Ipilimumab as a Cause of Severe Pan-Colitis and Colonic Perforation

Abstract

Ipilimumab is a human monoclonal antibody that functions as a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor that is used to treat malignant melanoma. Due to ipilimumab’s removal of immune regulation, specifically through the inactivation of CTLA-4, it is commonly associated with inflammatory and autoimmune events. Gastrointestinal (GI) related immune-related adverse events such as diarrhea occur in 29% of patients with 7.6% of patients specifically suffering from colitis. We describe a case of colonic perforation with ipilimumab use. Our goal is to raise awareness and alert practicing gastroenterologists of this particular adverse effect.​A 74-year-old male patient presented to the emergency department with complaints of hematochezia, abdominal pain and decreased appetite. The patient’s past medical history included desmoplastic BRAF mutation negative melanoma with metastatic disease to the face, liver, and trigeminal nerve. He underwent his last treatment of ipilimumab three weeks prior to presentation. In total, the patient received four doses of 3 mg/kg of ipilimumab every three weeks. Since the initiation of ipilimumab, he reported diarrhea as its adverse effect, which was treated with tapering doses of prednisone one month at a time. Colonoscopy revealed mucosal ulceration and erosion in the rectum, sigmoid colon, and remaining descending colon up to the splenic flexure and cecum. After the colonoscopy, the patient became tachycardic, hypotensive and complained of sudden abdominal pain. A computed tomographic (CT) scan of the abdomen showed free intraperitoneal air. He was immediately taken to the operating room (OR) for an emergent laparotomy. In the operating room, perforations were noted at the splenic flexure and the cecum with large amounts of succus spilling from the perforations. The majority of the large bowel appeared cyanotic and dusky; consequently, a sub-total colectomy with terminal ileostomy was performed. After the procedure, the patient was started on antibiotics for severe peritonitis and admitted to the intensive care unit (ICU) with septic shock. His clinical status continued to deteriorate due to acute respiratory failure, nosocomial pneumonia, severe protein calorie malnutrition and coagulopathy from disseminated intravascular coagulation (DIC). The patient did not recover from his illness and died a few days later.It is imperative that physicians caring for patients receiving treatment with CTLA-4 inhibitors frequently monitor for and promptly treat possible immune-related adverse effects. For patients with ipilimumab-related colitis, prompt identification of symptoms and early treatment with steroids are crucial in preventing harmful or possibly fatal immune-related adverse events. Gastroenterologists should be wary of this adverse side effect in this high-risk population when performing colonoscopy and take necessary precautions.

Immune checkpoint inhibitor-induced colitis: A comprehensive review

“…While infections are more common, gastrointestinal metastases should also be ruled out as a potential etiology of symptoms. Patients with clinical signs of peritonitis such as fever, severe abdominal tenderness, distention, and rigidity should be evaluated with abdominal CT to rule out colonic perforation, which is a rare but well-documented adverse event that can be fatal[57-59].…”

Secondary causes of inflammatory bowel diseases

“…Severe forms of the disease are susceptible to develop bowel perforation. Extreme precautions should be taken if diagnostic colonoscopy is performed in these patients with severe disease[ 95 , 96 ].…”

Case of small bowel perforation secondary to nivolumab and ipilimumab related tumour regression

“…There have been other cases of bowel perforation secondary to nivolumab and ipilimumab use, however both perforations were caused by immunotherapy driven colitis and not tumour regression. These cases were far less acute with the patients experiencing diarrhoea and abdominal pain days prior to the perforation 10 11…”