Checkpoint inhibitor induced colitis is an inflammatory condition affecting the colon, which is caused by cancer immunotherapy. Symptoms typically consist of diarrhea, abdominal pain and rectal bleeding. Less commonly, nausea and vomiting may occur, which may suggest the present of gastroenteritis. The severity of diarrhea and colitis are graded based on the frequency of bowel movements and symptoms of colitis, respectively. The gold standard for the diagnosis of checkpoint inhibitor induced colitis is colonoscopy with evaluation of the terminal ileum. However, in most cases, a flexible sigmoidoscopy is sufficient. Infection should be ruled out with stool studies, including Clostridioides difficile, bacterial culture, ova and parasites. Symptoms of upper abdominal pain, nausea or vomiting warrant evaluation with upper endoscopy. Treatment of immune checkpoint inhibitor colitis is based on severity, as defined by the grade of diarrhea and colitis. Mild cases by managed with temporary interruption of immune checkpoint inhibitor therapy, dietary modification, and/or loperamide. More severe cases require immune suppression with corticosteroid therapy. If steroids are ineffective, infliximab may be considered. If colitis fails to improve with infliximab, then vedolizumab may be effective.
Epidemiology
The prevalence of checkpoint inhibitor induced colitis varies depending on the regimen of immunotherapy. The incidence is 0.7 – 1.6% for anti-programmed cell death protein 1 agents, 5.7 – 9.1% for anti-cytotoxic T-lympocyte associated protein 4, and about 13.6% for combination therapy. The risk associated with ipilimumab is dose dependent, such that higher doses are associated with higher rates of colitis. However, other agents are not associated with a dose dependent effect on the risk of immune mediated colitis. Risk factors for immune mediated colitis include Caucasian race, treatment with an anti-CTLA4 based regimen, melanoma as cancer type, nonsteroidal anti-inflammatory drug use, and a prior history of checkpoint inhibitor induced colitis.
Pathophysiology
Immune checkpoints are important for the normal development of T regulatory cells in the intestine. Mice with the CTLA-4 gene removed develop severe autoimmune disease, with diffuse infiltration of T cells in multiple organs and fatal enterocolitis. Immune checkpoint inhibitor colitis is typically characterized by either diffuse mucosal inflammation or focal active colitis with patchy crypt abscesses. Common findings of acute colitis include: intraepithelial neutrophilic infiltrates, crypt abscesses, and increased apoptotic cells within crypts. However, the histologic appearance varies, and evidence of chronic inflammation is seen in some cases, including intraepithelial lymphocytes or basal lymphocytes and crypt architecture distortion. Histologic inflammation may occur as early as 1-2 weeks after immune checkpoint inhibitor therapy, well before the onset of symptoms. Anti-PD-1 induced colitis may lead to more CD8+ T cell inflammation, whereas Anti-CTLA4 induced colitis may involve more CD4+ T cell infiltration and higher mucosal levels of the inflammatory molecule TNF alpha. Amongst people treated with immune checkpoint inhibitors, those with Faecalibacterium genus and other Firmicutes present in the colonic flora have longer progression-free survival and overall survival. In addition, a higher rate of checkpoint inhibitor induced colitis is associated with the presence of Faecalibacterium in the fecal microbiota.
Signs and symptoms
The most common symptom is diarrhea, which occurs in 92 percent of cases, followed by abdominal pain and rectal bleeding. About 46% of cases include fever and 36% involve nausea and vomiting. Less often, nausea and vomiting may be present.
Grading colitis and diarrhea
The extent of diarrhea is graded based on severity, from 1 to 5. Grade 1 diarrhea is defined by an increase in the number of stools below four per day. Grade 2 diarrhea is defined by an increase of 4–6 bowel movements per day. Grade 3 diarrhea is defined by an increase by 7 or more bowel movements per day. Grade 4 diarrhea involves life-threatening consequences, such as shock, whereas grade 5 results in death. The extent of colitis is also graded based on severity, from 1 to 5. Grade 1 colitis does not result in any symptoms, while grade 2 colitis leads to abdominal pain, mucous and blood in the stools. Grade 3 colitis is defined by severe pain, peritoneal signs and ileus. Grade 4 colitis is defined by life-threatening consequences, including perforation, ischemia, necrosis, bleeding, or toxic megacolon. Grade 5 colitis results in death.
Diagnosis
with evaluation of the terminal ileum is the gold standard in the diagnosis of checkpoint inhibitor induced colitis. However, in most cases, a limited evaluation of the distal colon with flexible sigmoidoscopy is all sufficient. Biopsies should be taken, as inflammation may not be immediately apparent and may only be seen on histology. Symptoms of nausea, vomiting and epigastric pain may suggest involvement of the upper gastrointestinal tract. If present, evaluation with upper endoscopy is warranted. Diagnostic evaluation should include ruling out infectious causes for diarrhea and colitis. Stool studies should include: Clostridioides difficile toxin, bacterial culture, ova and parasites. Testing for CMV infection should be considered. Though rare, gastrointestinal metastases should be considered as a cause of symptoms.
Treatment
Treatment varies depending on the severity of disease. For mild disease, supportive care may be sufficient, including loperamide and a low residue or bland diet. For more severe disease, the immune checkpoint inhibitor should be discontinued. Corticosteroid therapy is used to decrease inflammation, at a dose of roughly prednisone 1–2 mg per kg of body weight per day. In cases that do not respond to corticosteroid therapy, infliximab may be used. For cases that fail to respond to infliximab, or where infliximab is contraindicated, vedolizumab may be used.
Complications
High grade colitis may lead to severe complications, including perforation, toxic megacolon and death. Bleeding may occur due to colitis. Treatment with corticosteroids may lead to infectious complications, including: urinary tract infections, C. difficile infection, and pneumonia.
