69 It can also be considered in cases where patients have been previously exposed to immunosuppressants, as these patients are at risk of opportunistic infections. Endoscopically, the spectrum of severity of gastrointestinal irAE ranges from normal findings to severe inflammatory and/or ulcerative disease. Endoscopic findings are nonspecific but include edema, erythema, exudative changes, superficial erosions, aphthous ulcerations or deep ulcerations of the gastrointestinal mucosa with or without inflammatory changes.28,68 Clinical symptoms do not necessarily correlate with endoscopic findings.13 Anatomically, involvement can occur at any location within the gastrointestinal tract, from the esophagus to the colon. For colonic involvement, the distribution of the findings is usually located to the left side of the colon, although the entirety of the colon can be affected.70 The role of upper endoscopy or colonoscopy in Grades 2 or higher should be to risk-stratify patients for earlier treatment with infliximab, as well as to determine the optimal time to resume anti-PD-1/PD-L1 agents. Follow-up upper endoscopy or colonoscopy may be appropriate to monitor disease activity. Enteritis induced by ICI is managed similarly to colitis, but requires small bowel evaluation and biopsy to diagnose, which can potentially be obtained with conventional colonoscopy if the terminal ileum is involved, or with advanced endoscopic techniques such as balloon-assisted enteroscopy if the disease is beyond the reach of standard endoscopes. Endoscopic assessment should report on the specific anatomical location, distribution, pattern and extent of the lesion, as well as gross visual findings on direct endoscopic visualization. If applicable, the endoscopist should note whether the patient had undergone prior endoscopic evaluations and use those as a baseline for comparison.

The gross visual findings should be described by the presence of noninflammatory ulcerations, inflammation or normal findings. Ulcerations should be described with their respective morphologic appearance, depth and size. When evaluating inflammatory changes, careful characterization of the lesion should be performed, differentiating between erosive, granular, erythematous, exudative or vascular patterns, as well as reporting friability. Patterns of involvement can be reported as diffuse, patchy or segmental.68 Normal mucosal findings should also be reported, and obtaining biopsy specimens of normal tissue is encouraged to rule out microscopic inflammation, as up to 90% of patients with Grade 1 symptoms display early histologic changes.13,71 Upper gastrointestinal involvement is rare and may be under-reported. Esophageal edema with tissue friability, diffuse erythema or ulcerations (Figure 2), as well as gastric and duodenal mucosal atrophy and exudative, erosive or hemorrhagic lesions have been described (Figure 3).72-74

In lower gastrointestinal involvement, case series have observed that in patients with Grade 2 or greater irAE, ulcerations are present in 40%, non-ulcerative inflammation in 42%, and no gross findings in 19% of cases. In terms of anatomical location, 43% of patients had left-sided colitis only, 40% had pancolitis, 14% had ileo-colonic, and 2% only terminal-ileal involvement (Figure 4). In addition, Smith et al have reported on the use of narrow-band imaging (NBI) during endoscopic evaluation to facilitate detection of microerosions and villous hypertrophy.75 More than half (51%) of the inflammatory observations displayed a diffuse pattern, whereas 42% had patchy and only 7% segmental pattern.13

Histologic features Histologic findings can confidently determine whether there is presence of active or chronic inflammation related to ICI, or whether histologic findings are normal. The spectrum of histologic findings varies according to the associated subtype of ICI involved, as well as the different anatomical locations.70,76 In the setting of anti-PD-1 use, active colitis with crypt neutrophilic infiltration, crypt distortion, pronounced epithelial reactive changes consisting primarily of nucleolar prominence, and/or atrophy with formation of micro-abscesses may be observed. Colitis with increased intraepithelial lymphocytes and increased mononuclear cells has also been reported. With anti-CTLA-4 agents, lymphocytic, plasma cell and eosinophilic infiltration of the lamina propria is observed. Neutrophil infiltration of crypts, formation of micro-abscesses and crypt epithelial apoptosis may be observed. Gastric involvement has been observed to have expansion of the lamina propria by a lymphoplasmacytic cellular component. As with gastric involvement, duodenal and ileal involvement also displays lymphoplasmacytic expansion of the lamina propria, along with neutrophilic infiltration/inflammation or blunting of the villi.70,76 (Figure 5)

Conclusion Immunotherapy has demonstrated clinically meaningful efficacy in the treatment of several malignancies. These drugs have been shown to be associated with potentially severe gastrointestinal side effects that need to be quickly recognized. With a growing number of immunotherapy agents and indications, the number of patients exposed to these agents is increasing. For this reason, it is of paramount importance for the gastroenterologist to be aware of the presentation, diagnostic approach and management of patients with gastrointestinal immune-related adverse reactions.

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Figure Legends Figure 1. A 51-year-old patient with diagnosis of metastatic melanoma receiving ipilimumab and nivolumab combination therapy. The patient developed grade 2 diarrhea 4 weeks after rgw initial dose, and was admitted to the hospital 1 week later and was found to have grade 4 pancolitis. A, Coronal view evidencing transverse colon thickening with mesenteric vessel engorgement. B, Sagittal view displaying left-sided colonic thickening. C, Axial views revealing transverse colon wall thickening. D, Axial view evidencing sigmoid colon thickening and fat stranding compatible with inflammation (arrows).

Figure 2. An 84-year-old male patient was seen with dysphagia with a history non-small cell lung cancer treated with pembrolizumab for 12 months. Upper endoscopy showing diffuse inflammatory changes and monilial exudates. Biopsies confirmed characteristic histologic findings consistent with pembrolizumab-related inflammation, as well as presence of Candida albicans on brushings.

Figure 3. A 55-year-old female patient presenting with nausea and vomiting with a history of metastatic melanoma for 6 months treated with pembrolizumab. Direct endoscopic visualization evidenced (A) inflammation with superficial ulcerations, (B) deep ulcerations with necrotic material in the center, and (C) scattered superficial erosions with surrounding inflammatory changes. Histologic findings were

compatible with duodenitis related to pembrolizumab. Patient was started on vedolizumab and had resolution of symptoms. Photos are courtesy of Taha Qazi, MD.

Figure 4 - Spectrum of findings on direct colonoscopic visualization. A, Deep ulceration. B, Aphthous ulceration (yellow arrow). C, Superficial erosions with surrounding inflammatory changes. D, Diffuse inflammation with patchy erythema. E, Edema, erythema and exudates. F, Diffuse erythema with exudative changes. G, Diffuse erythema. H, Normal colon for comparison. Photo in panel A is courtesy of Yinghong Wang, MD, PhD.

Figure 5. A, Active colitis, characterized by lymphoplasmacytic inflammation in the lamina propria, cryptitis and crypt loss (H&E, orig. mag. x 100). B, Higher magnification showing the active inflammation. Scattered foamy macrophages are also present in the lamina propria. C, Higher magnification showing the inflammatory changes and a few crypt apoptoses. Images are courtesy of Murli Krishna MD.

Abbreviations CT – Computed tomography CTCAE – Common Terminology Criteria for Adverse Events CTLA – Cytotoxic T lymphocyte-associated antigen FDA – Food and Drug Administration HIV – Human immunodeficiency virus IBD – Inflammatory bowel disease ICI – Immune checkpoint inhibitor irAE – Immunotherapy-related adverse event NBI – Narrow band imaging NCCN – National Comprehensive Cancer Network PD – Programmed cell death PD-L – Programmed cell death ligand TNF – Tumor necrosis factor