Immune Checkpoint Inhibitor Colitis

Immune checkpoint inhibitor colitis is immune mediated inflammation of the colon (and often terminal ileum) caused by antibodies against CTLA-4, PD-1 or PD-L1. It is a common cause of treatment interruption.

Diarrhoea of any grade occurs in about 30% to 40% with ipilimumab and 10% to 20% with PD-1 inhibitors; severe colitis affects 5% to 10% with ipilimumab, 1% to 2% with PD-1 inhibitors and 10% to 15% with combinations. Onset is usually 5 to 10 weeks after starting, but can be later.

Grade 1: under 4 stools daily over baseline. Grade 2: 4 to 6 stools over baseline, or abdominal pain or blood. Grade 3: 7 or more over baseline, hospitalisation indicated, or severe symptoms. Grade 4: life threatening complications.

Pathophysiology.

Loss of checkpoint inhibition activates cytotoxic and helper T cells against the intestinal mucosa, with mucosal infiltration and cytokine release. The gut microbiota may modify risk.

Watery or bloody diarrhoea, abdominal pain, urgency, nocturnal stools, fever, nausea and weight loss. Severe disease leads to dehydration, toxic megacolon, ileus and perforation. Hepatitis, hypophysitis and other immune toxicities can coexist.

Red flags.

• Peritonitis or free air.
• Fever with hypotension.
• Severe bleeding.
• Colonic dilatation.

Exclude infection with stool Clostridioides difficile, culture and pathogen testing, and cytomegalovirus on biopsy when refractory.

Send full blood count, electrolytes, C-reactive protein, albumin, liver enzymes, thyroid function, and faecal calprotectin or lactoferrin. CT shows mesenteric vessel engorgement and wall thickening.

Perform flexible sigmoidoscopy or colonoscopy early in grade 2 or higher: ulceration predicts steroid refractoriness; biopsies show neutrophilic cryptitis, crypt abscess and apoptosis.

Screen for hepatitis B and tuberculosis before infliximab or vedolizumab.

Differential diagnosis.

• Infective colitis.
• Clostridioides difficile infection.
• Cytomegalovirus colitis.
• Ulcerative colitis or Crohn disease.
• Ischaemic colitis.
• Medication effect (chemotherapy, mycophenolate, NSAID).
• Faecal impaction with overflow.

• Grade 1: loperamide, fluids, diet, and continue the drug with close review.
• Loperamide: 4 mg orally initially, then 2 mg after each loose stool; while symptomatic; maximum 16 mg daily; monitor QTc at high doses and for ileus; avoid in infective colitis and obstruction; reduce in hepatic impairment.
• Grade 2: withhold the checkpoint inhibitor, start prednisolone if there is no improvement within 3 days.
• Prednisolone: 0.5 to 1 mg/kg orally once daily; taper over 4 to 6 weeks after symptoms fall to grade 1 or less; maximum 80 mg daily; monitor glucose, blood pressure, mood, infection and bone health; use cover with a proton pump inhibitor and calcium and vitamin D.
• Grades 3 and 4: stop the drug permanently for CTLA-4 inhibitors, admit, give intravenous fluids and steroid.
• Methylprednisolone: 1 to 2 mg/kg IV once daily; for 2 to 3 days with switch to oral prednisolone once improving, then taper over 4 to 6 weeks; maximum 2 mg/kg daily; monitor glucose, electrolytes and infection; avoid until sepsis and perforation are excluded.
• Steroid refractory disease (no improvement in 48 to 72 hours): infliximab or vedolizumab, after excluding infection and perforation.
• Infliximab: 5 mg/kg IV once, repeated once after 2 weeks if there is no response; maximum 10 mg/kg for this indication; monitor liver enzymes, infusion reactions and infection; avoid in perforation, sepsis, active tuberculosis and moderate to severe heart failure.
• Vedolizumab: 300 mg IV at weeks 0, 2 and 6, then every 8 weeks if needed; maximum 300 mg each dose; monitor infection and liver enzymes; no renal adjustment; preferred in hepatitis or when infliximab is contraindicated.
• Pneumocystis prophylaxis when prednisolone is 20 mg or more daily for 4 weeks or longer: co-trimoxazole 480 mg orally once daily or 960 mg three times weekly; maximum 960 mg daily; monitor blood counts, potassium and creatinine; halve the dose when creatinine clearance is 15 to 30 mL/min.

Restarting therapy after resolution is possible for PD-1 or PD-L1 inhibitors with surveillance, and is riskier for CTLA-4 inhibitors. Colectomy is needed for perforation, toxic megacolon or refractory disease.

Monitoring. Stool chart, C-reactive protein and electrolytes daily when admitted; repeat sigmoidoscopy before restarting therapy.

Referral and escalation. Gastroenterology and oncology urgently for grade 3 or higher; colorectal surgery for complications.