What are the next steps for a patient with active ulcerative colitis who has failed tofacitinib (Janus kinase inhibitor)?

Management of Acute Severe Ulcerative Colitis After Tofacitinib Failure

In patients with acute severe ulcerative colitis (ASUC) who have failed tofacitinib, proceed immediately to infliximab rescue therapy or colectomy, as these are the only evidence-based options for ASUC refractory to corticosteroids. 1

Immediate Assessment and Decision-Making

For hospitalized patients with ASUC who have failed intravenous corticosteroids (and now tofacitinib), the AGA guidelines specifically recommend either infliximab or cyclosporine as rescue therapy 1. However, given that this patient has already failed tofacitinib (a JAK inhibitor), the therapeutic landscape is significantly narrowed:

• Infliximab is the preferred rescue agent if the patient has not previously been exposed to anti-TNF therapy, or if prior anti-TNF exposure was remote with primary non-response rather than secondary loss of response 1
• Consider intensive infliximab dosing (though the AGA makes no formal recommendation on routine use of intensive vs. standard dosing in ASUC) 1
• Cyclosporine remains an alternative rescue option, though it requires specialized monitoring and has significant toxicity concerns 1

Critical Context: Why Other Biologics Are Not Appropriate in ASUC

The evidence base for advanced therapies in UC comes from outpatient trials of moderate-to-severe disease, not acute severe hospitalized patients 1. The specific recommendations for ASUC are limited to infliximab and cyclosporine because:

• Vedolizumab, ustekinumab, and other biologics lack data in the ASUC setting and have slower onset of action 1
• The VARSITY trial showed vedolizumab superiority over adalimumab at 52 weeks in moderate-to-severe UC, but this was in outpatients, not ASUC 1
• Tofacitinib has emerging data as rescue therapy in ASUC 2, but your patient has already failed this agent

If Patient Stabilizes and Transitions to Outpatient Management

Should the patient respond to rescue therapy and stabilize, or if the clinical scenario is actually moderate-to-severe UC (not true ASUC), then sequencing becomes relevant:

For Patients Who Failed Tofacitinib After Anti-TNF Exposure:

The optimal next agent is ustekinumab, with vedolizumab as an alternative 1:

• The 2020 AGA guidelines suggest that in patients previously exposed to infliximab (particularly with primary non-response), ustekinumab or tofacitinib are preferred over vedolizumab or adalimumab for induction of remission 1
• Since tofacitinib has failed, ustekinumab becomes the preferred option in this biologic-experienced, tofacitinib-failed population 1
• A 2024 multicenter study showed tofacitinib was more efficacious than ustekinumab as third-line therapy (HR for disease progression: 1.93 for ustekinumab vs. tofacitinib, p=0.030) 3, but this is reversed in your scenario since tofacitinib has already failed

Newer Agents to Consider:

The 2024 AGA living guideline now includes additional options 1:

• Upadacitinib (another JAK inhibitor) - though cross-class failure with tofacitinib is a concern
• Anti-IL-23 agents: risankizumab, guselkumab, or mirikizumab 1
• S1P receptor modulators: ozanimod or etrasimod 1

Combination Therapy Considerations

If pursuing medical management rather than surgery:

• Combining biologics with immunomodulators (thiopurines or methotrexate) is suggested for TNF antagonists, vedolizumab, or ustekinumab 1
• However, in the ASUC setting, monotherapy is typically initiated first given the acute nature and need for rapid response 1
• There is one case report of successful combination vedolizumab + tofacitinib in refractory UC 4, but this is not guideline-supported and represents experimental therapy

Common Pitfalls to Avoid

• Do not delay surgical consultation - colectomy remains definitive therapy and should be discussed early with patients failing medical rescue 1
• Do not use vedolizumab or other slower-acting biologics as rescue therapy in true ASUC - they lack evidence in this setting and have delayed onset of action 1
• Do not assume all JAK inhibitors will fail if tofacitinib failed - upadacitinib has different JAK selectivity, though cross-resistance is possible 1
• Do not continue 5-aminosalicylates once advanced therapies are initiated - they provide no additional benefit 1

Practical Algorithm

1. Confirm ASUC diagnosis: bloody stools ≥6/day plus tachycardia, fever, anemia, or elevated inflammatory markers 5
2. If true ASUC failing IV corticosteroids and tofacitinib: offer infliximab rescue (if not previously failed) or colectomy 1
3. If moderate-severe outpatient disease (not ASUC): sequence to ustekinumab or consider anti-IL-23 agents 1
4. Involve surgery early in decision-making regardless of chosen pathway 1

The FDA labeling for vedolizumab notes that 39% of UC trial patients had prior inadequate response to TNF blockers 6, supporting its use in biologic-experienced patients, but again, this is for moderate-to-severe outpatient disease, not ASUC rescue.