Skyrizi (Risankizumab) Should Not Be Used for Checkpoint Inhibitor Colitis
Risankizumab is not recommended for the treatment of checkpoint inhibitor-induced colitis, as current guidelines do not support its use for this indication, and established therapies with proven efficacy should be prioritized.
Established Treatment Algorithm for Checkpoint Inhibitor Colitis
First-Line Therapy: Corticosteroids
- Grade 2 or higher colitis requires systemic corticosteroids at 1-2 mg/kg/day prednisone equivalent, tapered over 4-6 weeks 1
- Exclude infectious causes (C. difficile, CMV, parasites) before initiating immunosuppression 1
- Obtain fecal lactoferrin and calprotectin to stratify risk and determine need for urgent endoscopy 1
- Endoscopic confirmation with colonoscopy and biopsy is highly recommended before high-dose steroids, as ulceration predicts steroid-refractory disease 1
Second-Line Therapy: Biologics for Steroid-Refractory Disease
- For patients failing to improve within 3 days of corticosteroids, infliximab and vedolizumab are the guideline-recommended biologic options 1
- These agents specifically target mechanisms relevant to immune-mediated colitis (TNF-alpha and gut-selective integrin pathways) 1
Third-Line Options for Infliximab-Refractory Cases
- Calcineurin inhibitors (tacrolimus, cyclosporine) achieve symptom resolution in 74% of infliximab-refractory cases with median time to resolution of 12 days, though associated with poorer oncologic outcomes 2
- Vedolizumab for infliximab-refractory disease achieves resolution in 53% with longer time to response (66 days) but superior event-free survival (24.5 months) and overall survival compared to calcineurin inhibitors 2
- Antimetabolites (mycophenolate, azathioprine) show 44% response rates in refractory cases 2
Why Risankizumab Is Not Appropriate
Mechanism of Action Mismatch
- Risankizumab selectively inhibits IL-23 p19, a mechanism validated for inflammatory bowel disease (ulcerative colitis and Crohn's disease) but not for checkpoint inhibitor-induced colitis 1, 3
- Checkpoint inhibitor colitis has distinct pathophysiology with marked mixed inflammatory infiltrates (neutrophils, lymphocytes, plasma cells, eosinophils) that differs from classic IBD 1
Lack of Evidence in This Population
- No guidelines (ASCO 2021, AGA 2021) mention IL-23 inhibitors as treatment options for checkpoint inhibitor colitis 1
- The 2024 AGA guideline on ulcerative colitis demonstrates risankizumab efficacy only in moderate-to-severe ulcerative colitis, not immune-related adverse events 1
- Clinical trials of risankizumab specifically excluded patients with checkpoint inhibitor colitis 3
Timing Considerations
- Checkpoint inhibitor colitis can progress rapidly within days, particularly with ipilimumab, requiring prompt treatment 1
- Risankizumab has slower onset of action compared to established therapies like infliximab 2
Critical Pitfalls to Avoid
- Do not delay proven therapies (corticosteroids, infliximab, vedolizumab) to trial unproven agents like risankizumab, as this increases risk of complications including perforation, abscess, and death 1, 2
- Do not confuse checkpoint inhibitor colitis with IBD despite clinical similarities—the treatment algorithms differ, and risankizumab's role is established only for IBD 1
- Monitor for complications with imaging (CT abdomen/pelvis) if pain, fever, or bleeding predominate, as these suggest perforation or abscess requiring surgical intervention 1
- Three deaths in infliximab-refractory cases were directly attributable to toxicity or its management, emphasizing the need for evidence-based therapy selection 2
When Biologics Are Indicated
- Early introduction of infliximab or vedolizumab should be considered for patients with high-risk endoscopic features (ulceration) even before steroid failure 1
- Mucosal healing on repeat endoscopy or fecal calprotectin <116 mg/g should guide decisions to stop biologic therapy and potentially resume checkpoint inhibitors 1