Is tofacitinib (Janus kinase (JAK) inhibitor) effective in treating chronic urticaria?

Tofacitinib for Chronic Urticaria

Tofacitinib shows promise as an emerging treatment option for antihistamine-refractory chronic spontaneous urticaria, though it is not currently guideline-recommended and carries significant safety concerns that require careful patient selection and monitoring.

Current Guideline-Recommended Treatment Hierarchy

The established treatment algorithm for chronic urticaria does not include tofacitinib, as the available guidelines predate its investigation for this indication:

• First-line: High-dose non-sedating H1-antihistamines (up to 4-fold standard dosing) 1
• Second-line for refractory cases: Cyclosporine (approximately 75% response rate at 4 mg/kg daily) or omalizumab (approximately 75% response rate) are the most effective options 1, 2
• Limited role: Corticosteroids should be restricted to short-term crisis management (≤10 mg/day with weekly 1 mg reductions) due to toxicity, except in severe pressure urticaria or urticarial vasculitis 1, 2
• Minimal benefit: Leukotriene antagonists, H2-antagonists, dapsone, sulfasalazine, and hydroxychloroquine show response rates not exceeding 30% placebo responses 2

Emerging Evidence for Tofacitinib in Urticaria

Efficacy Data

Small case series demonstrate substantial clinical benefit in antihistamine-refractory patients:

• In a 6-month pilot study of 7 patients with chronic spontaneous urticaria resistant to 4-fold antihistamine dosing, tofacitinib 5 mg twice daily produced dramatic improvement: mean UAS7 scores decreased from 24.86 to 3.83 (p<0.0001) and UCT scores increased from 0.57 to 14 (p<0.0001) 3
• A case series of 4 refractory chronic urticaria patients and 1 urticarial vasculitis patient showed significant improvement with tofacitinib, allowing tapering or discontinuation of cyclosporine or antihistamines 4
• The mechanism appears to involve downregulation of inflammatory phenomena associated with mast cells through JAK1/3 inhibition 4

Critical Limitations

These studies represent low-quality evidence (small case series without controls) and tofacitinib is not FDA-approved for urticaria 4, 3.

Major Safety Concerns Precluding Routine Use

Black Box Warnings and High-Risk Populations

Tofacitinib carries FDA black box warnings for serious infections, mortality, malignancy, and major cardiovascular events 5, 6:

• Age restrictions: Should only be used when no suitable alternatives exist in patients ≥65 years due to increased serious infection risk 1, 5
• Cardiovascular risk: Five-fold increased pulmonary embolism risk with 10 mg twice daily dosing compared to TNF inhibitors; increased MACE in patients >50 years with cardiovascular risk factors 5, 6
• Malignancy: Increased cancer risk, particularly lung and breast cancer 6
• Infection risk: Significantly elevated herpes zoster rates; serious infections including tuberculosis, opportunistic infections 6

Mandatory Monitoring Requirements

If tofacitinib is considered for refractory urticaria, intensive monitoring is required 5, 7:

• Pre-treatment screening: TB testing (interferon-γ release assay or PPD), hepatitis B/C serology, HIV testing in at-risk patients, pregnancy testing in women of childbearing potential 1, 5, 7
• Baseline labs: CBC with differential, comprehensive metabolic panel, lipid panel 1, 7
• Ongoing monitoring: CBC and liver function tests at 1-2 months, then every 3-4 months; lipid panel at 1-2 months 7
• Discontinuation thresholds: Stop immediately if hemoglobin <8 g/dL or drops >2 g/dL, ANC <500/mm³, or lymphocyte count <500/mm³ 6, 7

Contraindications

Absolute contraindications include 1, 5:

• Active serious infections
• Severe hepatic impairment (Child-Pugh C)
• Pregnancy and breastfeeding (teratogenic in animal studies)
• Lymphocyte count <500/mm³, ANC <1000/mm³, or hemoglobin <9 g/dL at baseline

Clinical Decision Algorithm

For antihistamine-refractory chronic spontaneous urticaria:

1. Optimize antihistamine dosing to 4-6 times standard daily dose 1, 2

2. If inadequate response, prioritize guideline-recommended options:

   • Cyclosporine 4 mg/kg daily (monitor BP, renal function, urinary protein every 6 weeks) 1, 2
   • Omalizumab (best efficacy/toxicity profile once approved for urticaria) 2

3. Consider tofacitinib ONLY if:

   • Patient has failed both high-dose antihistamines AND cyclosporine or omalizumab
   • Patient is <65 years old without cardiovascular risk factors
   • No history of malignancy, VTE, or recurrent serious infections
   • Patient accepts off-label use with significant safety risks
   • Intensive monitoring can be ensured

4. If tofacitinib is used:

   • Dose: 5 mg twice daily (lower than doses used for approved indications) 4, 3
   • Zoster vaccination before initiation if age >50 years 5, 6
   • Avoid live vaccines once started 5
   • Do not combine with other immunosuppressants or biologics 1, 5

Key Caveats

• The evidence for tofacitinib in urticaria consists only of small case series without controls—this represents the lowest quality evidence 4, 3
• The dramatic safety concerns documented in rheumatoid arthritis and inflammatory bowel disease trials apply equally to urticaria patients 1, 5, 6
• Cyclosporine and omalizumab have substantially more robust evidence and established safety profiles for urticaria 1, 2
• Refractoriness to both cyclosporine and omalizumab is expected in <5% of patients, making tofacitinib relevant only for this highly select minority 2