What is checkpoint inhibitor (immune checkpoint inhibitors) colitis?

Checkpoint Inhibitor Colitis: Diagnosis and Management

Checkpoint inhibitor colitis is an immune-related adverse event characterized by inflammation of the colon due to immune checkpoint inhibitor therapy, presenting with diarrhea, abdominal pain, and sometimes rectal bleeding, requiring prompt diagnosis and treatment to prevent serious complications. 1

Clinical Presentation and Epidemiology

• Incidence: Varies by agent type

  • CTLA-4 inhibitors (ipilimumab): 23-33% of patients
  • PD-1/PD-L1 inhibitors: ≤19% of patients
  • Combination therapy: Up to 44% of patients 1

• Onset: Typically after an average of three infusions, but can occur as early as after the first infusion 1

• Symptoms:

  • Diarrhea (primary symptom)
  • Abdominal pain
  • Rectal bleeding
  • Mucus in stool
  • Fever 1

• Severity: Higher with combination therapy than monotherapy; more severe with CTLA-4 inhibitors than with PD-1/PD-L1 agents 1

Pathophysiology

Checkpoint inhibitor colitis occurs when ICIs trigger:

• Resident and circulating T cell activation
• Infiltration of myeloid cells in the colon
• Gut microbiota disruption contributing to intestinal immune dysregulation
• Loss of barrier function, propagating local and systemic inflammation 2

Diagnostic Evaluation

Initial Assessment

1. Rule out infectious causes:

   • Stool culture
   • Clostridioides difficile testing
   • CMV PCR
   • Stool ova and parasites 1, 3

2. Laboratory testing:

   • CBC with differential
   • CMP
   • ESR and CRP (inflammatory markers)
   • TSH 1, 3

3. Stool inflammatory markers:

   • Fecal lactoferrin
   • Fecal calprotectin (help stratify high-risk patients for endoscopic evaluation) 1, 3

Endoscopic Evaluation

• Indication: Recommended for grade ≥2 colitis to confirm diagnosis and assess severity 3
• Findings: Two distinct patterns on CT imaging:
  • Diffuse colitis with mesenteric vessel engorgement (more common)
  • Segmental colitis with moderate wall thickening 1
• Histology:
  • Neutrophilic inflammation with increased intraepithelial lymphocytes
  • Crypt epithelial cell apoptosis
  • Few or no features of chronicity 1
  • May present as active colitis with apoptosis or lymphocytic colitis 1

Important: Even with normal-appearing mucosa on endoscopy, random biopsies should be performed as histological inflammation may be present despite normal endoscopic appearance 4

Management

Grading System (CTCAE v5)

• Grade 1: Increase of <4 stools/day over baseline
• Grade 2: Increase of 4-6 stools/day over baseline
• Grade 3: Increase of ≥7 stools/day over baseline; hospitalization indicated
• Grade 4: Life-threatening consequences 1

Treatment Algorithm

1. Grade 1 (Mild):

   • Close follow-up within 24-48 hours
   • Continue ICI therapy
   • Consider bland diet
   • Anti-diarrheal medications optional but not highly recommended 1

2. Grade 2 (Moderate):

   • Hold ICI therapy
   • If diarrhea only, observe for 2-3 days; if no improvement, start prednisone 1 mg/kg/day
   • If diarrhea with colitis symptoms, start prednisone 1 mg/kg/day immediately
   • If no improvement in 48 hours, increase to prednisone 2 mg/kg/day
   • Taper corticosteroid over 4-6 weeks 1

3. Grade 3-4 (Severe):

   • Withhold ICI (Grade 3) or permanently discontinue (Grade 4)
   • Hospitalize patient
   • Start IV methylprednisolone 1-2 mg/kg/day
   • Consider early introduction of infliximab (5 mg/kg) or vedolizumab (300 mg) for:
     • High-risk endoscopic features (ulcerations)
     • Inadequate response to steroids after 3 days 1, 3

4. Steroid-Refractory Cases:

   • Infliximab 5 mg/kg (can be given again after two weeks if needed)
   • Vedolizumab 300 mg IV at weeks 0,2, and 6
   • Other options: tofacitinib, ustekinumab, fecal microbiota transplant 1, 3

Resuming Immunotherapy

• Consider resuming when symptoms improve to grade ≤1 and corticosteroids are tapered to ≤10 mg/day 1
• PD-1/PD-L1 agents have lower risk of colitis recurrence than CTLA-4 inhibitors 1
• If using combination therapy, consider continuing only the anti-PD-1 agent 1

Potential Pitfalls and Caveats

1. Delayed diagnosis: Rapid progression of ICI colitis may occur within days, particularly with ipilimumab, requiring prompt diagnosis and treatment 1

2. Endoscopic-histologic dissociation: Normal-appearing mucosa on endoscopy may still show significant inflammation on histology; always obtain biopsies 4

3. Infectious complications: Ensure infectious causes are ruled out before starting immunosuppression 3

4. Recurrence after treatment: Colitis may recur months after discontinuation of immunotherapy and can mimic chronic IBD 1

5. Steroid dependence: Some patients may develop steroid-dependent disease requiring biologic therapy 3

6. Concurrent hepatitis: In patients with both ICI-related hepatitis and colitis, infliximab is contraindicated; consider other immunosuppressants like prednisone and mycophenolate 1

By following this structured approach to diagnosis and management, clinicians can effectively treat checkpoint inhibitor colitis while minimizing morbidity and mortality for patients receiving these life-saving cancer therapies.