Immune-mediated Enterocolitis

Immune-mediated enterocolitis is a serious inflammatory condition affecting the intestines that can develop in people taking immune checkpoint inhibitors for cancer treatment, occurring in up to 44% of patients treated with combination therapies and requiring prompt recognition and treatment to prevent life-threatening complications.

Table of contents

• What Is Immune-mediated Enterocolitis?
• What Causes This Condition?
• Symptoms and Warning Signs
• Who Is at Risk?
• How Is It Diagnosed?
• Treatment Options
• Outlook and Survival

What Is Immune-mediated Enterocolitis?

Immune-mediated enterocolitis is an inflammation that occurs throughout the intestines as a side effect of cancer treatment with immune checkpoint inhibitors (ICIs), which are medications designed to help the immune system fight cancer. The term combines “enteritis,” meaning inflammation of the small intestine, with “colitis,” meaning inflammation of the large intestine.^[1]

This condition is also known as immune-mediated diarrhea and colitis (IMDC) when it causes symptoms like diarrhea.^[2] When inflammation occurs in both the small and large intestines at once, it tends to be more severe than inflammation affecting only one part of the digestive system.^[8]

immune-mediated diarrhea and colitis, IMDC, ICI-induced colitis, immune checkpoint inhibitor-induced colitis

What Causes This Condition?

Immune-mediated enterocolitis occurs as a side effect of cancer treatment with immune checkpoint inhibitors. These medications work by blocking certain proteins that normally keep the immune system in check, such as cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed death-ligand 1 (PD-L1).^[1]

By releasing these natural brakes on the immune system, checkpoint inhibitors help immune cells recognize and attack cancer cells more effectively. However, this activation can also cause the immune system to attack normal, healthy tissues in the body, including the intestines.^[3] When this happens, inflammation develops throughout the gastrointestinal tract, leading to enterocolitis.

The condition is thought to result from autoreactive T-cells, which are immune cells that have been freed from normal controls and begin attacking the body’s own tissues. This creates inflammation in the intestinal lining that can range from mild to severe.^[7]

Symptoms and Warning Signs

The hallmark symptom of immune-mediated enterocolitis is diarrhea, which may be accompanied by mucus or blood in the stool. Patients typically experience an increase in the number of bowel movements compared to their usual pattern.^[2]

Other common symptoms include:^[2][5]

• Abdominal pain and cramping
• Fever
• Nausea and vomiting
• Loss of appetite and poor oral intake
• Abdominal tenderness
• Tenesmus (a feeling of needing to pass stool even when the bowels are empty)
• Hematochezia (blood in the stool)
• Fatigue
• Swollen, distended abdomen

The median time for symptoms to appear is approximately 6 weeks after starting immune checkpoint inhibitor therapy, though they can develop as early as one week or as late as six months after the first dose.^[3][5] Early detection and prompt treatment are crucial to avoid serious, potentially life-threatening complications.^[2]

Who Is at Risk?

The incidence of immune-mediated enterocolitis varies significantly depending on the type of immune checkpoint inhibitor used. In patients treated with combination therapy using both CTLA-4 and PD-L1 antibodies (such as ipilimumab and nivolumab), approximately 44% experience diarrhea and 16% develop colitis. Among those treated with PD-L1 antibodies alone, about 11% report diarrhea and 1% develop colitis.^[5]

The incidence ranges from 1% to 25% depending on the specific checkpoint inhibitor regimen used.^[1] Anti-CTLA-4 antibodies are generally associated with earlier onset and more severe immune-related side effects than PD-1/PD-L1 inhibitors, and combination therapy increases both the frequency and severity of these effects even further.^[7]

Risk factors for developing immune-mediated enterocolitis include:^[2]

• Baseline gut microbiota composition
• Preexisting autoimmune disorders
• History of inflammatory bowel disease
• Type of cancer being treated

Patients with a history of inflammatory bowel disease (IBD) face a particularly high risk. Studies show that the flare-up rate among patients with preexisting IBD receiving immune checkpoint inhibitors can be as high as 42%, even with PD-1/PD-L1 monotherapy, which is typically considered a lower-risk regimen. In contrast, PD-1/PD-L1 monotherapy causes enterocolitis in approximately 15% of patients without underlying IBD.^[6]

How Is It Diagnosed?

Diagnosis of immune-mediated enterocolitis should be considered in any patient experiencing diarrhea or abdominal pain while being treated with immune checkpoint inhibitors.^[5] The first step is to rule out infectious causes of diarrhea, as infections can produce similar symptoms.

Healthcare providers typically perform the following tests:^[7]

• Stool studies to check for common bacterial, viral, and parasitic pathogens, including Clostridioides difficile (C. diff)
• Lactoferrin and fecal calprotectin tests to assess inflammation levels
• Complete blood count and comprehensive metabolic panel
• C-reactive protein and erythrocyte sedimentation rate to measure inflammation
• Colonoscopy with biopsies
• Abdominal imaging studies

When immune checkpoint inhibitor enterocolitis is suspected, patients are routinely evaluated with stool studies, endoscopy (a procedure using a flexible tube with a camera to view the inside of the digestive tract), and histologic examination (microscopic study of tissue samples) to confirm inflammation and assess its severity. These objective findings are critical for guiding appropriate treatment decisions.^[6]

Immune checkpoint inhibitor enterocolitis can closely resemble inflammatory bowel disease on endoscopy, with findings such as ulcers, redness, exudates, granulation tissue, and mucosal friability (tissue that bleeds easily). However, the condition encompasses a broader spectrum of presentations than classical IBD. For example, it may manifest as microscopic colitis, where endoscopic findings appear normal but tissue examination reveals inflammation.^[6]

Patients are typically categorized into one of five grades based on the National Cancer Institute’s Common Terminology Criteria for Adverse Events. This grading system helps guide treatment decisions.^[3]

Treatment Options

Treatment of immune-mediated enterocolitis depends on the severity of symptoms. Current management is based on corticosteroids as first-line therapy, with immunosuppressants used for cases that do not respond to initial treatment.^[2]

Patients with mild symptoms (grade 1) can often be managed conservatively with supportive care alone. This may include dietary modifications, increased fluid intake, and anti-diarrheal medications such as loperamide.^[3][4]

For patients with grade 2 or higher symptoms, treatment typically includes:^[3]

• Colonoscopy to assess the extent and severity of inflammation
• Systemic corticosteroids as initial therapy
• Biologic therapy if corticosteroids are not effective

More severe cases may require immunomodulators such as steroids, and refractory cases may need tumor necrosis factor (TNF) inhibitors such as infliximab or vedolizumab in addition to steroid treatment.^[4] These medications work by suppressing the overactive immune response causing the inflammation.

Emerging treatments being investigated include microbiota transplantation, specific cytokines, and lymphocyte replication inhibitors.^[2] Research has shown that fecal microbiota transplantation (FMT) offers a promising option, inducing sustained long-term remission of colitis even during ongoing immune checkpoint inhibitor therapy, lasting over a year in some cases. This approach is fast-acting, effective, and safe.^[11]

With timely and appropriate management, enterocolitis can achieve rapid remission. Immunosuppressive therapy can be safely continued while resuming immune checkpoint inhibitor treatment long-term, with excellent success in preventing colitis recurrence.^[11]

Outlook and Survival

Interestingly, patients who experience immune-related adverse events of any organ system, including gastrointestinal events, have improved overall survival compared to those without such events. There is a specific survival benefit associated with gastrointestinal-related immune side effects.^[7]

Data from advanced melanoma studies show that patients who discontinued immune checkpoint inhibitors due to treatment-related side effects had similar overall survival at five years compared to the overall population treated with these medications. This suggests that immune-related adverse events like enterocolitis, if tolerable and responsive to treatment, are not necessarily associated with worse survival. In some circumstances, they may even correlate with more robust antitumor activity and a higher likelihood of favorable treatment response.^[7]

Optimal patient care requires maintaining a balance between treatment toxicity and efficacy. Early identification and prompt treatment of immune-mediated enterocolitis can help avoid detrimental outcomes while preserving the cancer-fighting benefits of immune checkpoint inhibitors.^[3]

For patients with preexisting inflammatory bowel disease, oncologic outcomes remain comparable to those without IBD. Despite the increased risk of flare-ups, patients with IBD who receive immune checkpoint inhibitors demonstrate cancer response rates equivalent to those of non-IBD patients.^[6]