Gastrointestinal Perforation Risk with Tofacitinib
Tofacitinib carries a documented risk of gastrointestinal perforation, particularly in the lower GI tract, and should be used with extreme caution in patients with risk factors such as diverticulitis, concurrent NSAID or corticosteroid use, or history of GI perforation. 1
Magnitude of Risk
The incidence of gastrointestinal perforation with tofacitinib is low but clinically significant:
- Overall GI perforation rate: 0.09-0.10 per 100 patient-years in ulcerative colitis clinical trials with up to 9.2 years of exposure 2, 3
- Lower GI tract perforation is the predominant site, with an incidence of 0.86 per 1,000 patient-years in rheumatoid arthritis patients receiving tofacitinib 4
- Numerically elevated risk compared to TNF inhibitors (adjusted HR 1.94,95% CI 0.49-7.65), though not reaching statistical significance due to the rarity of events 4
High-Risk Patient Populations
Avoid or use with extreme caution in patients with:
- History of diverticulitis or other GI conditions (HR 3.25,95% CI 1.62-6.50 for lower GI perforation) 4
- Concurrent prednisone use >7.5 mg/day (HR 2.29,95% CI 1.39-3.78) 4
- Concurrent NSAID use, which independently increases perforation risk 1
- Older age (HR 1.16 per 5-year increment, 95% CI 1.10-1.22) 4
- Acute severe ulcerative colitis (ASUC), where the underlying disease itself increases perforation risk 1
Clinical Recognition and Management
Key challenge: JAK inhibitors may mask typical signs of perforation by blunting fever and acute phase reactant elevation 1
Maintain high clinical suspicion for perforation when patients present with:
- New onset abdominal pain or tenderness
- Change in bowel habits
- Abdominal distension
- Any new GI symptoms, even without fever or elevated inflammatory markers 1
Immediate evaluation protocol:
- Obtain abdominal imaging (CT preferred over plain radiography) for any new abdominal symptoms 1
- Urgent surgical consultation if perforation suspected
- Do not delay imaging while awaiting laboratory results 1
Comparative Risk with Other Agents
Tocilizumab carries the highest documented risk of lower GI perforation among advanced therapies (adjusted HR 2.51,95% CI 1.31-4.80 vs TNF inhibitors), significantly exceeding tofacitinib's risk 4
Tofacitinib's perforation risk in UC clinical trials (0.09-0.10/100 PY) is comparable to or lower than real-world TNF inhibitor-treated UC populations (0.31/100 PY in claims database analysis) 2, 3, 5
Practical Risk Mitigation Strategy
Before initiating tofacitinib:
- Screen for history of diverticulitis, inflammatory bowel strictures, or prior GI perforation
- Document current corticosteroid and NSAID use
- Consider colonoscopy if not recently performed to identify high-risk features (deep ulceration, strictures) 1
During treatment:
- Minimize or eliminate concurrent corticosteroids when possible (target ≤7.5 mg/day prednisone equivalent) 4
- Avoid NSAIDs; use alternative analgesics 1
- Educate patients to report any new abdominal symptoms immediately 1
- In ASUC patients receiving tofacitinib, maintain daily surgical review and low threshold for imaging 1
The 2025 British Society of Gastroenterology guidelines specifically recommend daily surgical review and abdominal imaging for any suspicion of perforation in ASUC patients, regardless of treatment agent 1