Immunotherapy-Induced Colitis: An Emerging Problem for the Hospitalist
Since their introduction for melanoma treatment, the use of immune checkpoint inhibitors (ICIs) has rapidly expanded. Though their impact on survival is irrefutable, these medications have been associated with autoimmune-like adverse events related to their ability to induce the immune system. One of the most commonly affected organ systems is the gastrointestinal (GI) tract, in which manifestations range from mild diarrhea to severe colitis with intestinal perforation. Because of the increased use of ICIs, hospitalists are caring for an increasing number of patients experiencing their adverse events. We present a case-oriented review of the GI adverse events associated with the use of ICIs to familiarize the hospitalist with their mechanism of action and potential complications and to emphasize the importance of early diagnosis and treatment to decrease morbidity and mortality.
© 2018 Society of Hospital Medicine
Immune checkpoint inhibitors (ICIs), a form of immunotherapy, have changed the management of cancer since their introduction in 2011.1 They were initially tested on melanoma.2 Their use in the advanced stages of the disease demonstrated a 2-year survival of 18% compared with 5% by using other therapies.3 Similar results were observed in nonsmall cell lung carcinoma (NSCLC); the overall survival benefit was 3 months with the use of ICIs compared with traditional chemotherapy (42% and 24% at 1 year, respectively).4 Antitumor activity has also been seen in the treatment of other malignancies, including renal cell carcinoma,5 bladder carcinoma,6,7 head and neck carcinoma,8 colorectal cancer,9 Hodgkin lymphoma,10 and, more recently, hepatocellular carcinoma.11 The use of ICIs has also been linked to serious complications.12 Although the skin, kidneys, lungs, and endocrine and nervous systems may be affected, complications of the gastrointestinal (GI) tract are frequent and can be life-threatening.12-16 We performed a thorough review of the literature to familiarize hospitalists with the mechanism of action and uses of ICIs, the clinical presentation of their GI toxicity, and the current recommendations regarding diagnosis and treatment.
CASE PRESENTATION
A 66-year-old man was admitted to our institution with a 1-week history of severe, diffuse abdominal pain and profuse watery diarrhea. He reported having more than 8 watery bowel movements per day and denied fever, recent travel, ill contacts, or ingestion of undercooked food. He had a history of metastatic melanoma and was undergoing treatment with both nivolumab and ipilimumab; the drugs were started 6 weeks prior to presentation. Physical examination revealed a heart rate of 110 beats/minute while supine and 123 beats/minute while standing, blood pressure of 112/69 mm Hg while supine and 92/62 mm Hg while standing, and a temperature of 37.2°C. He was in mild distress and had dry oral mucosa. Abdominal examination revealed hyperactive bowel sounds and mild diffuse abdominal tenderness with no guarding or rebound. His extremities were cool, but peripheral pulses were present. Initial laboratory results included a hemoglobin level of 15.3 g/dL (range 12.0-16.0 mg/dL), white blood cell count 14.2 × 109/L (range 4.5-11.0 × 109/L), and platelet count 236 × 109/L (range 150-400 × 109/L); other test results included a sodium level of 130 mmol/L (range 135-145 mmol/L), potassium 2.3 mmol/L (range 3.5-5.5 mmol/L), serum creatinine 2.2 mg/dL (range 0.8-1.3 mg/dL), blood urea nitrogen 72 mg/dL (range 8-21 mg/dL), and serum venous lactate 5.9 mmol/L (range 0.9-1.7 mmol/L).
MECHANISM OF ACTION AND USES OF ICIS
T-cell lymphocytes play a pivotal role in acquired immunity, but their function requires an appropriate balance between stimulatory and inhibitory signals to prevent autoimmunity.17 Immune checkpoint molecules are used by the immune system to assist with this balance.18 Although several of these molecules exist, the cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) are among the most widely studied.12
Ipilimumab is a monoclonal antibody directed against CTLA-4.24 After demonstrating survival benefits in patients with unresectable and metastatic melanoma, ipilimumab was the first ICI approved for use by the US Food and Drug Administration (FDA).1,3 Another monoclonal antibody directed against CTLA-4, tremelimumab, is not currently approved for use by the FDA.
