Why does Tofacitinib (Janus kinase inhibitor) cause gastrointestinal perforation?

Mechanism of Tofacitinib-Associated Gastrointestinal Perforation

Tofacitinib causes gastrointestinal perforation primarily through JAK inhibition's suppression of inflammatory responses that normally signal bowel wall injury, combined with impaired tissue repair mechanisms, allowing silent progression of underlying GI pathology (particularly diverticulitis) until frank perforation occurs. 1, 2

Pathophysiologic Mechanisms

Masking of Warning Signs

• JAK inhibition blunts fever and acute phase reactant elevation, preventing early recognition of evolving perforation 1
• The anti-inflammatory effects suppress typical peritoneal signs, allowing patients to present late with established perforation rather than early peritonitis 1
• This diagnostic delay is the primary mechanism by which tofacitinib increases perforation-related morbidity and mortality 1

Impaired Mucosal Defense and Repair

• Tofacitinib inhibits multiple cytokine pathways (IL-6, IL-12, IL-23, interferon-gamma) that are essential for maintaining intestinal barrier integrity 3, 4
• JAK-STAT signaling is critical for epithelial cell proliferation and wound healing in the GI tract 3
• Suppression of these pathways may prevent adequate repair of microscopic mucosal injuries, allowing progression to full-thickness defects 4

Predominant Lower GI Tract Involvement

• Lower GI tract perforations occur more frequently than upper GI perforations with tofacitinib 5
• The incidence of lower GI perforation is 0.86 per 1,000 patient-years with tofacitinib, compared to 0.46 per 1,000 patient-years with TNF inhibitors (adjusted HR 1.94,95% CI 0.49-7.65) 5
• Most perforations occur in the colon, particularly in patients with pre-existing diverticular disease 2, 5

High-Risk Clinical Scenarios

Synergistic Risk Factors

• Concurrent NSAID use independently multiplies perforation risk through additive mucosal injury 1, 2
• Corticosteroid use at doses >7.5 mg/day prednisone increases lower GI perforation risk (HR 2.29,95% CI 1.39-3.78) 5
• History of diverticulitis or other GI conditions increases risk 3.25-fold (95% CI 1.62-6.50) 5
• Older age confers incrementally higher risk (HR 1.16 per 5-year increase, 95% CI 1.10-1.22) 5

Acute Severe Ulcerative Colitis

• ASUC patients receiving tofacitinib face elevated perforation risk due to severe transmural inflammation combined with immunosuppression 1
• The combination of deep ulceration and impaired inflammatory signaling creates a perfect storm for silent perforation 1

Incidence Data from Clinical Programs

Overall Perforation Rates

• In the completed global UC clinical program (up to 9.2 years exposure), the incidence rate of GI perforation was 0.09 per 100 patient-years (95% CI 0.02-0.27) 6
• Earlier analysis with 7.8 years maximum exposure showed IR of 0.10 per 100 patient-years (95% CI 0.02-0.28) 7
• While the absolute rate appears low, the clinical significance is amplified by the masking of symptoms and delayed diagnosis 1

Comparative Risk

• Real-world data from 167,113 RA patients showed tofacitinib perforation incidence of 0.86 per 1,000 patient-years versus 0.83 for TNF inhibitors 5
• The adjusted hazard ratio suggests numerically elevated but not statistically significant increased risk compared to TNF inhibitors 5

Critical Clinical Pitfalls

Diagnostic Challenges

• Do not rely on fever or elevated inflammatory markers to rule out perforation in tofacitinib-treated patients 1
• Maintain high suspicion for any new abdominal pain, tenderness, change in bowel habits, or abdominal distension 1, 2
• Plain radiography is insufficient—obtain CT imaging for any new GI symptoms 1

Management Imperatives

• Do not delay imaging while awaiting laboratory results 1
• Urgent surgical consultation is mandatory if perforation is suspected 1
• In ASUC patients on tofacitinib, implement daily surgical review and maintain a low threshold for abdominal imaging 1

Risk Mitigation Strategy

Medication Management

• Avoid NSAIDs entirely; use alternative analgesics such as acetaminophen 1
• Minimize corticosteroid doses when possible, recognizing the synergistic perforation risk 5
• Screen for and treat diverticulitis before initiating tofacitinib 2, 5

Patient Education and Monitoring

• Educate all patients to report any new abdominal symptoms immediately, emphasizing that absence of fever does not exclude serious pathology 1
• The FDA label specifically warns to use tofacitinib with caution in patients at increased risk for GI perforation and to evaluate new abdominal symptoms promptly 2

Special Populations

• For ASUC patients, the British Society of Gastroenterology recommends daily surgical review regardless of treatment agent, with immediate imaging for any perforation suspicion 1
• This heightened vigilance is essential given JAK inhibitors' propensity to mask clinical signs 1