What are the management options for diarrhea caused by steroid treatment?

Management of Steroid-Induced Diarrhea

The question appears to conflate two distinct clinical scenarios: diarrhea caused BY steroids (as a side effect) versus diarrhea TREATED WITH steroids (as in immune-related adverse events from checkpoint inhibitors). Based on the evidence provided, which focuses entirely on immune checkpoint inhibitor (ICI)-related diarrhea/colitis managed WITH corticosteroids, I will address that scenario, as true steroid-induced diarrhea is exceedingly rare and not covered in the provided evidence.

Initial Assessment and Workup

Rule out infection immediately before initiating any antidiarrheal therapy, as this is the most critical first step. 1

• Obtain stool studies for enteropathogens and Clostridium difficile toxin in all patients with diarrhea 1
• Measure fecal lactoferrin or calprotectin as inflammatory markers; positive lactoferrin has 90% sensitivity for histologic inflammation and predicts need for aggressive therapy 1
• Consider abdominal/pelvic CT with contrast for grade ≥2 symptoms 1
• Perform early endoscopy (colonoscopy or flexible sigmoidoscopy) within 7-14 days of symptom onset, especially if lactoferrin is positive, even with only grade 1 symptoms 1

Grade 1 Diarrhea (<4 Additional Bowel Movements/Day)

Manage conservatively with hydration and consider holding immunotherapy. 1

• Provide oral rehydration and electrolyte replacement 1
• Loperamide may be used cautiously (maximum 16 mg/day) if infection is ruled out, though some experts prefer to wait to avoid masking worsening symptoms 1, 2
• Add mesalamine or cholestyramine if symptoms persist with negative lactoferrin 1
• If lactoferrin is positive or symptoms persist >2-3 days, escalate to grade 2 management 1

Grade 2 Diarrhea (4-6 Additional Bowel Movements/Day)

Hold immunotherapy and initiate corticosteroids at 1 mg/kg/day prednisone equivalent unless diarrhea is transient. 1

• Start with oral prednisone 1 mg/kg/day (or budesonide 9 mg once daily if no bloody diarrhea) 1
• Consider gastroenterology consultation 1
• Perform endoscopy to stratify risk based on endoscopic findings; presence of ulcers predicts steroid-refractory course in 88% of cases 1, 3
• If symptoms worsen or persist >3-5 days despite steroids, escalate to grade 3 management 1
• Taper steroids over 4-6 weeks once symptoms improve to grade ≤1 1

Grade 3 Diarrhea (≥7 Additional Bowel Movements/Day, Incontinence, or Hospitalization Required)

Administer IV methylprednisolone 1-2 mg/kg/day and consider early biologics if high-risk endoscopic features or inadequate steroid response after 3 days. 1

• Use IV methylprednisolone especially if concern for upper GI inflammation 1
• Add infliximab 5 mg/kg or vedolizumab if no improvement within 3 days of steroids or if colonic ulcers present on endoscopy 1, 3, 4
• Initiating infliximab within 14 days of steroid failure achieves 94.4% resolution rate 4
• Consider hospitalization for dehydration or electrolyte imbalance 1
• Avoid loperamide and opioids at this stage 1
• Should consider permanently discontinuing CTLA-4 agents 1

Grade 4 Diarrhea (Life-Threatening)

Permanently discontinue immunotherapy, provide inpatient care, and administer IV methylprednisolone 1-2 mg/kg/day with early biologics. 1

• Give infliximab or vedolizumab if inadequate response to steroids after 3 days 1
• Consider repeat colonoscopy if refractory to treatment 1
• For refractory cases, consider fecal microbiota transplant, tofacitinib, or ustekinumab 1

Critical Timing Considerations

Early endoscopy within 7 days reduces symptom duration from 47 to 19 days and steroid treatment duration from 74 to 49 days. 1

• Endoscopy within 30 days reduces symptom recurrence from 50% to 21.8% 1
• Earlier initiation of infliximab/vedolizumab (15 vs 31 days) improves outcomes 1

Special Considerations and Pitfalls

Never use infliximab in patients with concurrent hepatic immune-related adverse events; it is contraindicated. 1

• Vedolizumab is gut-specific and may preserve antitumor immunity better than infliximab 1
• Add Pneumocystis prophylaxis (trimethoprim/sulfamethoxazole 400 mg daily) when immunosuppression is prolonged 1
• Fecal calprotectin ≤116 mg/g may serve as surrogate for endoscopic/histologic remission before resuming immunotherapy 1
• PD-1/PD-L1 agents have lower flare risk upon resumption than CTLA-4 inhibitors 1
• Avoid concurrent NSAIDs as they dramatically increase ulcer risk 5
• Consider proton pump inhibitors for gastroprotection in high-risk patients 5