What is the mechanism of action, efficacy, and safety profile of tofacitinib (Janus kinase (JAK) inhibitor) in treating rheumatoid arthritis (RA), and how does it compare to other JAK inhibitors like upadacitinib and baricitinib?

Tofacitinib in Rheumatoid Arthritis: Mechanism, Efficacy, Safety, and Comparison with Other JAK Inhibitors

Tofacitinib is an oral JAK1/JAK3 inhibitor approved at 5 mg twice daily for moderate-to-severe RA in patients who have failed conventional DMARDs, with proven efficacy comparable to biologics but requiring caution due to increased risks of herpes zoster and venous thromboembolism, particularly in older patients with cardiovascular risk factors. 1, 2

Mechanism of Action

Tofacitinib is a potent, selective inhibitor of JAK1 and JAK3 that blocks intracellular signal transduction of multiple inflammatory cytokines critical to RA pathogenesis. 1, 3 By inhibiting these Janus kinases, tofacitinib interrupts the phosphorylation of cytokine-bound receptors and subsequent gene transcription that drives immune cell recruitment, activation, and inflammatory responses in the synovium. 3 This represents a fundamentally different approach than biologics, as it targets intracellular signaling pathways rather than extracellular cytokines themselves. 3

Efficacy in Rheumatoid Arthritis

Clinical Trial Evidence

Tofacitinib demonstrates robust efficacy superior to placebo and comparable to methotrexate across multiple outcome measures. A pooled meta-analysis of 10 trials showed tofacitinib achieved significantly higher ACR20 response rates compared to placebo (OR 2.44,95% CI 1.97-3.02) and compared to MTX monotherapy (OR 2.38,95% CI 1.66-3.43). 1

• Tofacitinib effectively reduces signs and symptoms of RA, improves physical function (HAQ-DI scores), and appears to reduce structural damage progression. 1
• Efficacy is maintained whether used as monotherapy or in combination with conventional DMARDs like methotrexate. 1, 4
• Clinical improvements are sustained during long-term therapy extending beyond 2 years. 1, 5

Real-World Evidence

Real-world observational studies confirm the effectiveness demonstrated in clinical trials, with treatment persistence comparable to biologic DMARDs and safety profiles consistent with the approved 5 mg twice daily dose. 4

Safety Profile and Adverse Events

Common Adverse Events

The most frequently reported adverse events are infections and infestations, with the majority being mild to moderate in severity. 2, 5

Herpes Zoster Risk

A specific and clinically important safety concern is the increased risk of herpes zoster infection, which occurs more frequently with tofacitinib than with TNF inhibitors. 1, 2 While most cases have been clinically mild, this risk appears particularly elevated in Japanese patients (incidence rate 7.4 per 100 patient-years). 5 Regular monitoring for herpes zoster is essential during treatment. 2

Venous Thromboembolism Risk

A critical safety signal has emerged regarding venous thromboembolism (VTE) and pulmonary embolism, particularly at the 10 mg twice daily dose but also present at the approved 5 mg twice daily dose. 1, 2 This data derives from an ongoing cardiovascular outcomes study (A3921133) comparing tofacitinib to TNF inhibitors in RA patients with cardiovascular risk factors. 1

• VTE risk is especially elevated in patients with previous thromboembolic events, high body mass index, hormone replacement therapy, and advanced age. 1
• JAK inhibitors should be used with caution in patients at high risk for thromboembolic events. 1
• In patients ≥65 years with smoking history or cardiovascular/malignancy risk factors, JAK inhibitors should only be used if no suitable alternatives exist. 2

Other Safety Considerations

• Serious infections including tuberculosis and opportunistic infections have been reported; TB screening is mandatory before initiation. 2
• Hematologic abnormalities including lymphocytopenia and anemia require regular complete blood count monitoring. 2
• CRP and ESR may be reduced independently of disease activity reduction, potentially masking infections. 2
• Dose reduction is required for creatinine clearance <30 mL/min, and tofacitinib is contraindicated in severe hepatic impairment (Child-Pugh C). 2

Positioning in Treatment Algorithm

According to EULAR 2019 recommendations, tofacitinib is classified as a targeted synthetic DMARD (tsDMARD) and should be added after failure of conventional synthetic DMARDs in patients with unfavorable prognostic markers. 1, 2

The treatment sequence is:

1. Start with conventional synthetic DMARDs (particularly methotrexate) as first-line therapy. 2
2. If treatment targets are not achieved, add a biologic DMARD or tsDMARD (including tofacitinib). 1, 2
3. Tofacitinib can be used as monotherapy when methotrexate is contraindicated or not tolerated. 2

The EULAR task force concluded that bDMARDs and tsDMARDs should be "added" rather than merely "considered," representing stronger support for combination therapy. 1

Comparison with Upadacitinib and Baricitinib

Efficacy Comparison

The EULAR task force determined that bDMARDs and tsDMARDs have on average similar efficacy, with no preference given to any agent based solely on efficacy. 1

• While baricitinib and upadacitinib showed statistical superiority to adalimumab in non-inferiority trials, tofacitinib plus MTX did not demonstrate such superiority. 1
• The clinical relevance of small differences in clinical trials was not considered convincing enough to prefer one JAK inhibitor over another. 1
• Inflammatory markers like swollen joint counts did not differ significantly among groups. 1
• Upadacitinib at 15 mg showed non-inferiority for ACR20 response compared to adalimumab, while the 30 mg dose showed superiority in some endpoints. 6, 7

Selectivity Differences

• Tofacitinib: JAK1/JAK3 selective inhibitor 1, 3
• Baricitinib: JAK1/JAK2 selective inhibitor 1
• Upadacitinib: More selective JAK1 inhibitor, theoretically reducing JAK2/JAK3-related side effects 7

Despite upadacitinib's greater JAK1 selectivity, it appears to have a similar safety profile to less-selective JAK inhibitors, including VTE risk. 1, 7

Safety Comparison

All three JAK inhibitors share similar safety concerns:

• Increased herpes zoster infections 1, 2
• VTE and pulmonary embolism risk, particularly in high-risk patients 1
• Infections and opportunistic infections 2
• Hematologic abnormalities 2

The decision regarding which JAK inhibitor to prescribe should be based on an aggregate of contraindications, patient preference, and costs, rather than efficacy differences alone. 1

Dosing Recommendations

The approved and recommended dose for RA is tofacitinib 5 mg twice daily. 1, 2, 4 The 10 mg twice daily dose carries increased VTE risk and should be avoided in routine RA treatment. 1