Can Tofacitinib (JAK inhibitor) be used as an alternative to Ruxolitinib (JAK inhibitor) in a patient with VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome who has failed or is intolerant to Ruxolitinib?

Can Tofacitinib Be Used as an Alternative to Ruxolitinib in VEXAS Syndrome?

Yes, tofacitinib can be tried in VEXAS syndrome patients who have failed or are intolerant to ruxolitinib, though the evidence is limited and response rates appear inferior to azacitidine and tocilizumab.

Evidence for JAK Inhibitors in VEXAS Syndrome

The largest UK cohort study of VEXAS syndrome treatment outcomes provides the most relevant data for this clinical scenario:

• Baricitinib (another JAK inhibitor) showed only 40% response rate at 6 months with no complete responses in the five patients who continued therapy, suggesting JAK inhibitors as a class may have limited efficacy in VEXAS 1

• Ruxolitinib has demonstrated favorable mid-term responses in VEXAS syndrome and is considered among the more effective treatment options alongside azacitidine 2

• Momelotinib, a newer JAK inhibitor, has shown effectiveness in two case reports of VEXAS patients with anemia, improving both anemia and inflammation markers 3

Comparative Effectiveness Data

When considering alternatives to ruxolitinib, the evidence hierarchy is clear:

• Azacitidine demonstrated superior effectiveness with 91% response rate at 6 months (including 27% complete responses) and was significantly more likely to produce responses than other therapies (risk ratio 2.47,95% CI 1.18-5.20; p=0.018) 1

• Tocilizumab showed 64% response rate at 6 months with 36% complete responses and the greatest reduction in CRP levels (from median 30 mg/L to 4 mg/L) 1

• Anakinra achieved 100% response rate in the three patients who tolerated it, but had a 62% discontinuation rate primarily due to severe injection-site reactions 1

Safety Considerations for Tofacitinib in VEXAS

Critical safety issues must be addressed before initiating tofacitinib:

• Mandatory tuberculosis screening with interferon-gamma release assay or tuberculin skin test, with at least 1 month of latent TB treatment before starting tofacitinib if positive 4, 5

• Baseline laboratory requirements: CBC with differential (contraindicated if lymphocyte count <500/mm³, ANC <1000/mm³, or hemoglobin <9 g/dL), comprehensive metabolic panel, lipid profile, hepatitis B/C serology 6, 4

• Venous thromboembolism risk is significantly elevated with tofacitinib, particularly concerning given that VEXAS syndrome itself carries high thromboembolic risk 7, 6, 1

• Increased infection risk, particularly herpes zoster, serious bacterial infections, and opportunistic infections 7, 6, 5

• Recombinant zoster vaccine (Shingrix) should be administered before initiating tofacitinib with a 2-dose series separated by 2-6 months 4

Practical Dosing and Monitoring

If tofacitinib is selected despite limited evidence:

• Standard dosing is 5 mg twice daily orally, with dose adjustments required for renal impairment (reduce to 5 mg once daily if CrCl <30 mL/min) 8, 5

• Monitoring schedule: CBC with differential and CMP at 4-8 weeks, then every 3 months; lipid panel at 12 weeks then annually 8, 4

• Discontinuation thresholds: Stop immediately if hemoglobin <8 g/dL or drops >2 g/dL, ANC <500/mm³, or lymphocyte count <500/mm³ 6

Clinical Algorithm for Treatment Selection

When ruxolitinib has failed or is not tolerated:

1. First-line alternative: Azacitidine - highest response rate (91%) and greatest improvement in hemoglobin, particularly beneficial given the macrocytic anemia common in VEXAS 1, 2

2. Second-line alternative: Tocilizumab - 64% response rate with excellent CRP reduction, though infection risk (47%) must be considered 1

3. Third-line consideration: Tofacitinib or other JAK inhibitors - only if azacitidine and tocilizumab are contraindicated, unavailable, or have failed; momelotinib may be preferred if significant anemia is present 1, 3

4. Consider hematopoietic stem cell transplantation for younger, fit patients with poor prognostic factors or recalcitrant symptoms, as this is the only curative option 2

Critical Pitfalls to Avoid

• Do not assume class effect among JAK inhibitors - baricitinib showed poor response rates in VEXAS, suggesting tofacitinib may similarly underperform compared to ruxolitinib 1

• Do not overlook thromboembolism prophylaxis - VEXAS patients already have elevated VTE risk, and tofacitinib further increases this risk, particularly in patients >50 years with cardiovascular risk factors 7, 6, 1

• Do not initiate tofacitinib without completing mandatory screening for latent TB, hepatitis, and baseline cytopenias 4, 5

• Absence of fever or thromboembolism at diagnosis predicts better treatment outcomes across all therapies, which should inform treatment selection 1