What is the role of Tofacitinib (Janus kinase inhibitor) in treating Interstitial Lung Disease (ILD) associated with Sjogren's syndrome?

Role of Tofacitinib in Sjögren's Syndrome-Associated Interstitial Lung Disease

Tofacitinib is not recommended as a first-line treatment for Sjögren's syndrome-associated interstitial lung disease (SjD-ILD), but may be considered as a treatment option in patients with inflammatory myositis-associated ILD (IIM-ILD) who have failed first-line therapies. 1

Current Treatment Recommendations for SjD-ILD

First-Line Treatment Options

• Mycophenolate mofetil: Recommended as first-line therapy for SjD-ILD based on evidence of efficacy in various systemic autoimmune rheumatic disease (SARD)-associated ILDs 1
• Azathioprine: Alternative first-line option if mycophenolate is not tolerated 1
• Rituximab: Considered for SjD-ILD based on observational studies showing FVC stabilization or improvement 1

Second-Line Treatment Options for Progressive SjD-ILD

For patients with SjD-ILD who progress despite first-line treatment, the following options are recommended:

• Mycophenolate (if not used as first-line)
• Rituximab
• Cyclophosphamide
• Nintedanib (particularly for those with progressive fibrosing disease on HRCT) 1

Therapies Not Recommended for SjD-ILD

The 2023 ACR/CHEST guidelines specifically recommend against:

• Tocilizumab for SjD-ILD progression (conditionally recommended against) 1
• JAK inhibitors (including tofacitinib) as first-line therapy for SARD-ILD other than inflammatory myositis-associated ILD 1
• Calcineurin inhibitors for SARD-ILD other than IIM-ILD 1
• Pirfenidone for SARD-ILD other than RA-ILD 1

JAK Inhibitors in SARD-ILD

Current Evidence for Tofacitinib in SjD-ILD

• Limited evidence exists for tofacitinib specifically in SjD-ILD
• A clinical trial protocol has been published to investigate tofacitinib compared to cyclophosphamide plus azathioprine for pSS-ILD, but results are not yet available 2
• Case reports have shown potential benefit of tofacitinib in other manifestations of Sjögren's disease (e.g., immune thrombocytopenia) 3, but not specifically for ILD

JAK Inhibitors in Other SARD-ILDs

• IIM-ILD: JAK inhibitors are conditionally recommended as both first-line treatment and for disease progression 1
• Anti-MDA5 antibody-positive dermatomyositis with ILD: Case series suggests potential benefit of tofacitinib in refractory cases 4
• RA-ILD: Case reports suggest tofacitinib may stabilize ILD in some patients 5, but safety data shows an incidence rate of 0.18 per 100 patient-years for ILD events in RA patients treated with tofacitinib 6

Treatment Algorithm for SjD-ILD

1. Initial assessment:

   • Determine severity and pattern of ILD on HRCT
   • Assess pulmonary function tests (FVC, DLCO)
   • Evaluate for poor prognostic factors

2. First-line therapy:

   • Mycophenolate mofetil (2-3g daily) or azathioprine if mycophenolate is not tolerated
   • Consider rituximab in severe cases

3. For progressive disease despite first-line therapy:

   • Switch to or add rituximab
   • Consider cyclophosphamide for severe, rapidly progressive disease
   • Consider adding nintedanib for progressive fibrosing phenotype

4. For refractory disease:

   • Consider clinical trials
   • Consider JAK inhibitors only in cases with overlap features of inflammatory myositis

Important Considerations and Caveats

• Safety profile: Tofacitinib has been associated with increased risk of infections, particularly viral infections, which must be carefully considered in patients with ILD 4
• Monitoring: If tofacitinib is used, regular monitoring of liver enzymes, neutrophil counts, and platelet counts is required 7
• Age and smoking status: Patients aged ≥65 years and current smokers have higher risk of ILD events with tofacitinib treatment 6
• Supportive care: All patients with SjD-ILD should receive appropriate supportive care including pulmonary rehabilitation, oxygen supplementation if needed, and management of gastroesophageal reflux 1

In conclusion, while tofacitinib may have a role in specific SARD-ILDs, particularly inflammatory myositis-associated ILD, current guidelines do not support its use in SjD-ILD based on available evidence. Treatment should focus on established therapies like mycophenolate, rituximab, cyclophosphamide, and nintedanib for progressive disease.