What is the dosing and usage of Tofacitinib (Xeljanz) for rheumatoid arthritis?

Tofacitinib (Xeljanz) for Rheumatoid Arthritis

For rheumatoid arthritis, use tofacitinib 5 mg orally twice daily (or the extended-release formulation 11 mg once daily), either as monotherapy or combined with methotrexate or other conventional DMARDs, but reserve this agent for patients who have failed at least one biologic DMARD due to safety concerns. 1, 2, 3

Standard Dosing

• The FDA-approved dose is 5 mg twice daily orally 1, 3, 4
• An extended-release formulation of 11 mg once daily is available as an alternative 1, 3
• Do NOT use the 10 mg twice daily dose for RA—this higher dose carries increased thromboembolic risk and is not recommended 5, 1, 3

Position in Treatment Algorithm

Tofacitinib should be used AFTER failure of at least one biologic DMARD, not as first-line therapy after conventional DMARDs. 5, 2

The treatment sequence should follow this pathway:

• First-line: Start with conventional synthetic DMARDs (csDMARDs), particularly methotrexate 2
• Second-line: If treatment targets are not met, advance to biologic DMARDs (bDMARDs) 2
• Third-line: After inadequate response or intolerance to at least one bDMARD, consider tofacitinib 5, 2

This conservative positioning reflects EULAR's 2014 recommendation that safety concerns with tofacitinib preclude its use before failure of biological agents, given that many bDMARDs are currently available and familiar to rheumatologists 5. The 2020 EULAR psoriatic arthritis guidelines similarly position JAK inhibitors after bDMARD failure 5.

Administration Guidelines

• Can be used as monotherapy or combined with methotrexate or other conventional DMARDs 1, 3
• Do NOT combine with potent immunosuppressants (azathioprine, cyclosporine) or biologic agents 1, 3
• According to European Medicines Agency approval for psoriatic arthritis, tofacitinib must be prescribed with methotrexate, though this may vary by indication 5

Required Dose Reductions

Reduce to 5 mg once daily in these specific situations: 1, 3

• Moderate to severe renal impairment (CrCl 30-60 mL/min)
• Moderate to severe hepatic impairment (Child-Pugh B or C)
• Concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole)
• Concomitant use of moderate CYP3A4 inhibitors plus potent CYP2C19 inhibitors (e.g., fluconazole)

Expected Clinical Efficacy

Patients typically see initial response within 2-4 weeks, with maximal benefit by 3-6 months. 1, 6

At 3 months, tofacitinib 5 mg twice daily demonstrates: 1, 7

• ACR20 response rates: 51.5-73.1%
• ACR50 response rates: significantly higher than placebo
• ACR70 response rates: significantly higher than placebo
• Mean HAQ-DI improvement: -0.40 to -0.44
• DAS28-ESR remission (<2.6): 5-10% at 3 months, 7.2-8.5% at 6 months

These improvements are sustained through 24 months of treatment 8. In head-to-head comparison, tofacitinib was noninferior to adalimumab when both were added to background methotrexate 4, 7.

Critical Safety Considerations and Monitoring

The safety profile is the primary reason tofacitinib is positioned after biologic failure rather than as first-line therapy. 5, 2

Pre-Treatment Screening

• Screen for latent tuberculosis before initiating therapy 1, 3
• Consider herpes zoster vaccination before starting, especially in patients >50-70 years 1
• Avoid in patients with active serious infections 1, 3

Key Safety Signals

Infections: 2, 4, 7, 9

• Herpes zoster infections occur more frequently with tofacitinib than with TNF inhibitors or the general RA population, though cases are typically clinically manageable 1, 2, 4, 9
• Serious infection rates show numerical increases compared to controls 2, 7
• Cases of tuberculosis and non-TB opportunistic infections have been reported 2

Thromboembolic Events: 5, 1

• Deep vein thrombosis risk is elevated, particularly with the 10 mg twice daily dose (which is why this dose is not recommended for RA)
• Use extreme caution in elderly patients (≥65 years) with cardiovascular risk factors 1

Hematologic Abnormalities: 2, 3

• Lymphocytopenia and anemia have been observed
• Regular monitoring of complete blood counts is necessary 2

Lipid Elevations: 3

• Dose-related elevations in total cholesterol, LDL, HDL, and triglycerides occur at one month and remain stable
• Mean LDL increases by 15% with 5 mg twice daily
• LDL/HDL ratios remain essentially unchanged
• Elevations respond to statin therapy

Ongoing Monitoring Requirements

• Monitor for infections, particularly herpes zoster 2
• Regular complete blood counts 2
• Lipid panel monitoring 3
• Liver function tests (ALT/AST elevations >3× ULN occur in approximately 1% of patients) 3
• Serum creatinine (dose-related elevations occur, though mean increase is <0.1 mg/dL) 3

Common Pitfalls to Avoid

• Do not use tofacitinib as first-line therapy after csDMARD failure—the limited long-term safety data compared to established bDMARDs justifies reserving it for later lines 5, 2
• Do not use the 10 mg twice daily dose for RA—this carries unacceptable thromboembolic risk 5, 1, 3
• Do not overlook cardiovascular risk factors in elderly patients—these patients have increased infection and thromboembolic risk 1
• Do not skip tuberculosis screening—this is essential before initiation 1, 3
• Do not forget dose adjustments for renal/hepatic impairment or drug interactions—failure to reduce dose appropriately increases toxicity risk 1, 3

Cost Considerations

The annual cost of tofacitinib (approximately US$25,000) is similar to biological agents, and the remarkably high price was a concern for the EULAR task force when making positioning recommendations 5, 2. The availability of biosimilars at potentially lower costs may influence treatment sequencing decisions 2.