What is the role of Janus Kinase (JAK) inhibitors, such as tofacitinib, in treating enthesitis?

JAK Inhibitors for Enthesitis in Psoriatic Arthritis

JAK inhibitors, particularly tofacitinib, are recommended for patients with enthesitis who have had an inadequate response to NSAIDs, local glucocorticoid injections, and at least one bDMARD (biological DMARD). 1

Positioning in Treatment Algorithm

• JAK inhibitors are classified as targeted synthetic DMARDs (tsDMARDs) and should be considered after failure of at least one biological DMARD in patients with enthesitis 1, 2
• According to the 2023 EULAR recommendations, JAK inhibitors may be considered in patients with peripheral arthritis and enthesitis who have had an inadequate response to at least one bDMARD 1
• For patients with clinically relevant axial disease with enthesitis who have had an insufficient response to NSAIDs, JAK inhibitors are among the recommended treatment options alongside IL-17A inhibitors, TNF inhibitors, and IL-17A/F inhibitors 1

Efficacy for Enthesitis

• JAK inhibitors have demonstrated significant efficacy in resolving enthesitis in psoriatic arthritis patients 3
• A meta-analysis of randomized controlled trials showed that JAK inhibitors were associated with superior enthesitis resolution compared to placebo (Risk Ratio 1.82,95% CI 1.56-2.12) 3
• Tofacitinib has shown significant improvement in enthesitis in phase III clinical trials (OPAL BROADEN and OPAL BEYOND) 4, 5
• Upadacitinib has also demonstrated efficacy in treating enthesitis in PsA patients 3

Available JAK Inhibitors for Enthesitis

• Tofacitinib is the most extensively studied JAK inhibitor for enthesitis in PsA and is approved for this indication 6, 4
• Other JAK inhibitors being studied for PsA with enthesitis include upadacitinib and filgotinib 7, 3
• Tofacitinib primarily inhibits JAK1 and JAK3, while other JAK inhibitors have different selectivity profiles 1

Safety Considerations

• JAK inhibitors are associated with an increased risk of adverse events compared to placebo, particularly infections 3
• Herpes zoster infections appear to be more common with JAK inhibitors than with TNF inhibitors 1, 2
• Recent data have shown an increased risk of venous thromboembolism and pulmonary embolism with tofacitinib, particularly at higher doses in patients with cardiovascular risk factors 1, 2
• The European Medicines Agency recommends cautious use of JAK inhibitors as first-line agents in patients at risk for adverse cardiovascular outcomes, including those aged 65 years or older, current or previous long-term smokers, and those with a history of cardiovascular disease or malignancy 1, 8
• In women of childbearing age actively contemplating pregnancy, JAK inhibitors should be avoided due to limited safety data 1

Dosing and Administration

• For tofacitinib in PsA with enthesitis, the recommended dose is 5 mg twice daily 2, 8
• Dose reduction is recommended in patients with renal impairment (creatinine clearance <30 mL/min) 2
• Tofacitinib is contraindicated in patients with severe hepatic impairment (Child Pugh C) 2, 8

Monitoring Recommendations

• Regular monitoring for infections, particularly herpes zoster, is essential 2, 8
• Complete blood count monitoring is recommended due to potential hematologic abnormalities 8
• Tuberculosis screening is required before initiating therapy 8
• Lipid levels should be checked at baseline and approximately 3 months after initiation 8

Treatment Algorithm for Enthesitis in PsA

1. First-line: NSAIDs and local glucocorticoid injections 1
2. Second-line: Biological DMARDs (TNF inhibitors, IL-17 inhibitors) 1
3. Third-line: JAK inhibitors (tofacitinib, upadacitinib) in patients with inadequate response to bDMARDs 1, 3

Special Considerations

• In patients with concomitant inflammatory bowel disease and enthesitis, JAK inhibitors may be particularly beneficial 1, 8
• For patients who prefer oral administration over injectable biologics, JAK inhibitors provide a convenient alternative 1, 6
• In patients with multiple domains of PsA (peripheral arthritis, enthesitis, dactylitis, and skin involvement), JAK inhibitors have shown efficacy across these manifestations 4, 3