What is the role of Tofacitinib (Xeljanz) in the treatment of rheumatoid arthritis?

Role of Tofacitinib in Rheumatoid Arthritis

Tofacitinib should be considered primarily after biological DMARD treatment failure in patients with rheumatoid arthritis, as it demonstrates proven efficacy but carries significant safety concerns including increased risk of infections, particularly herpes zoster, and potential cardiovascular risks. 1, 2, 3

Positioning in Treatment Algorithm

Tofacitinib (Xeljanz) is classified as a targeted synthetic DMARD (tsDMARD) that works by inhibiting Janus kinase (JAK) enzymes, particularly JAK1 and JAK3. Its position in the treatment algorithm is as follows:

1. First-line therapy: Methotrexate (MTX) remains the cornerstone first-line DMARD for active RA 1, 2
2. Second-line therapy: For patients with inadequate response to MTX:
   • Without poor prognostic factors: Switch to or add another conventional synthetic DMARD (csDMARD) 2
   • With poor prognostic factors: Add a biological DMARD (bDMARD) such as TNF inhibitors, IL-6 inhibitors, or T-cell costimulation modulators 2
3. Third-line therapy: Tofacitinib should be considered after biological treatment failure 1, 2

Efficacy Profile

Tofacitinib has demonstrated significant efficacy in multiple clinical trials:

• Improves clinical, functional, and structural outcomes in RA 1, 4
• Produces higher ACR20 response rates compared to placebo (OR 2.44; 95% CI 1.97-3.02) 1
• Shows similar efficacy to adalimumab when added to background methotrexate 4, 5
• Maintains clinical responses for up to 24 months of treatment 6
• May have greater efficacy in patients with fewer prior treatments 7

Safety Considerations

The FDA label and guidelines highlight important safety concerns that must be weighed against efficacy:

• Mortality: Higher rates of all-cause mortality compared to TNF inhibitors in patients over 50 with cardiovascular risk factors 3
• Malignancies: Increased risk of lymphomas and solid tumors, particularly in current or past smokers 3
• Cardiovascular events: Higher rates of major adverse cardiovascular events (MACE) in patients over 50 with cardiovascular risk factors 3
• Thrombosis: Increased risk of pulmonary embolism, deep venous thrombosis, and arterial thrombosis 3
• Infections: Higher incidence of herpes zoster compared to TNF inhibitors 1, 3, 8
• Laboratory abnormalities: Requires monitoring for lymphocytopenia, neutropenia, anemia, and elevated liver enzymes 3, 8

Dosing and Administration

• Standard dosing: 5 mg twice daily for RA 3
• Contraindication: 10 mg twice daily is not recommended for RA due to increased safety risks 3
• Administration: Can be taken with or without food 3
• Combination therapy: Should not be used in combination with biological DMARDs or potent immunosuppressants such as azathioprine and cyclosporine 3

Monitoring Recommendations

Patients on tofacitinib require careful monitoring:

• Pre-treatment: Screen for tuberculosis and assess baseline laboratory parameters 2, 3
• During treatment: Monitor for:
  • Infections, particularly herpes zoster 1, 2
  • Complete blood count (lymphocyte count, neutrophil count, hemoglobin) 3
  • Liver function tests 3, 8
  • Lipid profile (LDL/HDL) 8
  • Renal function 8

Common Pitfalls to Avoid

• Using tofacitinib as first-line therapy before trying MTX 1, 2
• Prescribing 10 mg twice daily dose for RA (not recommended due to safety concerns) 3
• Failing to screen for tuberculosis before initiation 2
• Inadequate monitoring of laboratory parameters 2, 3
• Using in combination with biological DMARDs or potent immunosuppressants 3
• Prescribing to patients with active serious infections 3
• Overlooking cardiovascular risk factors in patients over 50 years of age 3

Tofacitinib represents an important oral treatment option for patients with RA who have failed biological therapy, but its use requires careful consideration of the benefit-risk profile for each individual patient, with particular attention to infection risk, cardiovascular status, and appropriate laboratory monitoring.