Immune mediated colitis: a surgical perspective

This study aims to review and summarize the current up to date literature that explore the current treatment approaches to immune mediated colitis and the role of surgical specialties in the landscape of management.


Introduction
Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for oncology. They are now considered a cornerstone of oncological therapy alongside chemotherapy, radiotherapy and surgery.
Clinically, the most commonly used ICIs target two immune regulatory pathways: cytotoxic T lymphocyte antigen (CTLA)-4 and programmed death (PD)-1 or its ligand (PD-L1), both with key roles in regulating autoimmunity. 1 While ICIs have produced durable remission, their increasing use has unmasked a wide range of inflammatory toxicities, collectively termed immune-related adverse events (irAEs). [1][2][3] Gastrointestinal toxicities are among the most commonly encountered severe toxicities from current ICI therapy and are a frequent cause of morbidity, treatment interruption, and discontinuation. 1,[4][5][6] Immune mediated Colitis (IMC), also known as checkpoint inhibitor-induced colitis or immune checkpoint inhibitor-induced colitis, with or without accompanying enteritis, affects up to 40% of patients, depending on the pathway targeted and combination treatment. 1,[6][7][8][9] Of these, anti-inflammatory treatment and ICI delay or discontinuation is required in 5%-10% of patients. 4,6,7,10 The approach to managing GI toxicities such as IMC is guided by treating oncology and gastroenterology specialties. However, surgeons have important roles in the multidisciplinary team management of these patients, especially in atypical or refractory cases. Here we present an updated review on the management of immune colitis from a surgical perspective.

Methods
This narrative review was performed following a comprehensive search concordant with PRISMA guidelines. All relevant published studies were identified through a computer-assisted search of Medline, EMBASE and Cochrane Central with the search completed in November 2022. There were no restrictions on the date of publication. The following medical subject heading (MeSH) terms and text words were used for the search in all possible combinations: 'cancer' AND 'immunotherapy' AND 'colitis'. The cited references in each retrieved paper were also checked to ensure that all publications relevant to this study were captured. Additional articles were hand searched from the reference list of included articles. Screening was performed by two independent authors (KL and KC) and disagreements on eligibility were discussed between co-authors until a consensus decision was made.

Results and discussion
Immune mediated colitis: current clinical guidelines and practice points Current guidelines for the management of IMC are based on observational studies. Due to their similarities, these have drawn many parallels to the workup of inflammatory bowel disease (IBD). [11][12][13][14] IMC shows marked heterogeneity and variability, with no current validated severity indices existing due to the fact symptoms can poorly correlate with imaging findings, endoscopic severity and treatment response. 15 Current practices emphasize the role of endoscopic diagnosis and treatment, with surgical input considered if complications such as perforation arise. Herein, we describe the current landscape of the approach to IMC.

Clinical presentation
IMC typically develops at a median of 5-7 weeks post commencement of therapy. 7,9,10 There is, however, considerable variation in this timing, with case reports ranging from after 1 dose of immunotherapy to 4-6 months post completion of immunotherapy. 11,[13][14][15][16][17][18] The current literature and institutional guidelines recommend the use of the Common Terminology Criteria for Adverse Events (CTCAE) to grade severity from mild (grade 1) to death (grade 5) ( Table 1). 19 Mild cases may present with diarrhoea or increased frequency of loose stools which may be accompanied by non-specific symptoms including lethargy, nausea, vomiting and loss of appetite. Of note, fever is generally not apparent. 15 More severe cases may have features of explicit colitis including blood or mucus in the stool, abdominal pain/cramping or peritonism. 20

Diagnostic work up
Initial history seeks to identify reported risk factors for IMC such as non-steroidal anti-inflammatory treatment, prior history of IBD, dual immunotherapy regimen and types of cancers that require these, such as melanoma. However, the degree of risk conferred by each of these is poorly characterized and therefore are of limited value in terms of clinical utility. 15,21,22 The cornerstone of work up of a patient with suspected IMC symptoms seeks to rule out other causes of gastrointestinal tract symptoms in an immunocompromised patient undergoing systemic treatment for malignancy. This involves a thorough examination followed by stool tests, bloodwork and consideration of further evaluation using imaging and endoscopic techniques. 13 Stool tests aim to exclude infectious causes of diarrhoea. Acknowledging the low prevalence of these causes (5%), stool microscopy, culture and sensitivity seeks to rule out Clostridium difficile infection as well as cytomegalovirus (CMV) or other viral aetiology. 15,23 Additional ova, cyst and parasite tests are obtained in patients with risk factors and are based on local prevalence. 15 In a recent clinical practice update, the American Gastroenterological Association (AGA) advised including inflammatory markers lactoferrin and/or calprotectin as an additional stratification tool to select patients for endoscopic evaluation. 15 Blood tests, including a full blood count, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP), are then ordered as part of a complete metabolic panel paying attention to albumin levels. New onset hyperthyroidism and coeliac disease is a rare complication of ICI and therefore should be checked. 24,25 Evaluation of other non-infective diarrhoea causing pathologies in the immunocompromized patient such as small intestinal bacterial overgrowth, carbohydrate malabsorption and pancreatic exocrine insufficiency should be considered. 13 Abdominal imaging is usually not indicated in mild grade 1 cases. The use of computer tomography (CT) imaging of the abdomen and pelvis with oral and intravenous contrast should be considered with grade 2 or higher IMC as there is an increasing body of evidence suggesting CT findings have a strong positive predictive value in diagnosing as well as predicting potential steroid-refractory IMC that may require immunological agents for management. 16,23,26 CT findings however are indistinguishable from other forms of colitis (e.g., infectious and ischaemic) and therefore must be considered with other diagnostic modalities to formulate a diagnosis of IMC. [26][27][28] In severe cases, the use of CT is also an effective and non-invasive alternative to endoscopy for the diagnosis of complications of IMC including toxic megacolon, intra-abdominal collection and perforation. 11,29 In preparation for the use of steroids as well as immunomodulators, latent infections should be ruled out including hepatitis B virus infection and latent tuberculosis. 30 The AGA also recommends checking serology for human immunodeficiency virus and hepatitis C virus infection. 15

Management
Endoscopic evaluation Current guidelines recommend early endoscopy and tissue biopsies as the gold standard for diagnosing immune-mediated colitis, assessing disease severity, and risk-stratifying patients to guide further therapy in a timely manner. The British Society of Gastroenterology (BSG) recommends performing a colonoscopy on all patients with GI irAEs, whereas the American Gastroenterology Association (AGA) indicates endoscopic evaluation in patients with grade 2 or higher GI irAEs.
It is however important to recognize that endoscopic evaluation can demonstrate a range of findings from normal mucosa, mucosal edema, erythema, erosions, loss of vascular pattern to superficial or deep mucosal ulcerations, either in a patchy or continuous fashion. [31][32][33] While not sensitive, it is specific in confirming luminal features of colitis which in the setting of ICI would strongly raise the suspicion of IMC. The caveats to this are infectious causes which account for <5% of cases with this presentation and alternative diagnoses (diverticulitis and ischaemic colitis) which are less common in this patient group. 23,[34][35][36][37][38][39] Furthermore, endoscopic biopsies serve to exclude the presence of opportunistic infections before initiation of high-dose systemic glucocorticoids. In patients with corticosteroid-refractory disease, and in those previously exposed to immunosuppressants, a full colonoscopy is recommended as the index endoscopic procedure. 11,15,30,31,40,41 However, because 98% of GI irAEs involve the left colon and rectum, a flexible sigmoidoscopy rather than a full colonoscopy can be accepted in most cases. 18,20,42,43 As a prognostic feature, the presence of deep, large ulcers is a significant finding as it predicts the likelihood of escalating biologic therapy, increased need for hospitalization, and longer length of stay (LoS). 36 Currently, endoscopic findings in IMC are characterized using the MD Anderson Cancer Center Endoscopic Inflammation Grading and the Mayo Endoscopic Score (Tables 2 and 3). 16 Even if these scoring systems do not correlate with grade of diarrhoea, they can provide useful insight into predicting steroid refractory cases and therefore the use of biologic agents such as infliximab and other intense immunosuppressive regimens. 40 The threshold for colonoscopy varies depending on jurisdiction, particularly when comparing British and American guidelines. Important to recognize is in other jurisdictions such as Australia and Asia, the decision for colonoscopy is not as clear. In these contexts, clinicians should consider colonoscopy in situations which visualization and tissue sampling is required including working up the patient with a normal CT but symptoms consistent with IMC, working up a patient for alternative diagnoses, assessing moderate to severe (including steroid refractory) IMC to guide severity grading and subsequent decision making behind treatment and for ongoing monitoring. In this way, keeping in mind appropriate stewardship of available resources and mild nature of grade 1 colitis which is conservatively managed in the first instance, it is recommended that colonoscopy be pursued for grade 2+ colitis or   30 This is used as an adjunct to support faecal calprotectin levels, which are strongly associated with endoscopic severity in patients with IMC and may serve as a useful noninvasive marker of endoscopic and histologic remission. 36,44 Treatment Various governing bodies including the British Society of Gastroenterology (BSG), European Society for Medical Oncology (ESMO), American Society of Clinical Oncology (ASCO) and American Gastroenterology Association (AGA) agree that central to the IMC treatment approach is accurate stratification by severity (Fig. 1). 15,23,45,46 Grade 1 Grade 1 presentations are generally considered to be mild cases that are typically self-limiting. Supportive care is the main intention of treatment for this patient demographic. This approach involves anti-diarrheal agents such as loperamide, analgesia, nutritional support and oral rehydration in a supervised environment. 12,15,46 Often ICIs are continued in these mild presentations.
Close monitoring is still recommended given the potential for deterioration. As mentioned above, the British Society of Gastroenterology (BSG) recommends flexible sigmoidoscopy and biopsy for Grade 1 presentations as part of the initial workup. 46 They also recommend using the stool inflammatory markers lactoferrin and/or calprotectin as an alternative to risk-stratify patients with grade 1 colitis for endoscopic evaluation. This reflects the caution IMC demands, and all clinicians ought to reserve a high index of suspicion when managing such patients.

Grade 2+
Grade 2 presentations require urgent treatment with pharmacological intervention. 23 The cornerstone of management is the early initiation of corticosteroids. 46 In severe or steroid refractory cases, immunological agents such as infliximab or vedolizumab are then considered. In these cases, ICI treatment is withheld.
Often, grade 2+ presentations into mild, moderate or severe based on endoscopic findings. 15 The type of treatment regimen is then dictated by severity of these presentations. In mild grade 2 presentations, a step-up approach is recommended. Oral high dose corticosteroids (e.g., 0.5-1.0 mg/kg prednisolone equivalent per day) is commenced, with escalation to higher dose of prednisolone at 2 mg/kg or intravenous corticosteroids advised for those with no treatment response by 72 h. 15,46 If symptoms improve to grade 1, the corticosteroids can be tapered over 4-6 weeks to prevent adrenal insufficiency before the cautious recommencement of ICI. 15 However, if there is a persistent lack of complete response to IV corticosteroids, use of secondline immunosuppressants such as infliximab (at a dose of 5 mg/kg) or vedolizumab (at a dose of 300 mg) is indicated. 15 The exception to this step-up approach is the presence of endoscopic evidence of severe grade 2+ colitis, which is considered a predictor of steroid-refractory cases. In these situations, earlier consideration of immunosuppressive agents are recommended, either as a sole agent or in conjunction with corticosteroid therapy. Infliximab and vedolizumab have been shown to have comparable efficacy in achieving clinical remission in patients with immune-mediated colitis. Vedolizumab is a gut-selective agent sparing the systemic immunosuppression seen with the tumour necrosis factor-α (TNF-α) inhibitor infliximab. As a result, reported adverse events from long-term infliximab use have included opportunistic infections and even higher risk of new malignancies such as non-melanoma skin cancers. Unfortunately, vedolizumab requires a longer time to clinical response (6-8 weeks) and may not be preferred when rapid response is required. Nevertheless, the American Gastroenterology Association considers both drugs equivalent and recommends a switch from one to the other for nonresponders. 15 Repeat endoscopy is recommended for follow-up. For those with complete remission, steroid tapers are suggested and immunological agents are stopped if they are no longer required. For those with partial remission, biological agents are often continued and further endoscopy follow-up is required. For those patients who had no or minimal response despite judicious corticosteroid and immunological therapy, alternative therapies are considered (as below) and further diagnostic workup for other etiologies is once again revisited. 15

Surgical considerations
In untreated IMC, large trials in the US have suggested a natural course of progression that includes a 1% risk of perforation and 0.8% chance of death due to this. 13 This accounts for over a third of deaths related to ICI therapy as a whole, therefore necessitating the increasing role surgical specialties in the early recognition management of severe spectrum IMC and its complications including toxic megacolon and perforation.

Indications for surgery
While most cases of IMC are successfully managed with medical therapy, emergency colectomy is indicated for the 1% of patients that develop a colonic perforation from IMC, with a significant perioperative mortality and morbidity. Drawing on the similarities between IMC and IBD, clinicians should be vigilant for warning signs of impending complications related to the side effects of ICI.
A toxic patient warrants urgent surgical review. Cross sectional imaging in a deteriorating patient seeks to identify the presence of megacolon (diameter >6 cm), or any features of bowel compromise such as pneumatosis, patchy enhancement among other radiological features of impending perforation.
Unfortunately, the predictive risk factors for colon perforation are limited. Smith et al. found that patients who received combination therapy with ipilimumab followed by interleukin-2 treatment were more prone to develop perforation than patients who received one of these therapies alone. 47 Heightened vigilance and timely surgery to this severe complication, especially in a patient refractory to medical treatment, can improve the clinical outcomes effectively.
In these patients, a subtotal colectomy is preferred because colonic lesions are generally extensive and segmental colonic resection is generally followed by severe inflammation of the remaining colon in the postoperative phase. 24 In severe colitis without perforation, emergency formation of defunctioning ileostomy is a reasonable alternative to divert faecal stream during acute IMC. The choice of restorative surgery versus a diverting stoma would depend on the clinical picture, for example if a damage control situation was warranted.
Perioperatively, a multidisciplinary team approach would be required to manage the other facets of a patient on ICI therapy. A careful anaesthetic plan accounting for the electrolyte abnormalities as well as the high incidence of concurrent immune mediated hepatitis would be prudent.

Surgical outcomes
Morbidity and mortality of severe IMC requiring surgical intervention remains poorly characterized. Despite this, many of the surgical principles and expected outcomes mirror what is expected with similar pathologies including severe and refractory IBD.
In such patients who have underwent colectomy, there is an estimated incidence of 21% for short-term (<30 day) complications including postoperative infection (20%), ileus (18%), small bowel obstruction (8%), fistula (4%), anastomotic leak (3%) and mortality (1%). 48 Furthermore, long-term (>30 days) sequelae had an estimated incidence of 39% with a unique spectrum of complications including faecal incontinence (21%), small bowel obstruction (17%), ileus (11%), fistula (6%) and mortality (0.2%). 48 Surgeons must therefore be mindful that populations like those with severe IMC requiring resection are highly predisposed to a higher incidence of postoperative morbidity and mortality outcomes and therefore close short and long-term follow-up is necessary to ensure the early recognition and management of these outcomes should they arise.
For patients who have had a defunctioning stoma formed, the major disadvantage comes from the impact of having a long-lasting or permanent stoma and patients should be counselled regarding this outcome. In such patients, ICI therapy may be resumed sooner than those who have underwent colectomy due to lower risk of surgical complications, in particular anastomotic leak. 49 Decision for reversal must be balanced with risks of recurrence, which occurs at a rate of 30% and often more severe than the index case of IMC. 13 Furthermore, there are limited studies to support that bowel anastomosis is safe with ICI usage and therefore caution is advised in regard to decision for restorative surgery, especially in patients with severe IMC resulting in bowel perforation.
The decision for resuming ICIs, particularly following surgical intervention for severe IMCs warrants multidisciplinary decisionmaking balancing risks of postoperative complications and adequate healing alongside the need to resume therapy. Such decisions should occur on a case-by-case basis centred around consideration into patient comorbidities, postoperative progress, underlying malignancy and alternative therapy options.

Special populations
The role of prophylactic colectomy in patients with ulcerative colitis prior to commencing ICI in order to reduce risk of immune colitis is controversial. To date, there have been isolated case reports of this after multidisciplinary discussions. While there is no dependable way to predict who will develop IMC, including in patients with underlying IBD, up to 10% of treatment-related grade 3/4 colitis in combination ICI therapy as seen in Checkmate 067 trial of metastatic melanoma has prompted consideration of prophylactic surgery to avoid the need for treatment interruption with severe irAEs. 50 Faecal microbiota transplantation (FMT) While very much in its infancy, the role of FMT treatment for patients with IMC refractory to immunosuppressive therapy has shown promise in small cohort studies, and warrants mentioning.
Accumulating experimental and clinical evidence shows that the microbiome is involved in both anti-tumour and enterocolitis response in patients receiving ICI therapy. There is evidence that certain bacteria increase the risk for IMC, specifically in the context of anti-CTLA-4 therapy it has been shown that baseline microbiota enriched in Firmicutes and decreased in Bacteroides predict an increased risk of IMC. 51 Accordingly, a recent meta-analysis suggested FMT could generate a positive effect on the gut microbiome leading to increased immunological responses while reducing irAEs in several studies. 52 Thus, in ICI colitis, the use of gut-microbiome altering drugs, such as antibiotics, should be carefully considered. 53 The possibility of altering a patient's microbiome via FMT to improve the chances of success of ICI therapy and minimizing adverse events carries much hope and drives much of the current microbiome research.

Restarting therapy
There are no specific guidelines surrounding the decision to restart ICIs. However, it is known that most cases of IMC will not recur unless a patient receives further ICIs. 45 The risk of recurrence of IMC is estimated to be 30% with resumption of therapy. 54 Importantly, colitis itself has been shown to have significantly higher recurrence rates often of higher degree of severity than irAEs of other organ systems. 55,56 Decision making should involve consideration into type of malignancy, alternative agents for management as well as severity of the IMC and endoscopic findings. Recommencement of ICIs is recommended in select cases of those with grade 2 or higher IMC and permanent discontinuation is highly recommended for severe cases as well as in those with toxicity recurrence post rechallenge. 30,45 The decision for recommencement or rechallenge should be made on a case-by-case basis with close monitoring for signs and symptoms of IMC. There should be a low threshold for repeat diagnostic workup if clinical suspicion arises.

Prevention
There is currently no evidence to support the efficacy of any prophylactic measures to prevent the onset of IMC or other gastrointestinal irAEs. 15 The use of budesonide, an effective steroid sparing agent at high doses for steroid-refractory diarrhoea, has been considered and trialled in the context of prophylaxis, but it was proven to be ineffective at preventing development of grade 2+ symptoms. 57-59 Current practices, therefore, emphasize a multidisciplinary approach with specialist gastroenterologists, surgeons, treating oncologists and researchers for early recognition and subsequent management of ICM to achieve the most beneficial outcomes. 60 Conclusion ICI therapy remains an exciting frontier in oncology treatment, but patients need to be monitored closely for irAEs. To facilitate prompt diagnosis and management of immune-mediated colitis, surgeons need to be familiar with the topic and latest recommendations. This review provides an updated overview of this fast moving field.