Is tofacitinib (Xeljanz) a viable treatment option for patients with moderate to severe Sjogren's syndrome?

Tofacitinib for Sjögren's Syndrome

Tofacitinib is not currently recommended for routine treatment of Sjögren's syndrome, as it lacks regulatory approval for this indication and is not mentioned in current EULAR guidelines for Sjögren's management. However, emerging mechanistic evidence and early-phase clinical trials suggest potential benefit, particularly for systemic manifestations and interstitial lung disease 1, 2.

Current Guideline Position

• EULAR 2020 guidelines for Sjögren's syndrome management do not include JAK inhibitors among recommended systemic therapies 1.
• The guidelines restrict systemic immunosuppressive therapies (glucocorticoids, antimalarials, immunosuppressants, biologics) to patients with active systemic disease, defined as ESSDAI score >5 or moderate activity in at least one clinical domain 1.
• B-cell targeted therapies (rituximab, belimumab) are the only biologics specifically mentioned for severe, refractory systemic disease 1.

Emerging Evidence for Tofacitinib in Sjögren's

Mechanistic Rationale

• JAK-STAT pathway activation is prominently upregulated in Sjögren's disease tissues, with elevated interferon-stimulated genes (ISGs) in both salivary glands and peripheral blood mononuclear cells 2.
• Single-cell RNA sequencing demonstrates cell type-specific upregulation of JAK-STAT signaling, particularly in monocytes and salivary gland epithelial cells 2.
• Ex vivo studies show tofacitinib normalizes aberrant JAK-STAT signaling in patient-derived salivary gland tissues and PBMCs without cytotoxicity 2.
• ISG expression correlates with clinical severity markers including focus scores and anti-SSA antibody positivity 2.

Clinical Trial Data

• A phase Ib/IIa randomized controlled trial of tofacitinib for Sjögren's disease has been initiated based on the mechanistic data showing JAK-STAT pathway correction 2.
• A prospective randomized trial (ChiCTR2000031389) is comparing tofacitinib to cyclophosphamide plus azathioprine specifically for Sjögren's-associated interstitial lung disease over 52 weeks, with forced vital capacity as the primary endpoint 3.
• One case report documented successful treatment of Sjögren's-associated immune thrombocytopenia with tofacitinib after failure of multiple conventional immunosuppressants, achieving stable platelet counts for >2 years 4.

Safety Considerations Specific to Sjögren's Patients

• Lymphoma risk is particularly relevant, as 2-5% of Sjögren's patients develop lymphoma independent of treatment 5.
• In the rheumatoid arthritis tofacitinib program, patients with baseline Sjögren's syndrome had numerically higher lymphoma rates compared to matched controls, though numbers were small 6.
• The lymphoma incidence rate in RA patients receiving tofacitinib was 0.10 per 100 patient-years (SIR 2.62 compared to general population) 6.
• FDA black box warnings apply: increased risk of major adverse cardiovascular events, venous thromboembolism, malignancies, and death, particularly in patients ≥50 years with cardiovascular risk factors 7.

Clinical Decision Algorithm

For patients with moderate-to-severe systemic Sjögren's disease (ESSDAI >5):

1. First-line systemic therapy should follow EULAR guidelines: glucocorticoids with or without conventional immunosuppressants (hydroxychloroquine, methotrexate, azathioprine, mycophenolate) 1.

2. For severe, refractory disease after conventional therapy failure: consider B-cell targeted therapies (rituximab, belimumab) as these have the highest level of evidence 1.

3. Tofacitinib may be considered investigationally in the following specific scenarios:

   • Sjögren's-associated interstitial lung disease refractory to conventional therapy 3
   • Severe systemic manifestations (e.g., immune thrombocytopenia) after failure of multiple immunosuppressants 4
   • Only in patients <50 years without cardiovascular risk factors, no malignancy history, and no active infections 7

4. If tofacitinib is used off-label, standard dosing would be 5 mg orally twice daily based on other autoimmune indications 7.

Required Monitoring if Tofacitinib is Used

• Pre-treatment screening: tuberculosis testing (IGRA or TST), hepatitis B/C, HIV in high-risk populations, complete blood count, comprehensive metabolic panel, lipid profile 7, 8.
• Herpes zoster vaccination (Shingrix 2-dose series) before initiation in patients ≥18 years 8.
• During treatment: CBC with differential at 4-8 weeks then every 3 months, liver enzymes at 4 weeks then every 3 months, lipids at 4-12 weeks then annually 8.
• Enhanced lymphoma surveillance given baseline Sjögren's-associated lymphoma risk 5, 6.

Critical Caveats

• No regulatory approval exists for tofacitinib in Sjögren's syndrome in any jurisdiction 1.
• The drug is approved only for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, ulcerative colitis, and polyarticular juvenile idiopathic arthritis 7.
• Ongoing clinical trials have not yet reported efficacy or safety outcomes specific to Sjögren's disease 2, 3.
• Use would be entirely off-label and should ideally occur within clinical trial settings or after exhausting guideline-recommended therapies 1.