Can Tofacitinib (Tofacitinib) be effective in treating active Rheumatoid Arthritis (RA) in a patient with Interstitial Lung Disease (ILD) of a Usual Interstitial Pneumonia (UIP) pattern, who is already on Leflunomide (Leflunomide) and Mycophenolate Mofetil (Mycophenolate Mofetil)?

Tofacitinib Should NOT Be Used as First-Line Therapy for RA-ILD with UIP Pattern

The 2023 ACR/CHEST guidelines conditionally recommend AGAINST JAK inhibitors (including tofacitinib) as first-line treatment for RA-ILD, and you should prioritize switching from leflunomide to preferred immunosuppressive agents while addressing the active arthritis with alternative strategies. 1

Critical Safety Concern: Leflunomide Must Be Stopped

• Leflunomide has been associated with development or worsening of ILD in rare cases and should be discontinued in patients with RA-ILD. 1
• This is a priority action given the patient already has established ILD with a UIP pattern, which carries worse prognosis.

Recommended First-Line Treatment Approach for RA-ILD

Preferred Immunosuppressive Options (in order of preference):

Mycophenolate is the preferred first-line agent for RA-ILD based on trial evidence and observational studies, particularly when switching from inadequate therapy. 1

Alternative preferred options include:

• Rituximab - supported by indirect evidence showing FVC stabilization or improvement in RA-ILD 1
• Cyclophosphamide - demonstrates FVC stabilization despite side effect concerns, and retrospective data shows improved survival (HR: 0.210) 1, 2
• Azathioprine - conditionally recommended as first-line option 1

The Patient Is Already on MMF

Since the patient is already receiving mycophenolate mofetil (MMF) but has active arthritis, this suggests:

• The ILD may be stable on MMF (which is appropriate)
• The arthritis requires additional disease control

Why NOT Tofacitinib for RA-ILD?

The ACR/CHEST guidelines explicitly state: "For people with SARD-ILD other than IIM-ILD, we conditionally recommend against JAKi as first-line ILD treatment option." 1

Limited Evidence Base:

• JAK inhibitors were only conditionally recommended for IIM-ILD (inflammatory myopathy), not RA-ILD 1
• The single observational study supporting JAKi was in anti-MDA-5 associated ILD, not RA-ILD 1
• Guidelines note "limited data and experience" for JAKi in non-IIM SARD-ILD 1

Emerging but Insufficient Data:

While case reports 3 and small prospective studies 4 show potential benefit of tofacitinib in RA-UIP, these represent low-quality evidence that did not influence the 2024 guideline recommendations. The prospective study showed FVC improvement with tofacitinib plus iguratimod versus conventional DMARDs 4, but this is insufficient to override guideline recommendations.

Special Consideration: UIP Pattern

Some panelists would consider nintedanib specifically for RA-ILD patients with fibrotic/UIP pattern, though the panel could not reach consensus on this recommendation. 1

• Nintedanib may be added to immunosuppression, particularly for progressive fibrosing disease 1
• However, it only attenuates FVC decline rather than stabilizing or improving lung function 1
• Cost and gastrointestinal side effects (especially diarrhea) are significant concerns 1

Recommended Management Algorithm

Step 1: Discontinue Leflunomide Immediately

• Associated with ILD development/worsening 1

Step 2: Continue MMF for ILD Management

• Already receiving this preferred first-line agent 1
• Guidelines recommend against adding antifibrotics to MMF without evidence of ILD progression 1

Step 3: Address Active Arthritis

For the active arthritis component, consider:

• Rituximab - can address both arthritis and ILD (some panelists add to mycophenolate for dual benefit) 1
• Tocilizumab - conditionally recommended for RA-ILD progression, showed stabilization in retrospective studies 1, 5
• Abatacept - studies suggest no worsening of ILD, though efficacy for ILD is uncertain; can be used for arthritis 1

Step 4: Monitor for ILD Progression

If ILD progresses despite first-line therapy:

• Consider adding nintedanib (especially given UIP pattern) 1
• Consider adding pirfenidone (conditionally recommended specifically for RA-ILD progression with UIP pattern) 1
• Switch to or add rituximab or cyclophosphamide 1

Critical Pitfalls to Avoid

• Do not continue leflunomide - clear association with ILD worsening 1
• Do not use TNF inhibitors - observational data suggest harm or no effect on SARD-ILD 1
• Do not add antifibrotics without ILD progression - guidelines recommend against this due to cost, adverse effects, and limited efficacy data 1
• Methotrexate caution - while not associated with ILD progression in observational data, some would stop if ILD developed while on methotrexate 1

Bottom Line

Tofacitinib is not recommended for RA-ILD based on current guidelines. Stop leflunomide, continue MMF for ILD, and add rituximab or tocilizumab to control the active arthritis while monitoring lung function closely. 1 Reserve nintedanib or pirfenidone for documented ILD progression given the UIP pattern. 1