Immunotherapy – Induced Colitis

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ACHAIKI IATRIKI | 2025; 44(2):84–92

Review

Gerasimia-Marina Chardalia, Angelos Koutras

Division of Oncology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece

Received: 07 Jun 2024; Accepted: 07 Oct 2024

Corresponding author: Angelos Koutras, Associate Professor, Division of Oncology, Department of Internal Medicine, Medical School, University of Patras, Patras, Greece, PC 26504 Tel.: +30 2610999535, E-mail: angkoutr@otenet.gr

Key words: Immune checkpoint inhibitors, diarrhea; colitis, immune-related adverse events

 

Abstract

The introduction of Immune Checkpoint Inhibitors (ICIs) entirely altered the landscape of the oncologic therapeutic approach. The immunotherapy agents administered to date have been proven to be efficient and improve overall survival even in advanced malignancies, whose prognosis was poor before the emergence of ICIs. Nevertheless, the immune system’s overresponsive activity may lead to toxic consequences, gastrointestinal adverse events being the most frequently reported. Their clinical manifestations range from mild, self-restricted diarrhea to fatal complications such as intestinal perforation. Few studies have been conducted to detect the susceptibility factors leading to the development of immune-checkpoint inhibitor-mediated colitis (IMC) and clinicians remain incapable of identifying high-risk patients in time. Management of IMC principally includes corticosteroids, showing favorable outcomes and remission in a significant percentage of patients. However, refractory disease cases still require biologic agents such as Infliximab or Vedolizumab. This review aims to highlight the clinical importance of diagnosing IMC promptly and treating it according to the latest evidence-based guidelines, while discussing promising management approaches.

Introduction

Immunity checkpoint inhibitors (ICIs) have dramatically transformed the current treatment approach of malignancies. Since their incorporation into oncology, there has been a revolution in the management of cancers of all grades. The improvement of both overall survival and quality of life for patients represents a significant scientific breakthrough of the 21st century [1].It is well acknowledged that tumor cells employ mechanisms to escape the immunosurveillance system. Hence, scientists developed the ICIs, monoclonal antibodies targeting three critical molecules of this process: the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), the programmed cell death protein-1 (PD-1) and its ligand PD-L1 (PD-L1). These proteins consist of inhibitory receptors of the immune system, suppressing the T-cell-mediated activity against the tumor. Consequently, the ICIs, by blocking these receptors, lead to enhanced T cell activity in order to eliminate the tumor cells [2].

The introduction of immunotherapy as an additional tool against cancer has not only resulted in favorable outcomes, but has also posed challenges. Unfortunately, the overresponse of T cells has a potentially harmful effect on almost every healthy tissue, imitating the entities of autoimmune diseases, known as immune-related adverse events (irAEs) [3].One of the most common irAEs implicates the gastrointestinal tract, with clinical presentation ranging from diarrhea to severe colitis leading even to fatal perforation [4].Its prevalence in the population receiving ICIs ranges from 1 to 25%, depending on several parameters [5]. Wang et al. [6], in their meta-analysis, reported that the incidence of colitis across all grades varies depending on the type of immunotherapy administered. More specifically, the percentage of patients who presented ICIs-induced colitis was 1.4% for anti-PD1 agents, 1% for anti-PDL1 agents, and 9.1% for anti-CTLA4 agents. It is noteworthy that the combination of two types of agents, Nivolumab and Ipilimumab, is linked to even higher incidence [7].

This review aims to highlight the importance of promptly diagnosing Immune-checkpoint inhibitor-mediated colitis (IMC), differentiating it from other forms of colitis and effectively managing it according to the latest guidelines.

Pathophysiology

The precise mechanism underlying IMC remains obscure. Nevertheless, three events play a pivotal role in its pathology: the excessive activation of T effector cells (Teff), the lymphocyte infiltration of the intestinal mucosa, and the increased circulation of T memory cells [8-10].

CTLA-4 is a critical checkpoint inducing the suppressive function of CD4+ regulatory T cells (Tregs) [11]. Hence, the inhibition of CTLA-4 may contribute to the development of autoimmune diseases such as IMC. In addition, Luoma et al. [12]proposed that one of the initiating events of IMC is the conversion of resident CD8+ T memory cells in the intestinal mucosa into cytotoxic effector T cells (CTLs), overproducing inflammatory cytokines such as IL-17, IFN-γ, and TNF-α. Furthermore, the upregulation of chemokine receptors CXCR3, 6, 9/10, 16, and integrin receptors a4b7/aEb7 appears to enhance the T cell activity [13].

The role of gut microbiota is also in the spotlight of researchers of irAEs as an imbalance in the intestinal mucosa’s flora can affect both the patient’s response to immunotherapy and severity of IMC [14]. In most patients receiving ICIs, species such as Bacteroides fragilis, Burkholderiales, and Lactobacillus reuteri are decreased, while bacteria from the Faecalibacterium prausnitzii genus are enriched [13]. This dysbiosis in gut microbiota may play a predictive role in patients’ antitumor response and their likelihood of developing IMC.

Risk factors

Since the emergence and recognition of the IMC entity as an irAE, researchers have sought to identify the main parameters defining the level of patient’s susceptibility in developing IMC. As mentioned above, the type of immunotherapy agents administered must be considered as a risk factor. CTLA4 inhibitors are associated with a higher incidence of colitis compared to both anti-PD1 and anti-PDL1 agents [6]. Notably, Ascierto et al. [15], in their randomized, double-blind, multicenter study, concluded that patients with advanced melanoma who received higher doses of Ipilimumab were more susceptible to developing colitis in comparison with the patient group receiving lower Ipilimumab doses. Hence, this finding establishes Ipilimumab, an anti-CTLA4 factor, as the only demonstrating dose-dependent predisposition to colitis.

In the largest study examining the epidemiology of IMC, Farha et al. [16] were the first to identify the characteristics associated with increased susceptibility to developing IMC. Accordingly, it was discussed that female gender, Caucasian ancestry, alcoholism, obesity, and age over 65 years are the primary underlying risk factors to consider when administering immune checkpoint inhibitors. Furthermore, the same cohort study demonstrated that patients with a background of autoimmune disease have an elevated risk of developing colitis. The presence of preexisting autoimmune disease in patients with IMC was found to be 24.6%, with rheumatoid arthritis being the most prevalent, affecting 9.8% of the population studied. In addition, on a genetic basis, HLA-DQB1*03:01 was found to be associated with gastrointestinal adverse events [17].

Patients with a history of Inflammatory Bowel Disease (IBD) have a significantly higher median risk of developing IMC compared to those without an IBD background (41% vs 11%, respectively; P < .001) [18]. Therefore, clinicians should maintain a high level of suspicion in such cases but always consider the differential diagnosis with an exacerbation of IBD, as the clinical manifestations may overlap [19].

Clinical presentation and differential diagnosis

Based on clinical manifestations, the National Cancer Institute’s Common Terminology Criteria for Adverse Events (CTCAE) provides classification systems for both diarrhea and colitis in order to assess disease severity and guide proper management (Table 1) [20]. The classification of diarrhea is based on the number of daily bowel movements above the patient’s baseline. Diarrhea is often the first alarming sign of IMC and requires thorough examination [21]. Specifically, Grade 1 diarrhea is defined as fewer than four stools above baseline per day, while Grade 2 is characterized by four to six additional stools per day above baseline. Severe cases where the number of stools exceeds seven above baseline are classified as Grade 3. Grade 4 indicates life-threatening conditions requiring urgent intervention, such as hemodynamic collapse. Finally, both diarrhea and colitis classifications designate Grade 5 as death.

Regarding the classification of colitis, Grade 1 corresponds to asymptomatic patients, while Grade 2 refers to patients with a recent history of or currently receiving immunotherapy who present with abdominal pain, and bloody or mucousy diarrhea. Concomitant presentations that raise suspicion of IMC include fever, severe pain, signs of peritoneal irritation (Grade 3), or even life-threatening conditions (Grade 4) such as perforation, ischemia, bleeding, necrosis, and toxic megacolon [19]. Additionally, common clinical manifestations include hematochezia, vomiting, and nausea, while patients may also report less typical symptoms such as weight loss or loss of appetite [13]. Furthermore, IMC may also involve upper gastrointestinal symptoms, including dyspepsia, heartburn, and regurgitation. Clinicians must be mindful of the potential coexistence of immunotherapy-induced gastritis alongside IMC [22].

The diagnosis of IMC is based on exclusion, as other forms of colitis or clinical entities (Figure 1) may present with the same manifestations and may even share comparable laboratory, imaging, or histological findings [23].

Figure 1. Differential Diagnosis of Immune-checkpoint inhibitor-mediated colitis (IMC) [23].

Diagnosis

Clinical manifestations suggestive of IMC should prompt clinicians to undertake a thorough investigation to establish a timely diagnosis. A detailed patient history and physical examination play a crucial role in the initial assessment and in determining the grade of colitis. Moreover, a complete blood count and biochemical panel should be performed, as along with a measurement of C-reactive protein (CRP) and Erythrocyte Sedimentation Rate (ESR) [24]. Infectious causes of colitis should be ruled out from the beginning, and therefore, it is recommended to obtain stool cultures for detecting pathogens such as Clostridioides difficile. It may also be prudent to conduct a supplemental viral check and parasite test in patients residing in regions with a high prevalence of viruses and parasites known to cause colitis. Further investigation could include stool inflammatory markers such as lactoferrin and calprotectin. The American Gastroenterological Association (AGA) recommends the detection of these markers as they identify patients with Grade 1 colitis as being at high-risk for further endoscopic assessment. Regarding Grade 2 or higher colitis, their detection is strongly recommended, though not strictly required, before proceeding to endoscopy [25].Furthermore, exocrine pancreatic insufficiency is a rare complication of ICIs, but it must still be excluded from the differential diagnosis by measuring fecal pancreatic elastase [26].Additionally, the possibility of new-onset celiac disease following immunotherapy should be considered, and tissue transglutaminase immunoglobulin A (IgA) and total IgA tests should be ordered [27].

Endoscopic assessment through colonoscopy or sigmoidoscopy is the gold standard for diagnosing IMC. In patients receiving Ipilimumab, sigmoidoscopy could be considered a first-choice diagnostic procedure because the rectum and the sigmoid colon are the principal colon segments affected [10]. Random biopsies should always be performed, as 33% of patients with IMC undergoing colonoscopy show normal-appearing intestinal mucosa [28]. This subgroup of patients tends to have better clinical outcomes and a lower risk of developing refractory disease or biologic therapies [29]. Abnormal endoscopic findings may include loss of vascular patterns, erythema, ulcerations, edema, necrosis and friable mucosa, which are associated with a worse prognosis [30]. Furthermore, the biopsies obtained can be used to rule out microscopic colitis or infectious colitis caused by Clostridioides difficile or cytomegalovirus (CMV) [31]. Notably, endoscopy plays a multi-dimensional role in the management of IMC. Clinicians should be aware of indications for repeat endoscopy applied in Grade 2 and above, such as lack of response to immunosuppressive treatment, deterioration of symptoms despite initial improvement, and evaluation of the intestinal mucosa before resuming immunotherapy agents following temporary discontinuation [5].

Computed tomography (CT) has also proven useful in assessing probable IMC cases, especially if there is a high clinical suspicion index of life-threatening events such as toxic megacolon or perforation, which necessitate immediate surgical intervention [32]. Findings such as diffuse or segmental colitis patterns on CT cannot establish a definite diagnosis of IMC as CT is characterized by low sensitivity and a high rate of false negatives [33]. Consequently, in early-stage patients, combining sigmoidoscopy with CT may be beneficial [32].

Histopathologic findings from the biopsies obtained are suggestive of the diagnosis of IMC. Remarkably, histological differences have been noted depending on the ICI administered. For instance, CTLA-4-associated colitis is linked to lamina propria expansion and lymphocytic intraepithelial infiltration, along with cryptic apoptosis or occasional prevalence of eosinophils in the lamina propria [34]. Concurrently, the lamina propria expansion by lymphoplasmacytic infiltration may be a histologic feature of anti-PD1/anti-PDL1-associated colitis. In addition, neutrophils are the prominent inflammatory cells found, while they can also form cryptic abscesses[35,36]. Ischemic or collagenous colitis have also been described [37].Most of the patients’ biopsies, in both CTLA-4 and anti-PD1/anti-PDL1-induced colitis, show acute inflammatory changes that are indicative of IMC, while chronic inflammatory alterations of the intestinal submucosal tissue are found in approximately 50% of patients [33,37].However, it is noteworthy that these histologic findings are not pathognomonic for IMC and have been described in other clinical entities that mimic IMC, such as infectious colitis, IBD, and GvHD [38]. Consequently, the final diagnosis must be made by integrating the patient’s history, physical examination, laboratory work-up, and both endoscopic and histopathologic findings [32].

Management

Early-stage colitis, assessed as Grade 1, is typically managed conservatively. Specifically, liquid supplementation is imperative in case of dehydration and electrolyte imbalances, which should be corrected. Anti-diarrheal agents such as loperamide may be used, but they are only approved for patients with Grade-1 colitis [39].Foods containing a high percentage of fat and lactose should be avoided in order to prevent secondary lactose intolerance or deterioration of the disease [40].Moreover, the immunotherapy agent may be temporarily ceased or, depending on the patient’s tolerance, continued. At this stage of IMC, discontinuing ICIs is not usually considered. However, this decision should be made after a multidisciplinary discussion involving oncologists and gastroenterologists, who will assess the patient’s performance status, comorbidities, and clinical presentation [41].Persisting Grade-1 colitis for more than 14 days may lead to the addition of oral budesonide [42], which has been shown to improve colitis symptoms and prevent the immunotherapy discontinuation [43].Despite its efficacy, budesonide was tested in two randomized trials as possible prophylactic treatment for patients receiving Ipilimumab, but no statistically significant benefit was demonstrated [44,45].Systemic corticosteroids could be an alternative option in persisting colitis of Grade 1, but clinicians should assess their effectiveness within the first few days of administration and, in case of a positive reciprocation, taper them throughout four to six weeks [46].Furthermore, patients should be evaluated for stool inflammatory markers in order to determine whether they are low- or high-risk, with the latter requiring assessment with an endoscopy [25].

The therapeutic management of Grade-2 IMC differs as systemic corticosteroids intravenously (IV) should be initiated from the outset (preferably prednisone or methylprednisolone in doses of 1-2 mg/kg/day). If improvement is noted after introducing IV corticosteroids, the patient may transition to oral corticosteroids [47]. Abdominal CT and endoscopy should always be performed for further evaluation [13]. In addition, patients receiving CTLA4 inhibitors should likely discontinue treatment permanently, while anti-PD1 and anti-PDL1 agents may be temporarily withheld and reintroduced when clinical improvement is achieved [48]. Biologic agents such as Infliximab, an anti-TNFa antibody or Vedolizumab, an integrin blocker, can be administered in case of corticosteroid refractory disease, whose incidence may reach 40% [49]. Early initiation of such biologic agents typically leads to better results, including fewer hospitalizations, earlier disease remission and reduced corticosteroid requirements [50].

Grade-3 colitis necessitates hospitalization of all patients, with close monitoring of hydration level and electrolytes. Therapeutic management does not differ significantly from Grade 2. Discontinuation of CTLA-4 inhibitors is mandatory, while anti-PD1/PDL-1 agents can be temporarily withheld. Systemic corticosteroids should be administered intravenously at high doses but if there is no immediate clinical improvement (after three to five days), escalation therapy with the biologic agents discussed should be initiated [39]. The recommended dosages are the same as those used in IBD patients: 5 mg/kg for Infliximab and 300mg for Vedolizumab [51]. The responsiveness after the biologic agent’s infusion is typically rapid within the first week [52]. Notably, a single infusion may be adequate for complete remission of clinical manifestations with either Infliximab or Vedolizumab used, though there is a higher risk of relapse compared to 3 infusions [50]. Furthermore, there is currently no evidence to suggest whether either of the two biologic factors predominate. Clinicians should decide based on the availability or any contraindications that may arise [53].

Grade-4 colitis is managed similarly to Grade 3; however, in this case, immunotherapy agents are permanently discontinued regardless of the factor administered and reintroduction is not reconsidered (Table 2). CT imaging must be performed as life-threatening events such as intestinal necrosis, perforation or toxic megacolon may have occurred, potentially requiring further intervention or surgery [19].

According to the treatment algorithm of IMC (Figure 2), biologic agents, particularly Infliximab and Vedolizumab, play an indispensable role in the therapeutic arsenal considering their efficacy [54]. Besides their role as an escalation therapy, the multidisciplinary modified Delphi consensus [55] recommended their introduction as a first-line treatment in patients with high-risk endoscopic findings, including large ulcerations and extensive colitis [50]. Furthermore, in case of no significant clinical improvement after administering one of these two commonly used biologic agents, the introduction of the other is strongly recommended [24]. Nonetheless, in case of Infliximab and Vedolizumab refractory disease the American Society of Clinical Oncology (ASCO) suggests the introduction of Tofacitinib, a Janus kinase (JAK) inhibitor or Ustekinumab, an antibody blocking interleukin-12 (IL-12) [56].

Figure 2. Practical Guide for Immune-checkpoint inhibitor-mediated colitis (IMC) management [46,56].

Management of IMC can be particularly challenging for clinicians, as refractory disease is common, even with the use of biologic agents [57]. In response, researchers are conducting trials to discover alternative and more effective treatments. Specifically, the correlation between gut microbiome composition and the IMC, as well as the influence of gut microbiota on the efficacy of ICIs against tumor cells, has led scientists to explore the potential of fecal microbiota transplantation (FMT) [58-62]. The first two patients receiving FMT due to refractory IMC were reported by Wang et al. in 2018 [62]. Notably, the second patient underwent two cycles of FMT to achieve complete remission of colitis. Since these initial case reports, other researchers have applied FMT in refractory cases with favorable outcomes, rendering it an extremely promising treatment option [63-65].

Conclusion

Checkpoint inhibitors are among the most revolutionary oncologic treatments to date. However, they can result in various forms of toxicity, with IMC being one of the most frequently encountered adverse events. Clinicians must be aware that this side effect can arise even months after immunotherapy has been discontinued. Evaluating patients’ risk factors is essential for assessing susceptibility to developing IMC. Clinical manifestations are nonspecific, as many pathologies mimic IMC, necessitating a thorough investigation, including laboratory workup, imaging and endoscopic procedures. The management of these patients must be meticulous, with collaboration between oncologists and gastroenterologists being essential. Stratifying patients and defining the colitis grade is the first step in managing this irAE. Corticosteroids remain the cornerstone of treatment, but unfortunately, the rate of steroid-refractory disease is high. Hence, the use of biologic agents plays a crucial role and is associated with favorable outcomes. However, despite their efficacy, some patients fail to respond to this approach, prompting researchers to introduce new treatments aimed at achieving complete disease remission. Notably, FMT is one of the most promising alternatives, but further trials are needed to embed it as a safe and effective treatment in the management guidelines algorithm. Consequently, IMC is an adverse event that significantly affects a patient’s quality of life, requiring prompt diagnosis and evidence-based management to ensure optimal remission.

Conflict of interest disclosure

None to declare.

Declaration of funding sources

None to declare

Author contributions

Conception and Design, AK, GMC; Analysis and Interpretation of the data, GMC; Drafting of the article, GMC; Critical revision of the article for important intellectual content, AK; Final approval, AK.

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