What is the role of tofacitinib (Janus kinase inhibitor) in the treatment of severe ulcerative colitis?

Tofacitinib in Severe Ulcerative Colitis

Tofacitinib is an effective oral JAK inhibitor for moderate-to-severe ulcerative colitis, but its use in truly severe/acute severe UC is restricted to second-line rescue therapy after TNF antagonist failure, while FDA labeling and current guidelines recommend it primarily after biologic failure rather than as first-line therapy. 1

Positioning in Treatment Algorithm

For Moderate-to-Severe Outpatient UC

• The AGA strongly recommends tofacitinib over no treatment for both induction and maintenance of remission in moderate-to-severe UC (RR for induction: 3.22,95% CI 2.03-5.08; RR for maintenance at 5mg BID: 3.09,95% CI 1.99-4.79). 1

• In biologic-naïve patients, tofacitinib should only be used after TNF antagonist failure or intolerance per FDA labeling (updated July 2019), or within clinical/registry studies. 1

• In biologic-experienced patients (particularly those with primary non-response to infliximab), tofacitinib is suggested over vedolizumab or adalimumab for induction. 1

• The 2024 AGA update classifies tofacitinib as an "intermediate efficacy" medication, ranking below infliximab, vedolizumab, upadacitinib, and risankizumab but above adalimumab. 1

For Acute Severe UC (Hospitalized Patients)

• Tofacitinib is NOT appropriate as first-line rescue therapy in acute severe UC. 2

• After tofacitinib failure in ASUC, infliximab or cyclosporine are the recommended rescue agents (infliximab preferred if no prior anti-TNF exposure). 2

• Vedolizumab, ustekinumab, and other biologics lack data in the ASUC setting and have slower onset of action, making them inappropriate for acute rescue. 2

Dosing Regimen

Induction Phase

• Standard induction: 10 mg twice daily orally for 8 weeks. 1

• Extended induction: In patients with modest response at 8 weeks, high-dose tofacitinib (10 mg BID) may be continued for up to 16 weeks total. 1

• Clinical response is typically evident within 8 weeks of therapy. 3

Maintenance Phase

• Standard maintenance: 5 mg twice daily for most patients. 1

• Dose escalation: 10 mg twice daily may be considered in patients who lose response at 5 mg BID, but only after careful risk-benefit assessment. 1

• Critical safety concern: At higher maintenance doses (10 mg BID), an unexpected increase in risk of pulmonary embolism and all-cause mortality has been observed. 1

Safety Profile and Contraindications

Absolute or Strong Relative Contraindications

• Avoid in patients with:
  • History of venous thromboembolism 4, 3
  • Cardiovascular disease or uncontrolled cardiac risk factors 1, 4, 3
  • Age ≥65 years with cardiovascular risk factors (per European Medicines Agency guidance) 1
  • Current or previous long-term smokers with cardiovascular risk 1
  • History of malignancy 1, 3
  • Pregnancy and lactation 3

Infection Risk Management

• Herpes zoster infection shows dose-dependent increase: IR 4.1 per 100 patient-years in overall cohort, with maintenance IR of 6.6 (95% CI 3.2-12.2) at 10 mg BID versus 2.1 (95% CI 0.4-6.0) at 5 mg BID. 5

• Baseline screening required:

  • Test for and treat latent tuberculosis before initiation 3
  • Screen for hepatitis B infection 3
  • Complete adult vaccinations, including herpes zoster vaccine, before starting therapy where feasible 3

• Serious infections occurred at IR 2.0 per 100 patient-years (95% CI 1.4-2.8), similar to biologic agents. 5

Other Adverse Events

• Dose-dependent increases in both LDL and HDL cholesterol occur. 6

• Major adverse cardiovascular events: IR 0.2 per 100 patient-years (95% CI 0.1-0.6). 5

• Malignancy (excluding non-melanoma skin cancer): IR 0.7 per 100 patient-years (95% CI 0.3-1.2). 5

• Gastrointestinal perforations: IR 0.2 per 100 patient-years (95% CI 0.0-0.5). 5

Clinical Efficacy Data

• Phase 2 trial demonstrated dose-dependent efficacy: Clinical response at 8 weeks occurred in 78% with 15 mg BID (P<0.001), 61% with 10 mg BID (P=0.10), versus 42% with placebo. 6

• Clinical remission at 8 weeks: 48% with 10 mg BID (P<0.001) and 41% with 15 mg BID (P<0.001) versus 10% with placebo. 6

• Overall quality of evidence is moderate for both induction and maintenance, rated down for imprecision due to fewer than 200 events. 1

Common Pitfalls to Avoid

• Do not use tofacitinib as first-line therapy in biologic-naïve patients outside of clinical trials - FDA labeling restricts use to post-TNF failure. 1

• Do not use tofacitinib as rescue therapy in acute severe UC - it lacks evidence in this setting and has slower onset than infliximab/cyclosporine. 2

• Do not continue high-dose maintenance (10 mg BID) indefinitely without reassessing risk-benefit - increased thromboembolism and mortality risk at higher doses. 1

• Do not initiate in elderly patients with cardiovascular risk factors without careful consideration - European guidance recommends caution in this population. 1

• Do not forget herpes zoster vaccination before initiation - significantly elevated risk compared to other advanced therapies. 5, 3