Although ipilimumab has been shown to improve survival in patients with metastatic melanoma and cause regression of metastatic renal cell carcinoma, the associated immune-related toxicities are of concern. The resultant T cell activation by this monoclonal antibody causes an increased immune response, which has been associated with many immune-regulated adverse effects. One of the most concerning effects is the development of colitis. Upwards to 8% of patients have been reported to develop colitis, with 5% being severe (Grades 3-4). While initial treatment of such adverse effects is generally comprised of supportive and symptomatic treatment, more severe cases warrant the use of high dose steroids. Furthermore, use of anti-TNF agents is usually reserved for those cases that prove to be refractory to steroids. We describe a systematic case review of seven patients who developed gastrointestinal symptoms following initiation of ipilimumab immunotherapy, and present the steps in their evaluation, treatment and outcomes at our institution.

Although ipilimumab has been shown to improve survival in patients with metastatic melanoma and cause regression of metastatic renal cell carcinoma, the associated immune-related toxicities are of concern[1,2]. The resultant T cell activation by this monoclonal antibody causes an increased immune response, which has been associated with many immune-regulated adverse effects. One of the most concerning effects is the development of colitis. Upwards to 8% of patients have been reported to develop colitis, with 5% being severe (Grades 3-4). While initial treatment of such adverse effects is generally comprised of supportive and symptomatic treatment, more severe cases warrant the use of high dose steroids. Furthermore, use of anti-TNF agents is usually reserved for those cases that prove to be steroid resistant[3].

In March 2011, ipilimumab was approved for the treatment of patients with metastatic melanoma. This monoclonal antibody blocks inhibition of cytotoxic T lymphocyte antigen 4 (CTLA-4) causing T cell activation and proliferation, preventing tumor evasion. The resulting immune up-regulation has been associated with numerous immune-regulated adverse effects (irAEs) including colitis, dermatitis, hepatitis, and hypophysitis. Fatigue, weight loss, and electrolyte imbalances encompass the clinical manifestations of severe diarrhea, which can progress to colitis, and in the worst case, bowel perforation. Up to 46% of patients will experience such gastrointestinal toxicities after 7 wk of therapy[4]. Severity of diarrheal symptoms are graded based on the Common Terminology for Adverse Events (CTAE)[5], and further characterized as mild to moderate (Grades 1-2) or severe (Grades 3-4). Symptomatic management with loperamide is indicated for mild cases. If symptoms persist or become severe, initiation of steroid therapy is indicated along with endoscopy to assess for colitis. High dose steroids are used in severe cases, and infliximab being reserved for steroid resistant cases[6]. Here we report our experience in the diagnosis and treatment of gastrointestinal irAEs in our patients receiving ipilimumab.

A retrospective analysis was conducted to identify those patients who developed gastrointestinal symptoms in the setting of receiving ipilimumab treatment from December 2012 to December 2013. A total of 19 patients were identified as receiving ipilimumab as part of their infusion protocols. Seven cases were identified as having gastrointestinal symptoms warranting inpatient hospital evaluation. Of the 7 cases reviewed (four male, three female) a mean age of 58 years (range, 38-71 years) and diarrheal symptoms ranging from mild to severe (Grades 1-4) was noted. Below we present detailed descriptions of each of the seven cases and a summation presented in Table 1.

The majority of chief complaints were composed of diarrhea, fever, rash, abdominal pain, nausea and occurred three to eighteen weeks after initiation of ipilimumab (mean, 7 wk; following one to four doses of ipilimumab). Colonoscopy findings were consistent with those of colitis, including mucosal erythema, ulcerations, loss of vascular pattern, granulations, and friable mucosa. Common pathological observations on biopsy were granulomas, cryptitis, and crypt abscesses. Time to symptom resolution was noted to be variable (ranging from 1 d to 4 wk after initial treatment). CRP levels were elevated in all cases when measured, with normalization noted when measured serially post treatment in two of the cases. Two of the seven patients received infliximab infusions for treatment of their underlying colitis.

With the introduction of anti-CTLA-4 agent ipilimumab irAEs involving the digestive tract have become legitimate concern. Decision algorithms based on symptom grade have been developed to aid in the management of such toxicities, but much is to be elucidated. Although corticosteroids are recommended for moderate to severe symptoms, optimal dosing needs clarification. Management guidelines recommend starting prednisone or its equivalent (0.5 mg/kg/d for moderate and 1-2 mg/kg/d for severe enterocolitis), but case reports and trials have a myriad of steroid administration patterns. Furthermore, extended release formulations of the steroids have been developed, which have yet to be studied in such patients.

At our institution, cases of suspected ‘IpiColitis’ undergo colonoscopy with biopsies. We feel that colonoscopy is warranted early to confirm diagnosis. While clinical course may support the diagnosis of ipilimumab associated colitis, it is not sufficient, thus requiring tissue biopsy for confirmation. Once confirmed and infectious etiologies are ruled out, patients are started on prednisone (1 mg/kg/d). Simultaneously, patients are checked for tuberculosis and hepatitis B infections in preparation for possible future anti-TNF therapy. Intravenous steroids (1 mg/kg/d) are reserved for more persistent cases. If symptoms continue three to five days following intravenous steroid treatment, two doses of infliximab (5 mg/kg/dose) are administered two weeks apart with coinciding steroid taper. Patients are followed clinically and treatment success is based on resolution of the patient’s presenting symptoms and diarrhea. Repeat colonoscopy is not routinely conducted to confirm treatment response.

Phase 2 trials have shown no benefit of prophylactic budesonide use in the prevention of ipilimumab induced colitis[7]. To date we lack predictive and prognostic factors of severity of the immunological side effects prior to initiating ipilimumab therapy[8]. CRP, being a marker of acute inflammation, was noted to be elevated in all cases. The degree of elevation did not correlate to symptom severity, and did not serve as a surrogate indicator for the requirement of anti-TNF agents. In cases where CRP was checked after treatment, normal levels were noted, creating future interest in following this lab value as a measurement of treatment response (Figure 4). In Case 3, CRP levels were checked ten days following the first dose of infliximab and noted to have normalized. Similarly, in Case 5, CRP levels were noted to have normalized eight days following first dose of methylprednisolone.

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Figure 4 Graph demonstrating normalization of C-reactive protein levels after treatment in two of the seven cases. CRP: C-reactive protein.

With no definitive preventive strategy, and no predictive and prognostic factors, the physician has to assess disease severity and adjust medical treatment based on patient’s symptoms and the colonoscopy findings. Before attributing the diarrhea to ipilimumab, an infectious work-up should be done, including infectious enterocolitis and extra-intestinal infections, as illustrated by our patient diagnosed with Group G Beta Hemolytic Streptococcus bacteremia. The differential diagnosis of colitis remains broad and can arise from infectious pathogens, such as Escherichia coli, Salmonella, and Clostridium difficile. Immunocompromised individuals are more susceptible to colitis due to cytomegalovirus infections. Ischemic changes can also result in colonic inflammation representative of colitis. Furthermore, microscopic forms of colitis exist, including lymphocytic and collagenous forms[9].

Cases non-responsive to steroids will often proceed to a trial of anti-TNF agents such as infliximab. This monoclonal antibody has an established use in the treatment of inflammatory bowel disease, and builds much of the foundation of how we treat steroid resistant immune-mediated colitis. While endoscopic findings have been correlated with more clinically aggressive forms of Crohn’s disease, further data and more rigorous studies are required to make such a correlation in ipilimumab-induced colitis[10]. Endoscopy is indicated in those patients whose symptoms are severe or refractory to oral steroids. The use of early endoscopy, its associated findings, and treatment implications are yet to be studied.