What is the recommended treatment regimen for interstitial lung disease associated with systemic autoimmune rheumatic disease?

Treatment of SARD-ILD

For most patients with systemic autoimmune rheumatic disease-associated interstitial lung disease (SARD-ILD), mycophenolate is the preferred first-line therapy, with disease-specific modifications based on the underlying condition and severity of presentation. 1

First-Line Treatment by Disease Type

Systemic Sclerosis-ILD (SSc-ILD)

• Mycophenolate is the preferred first-line agent 1
• Strongly avoid glucocorticoids due to high risk of scleroderma renal crisis, particularly at prednisone doses >15 mg daily 1, 2
• Nintedanib is conditionally recommended as a first-line option and can be considered for progressive disease 1
• Additional first-line options include tocilizumab, azathioprine, rituximab, and cyclophosphamide 1

Inflammatory Myopathy-ILD (IIM-ILD)

• Mycophenolate is preferred first-line 1
• Short-term glucocorticoids (≤3 months) are conditionally recommended as part of initial therapy 2
• JAK inhibitors and calcineurin inhibitors (CNIs) are conditionally recommended as first-line options specifically for IIM-ILD 1
• Additional options include azathioprine, rituximab, and cyclophosphamide 1

Rheumatoid Arthritis-ILD (RA-ILD)

• Mycophenolate is preferred first-line 1
• Short-term glucocorticoids (≤3 months) are conditionally recommended 2
• Additional first-line options include azathioprine, rituximab, and cyclophosphamide 1
• The panel could not reach consensus on nintedanib as first-line therapy for RA-ILD 1

Mixed Connective Tissue Disease-ILD (MCTD-ILD)

• Mycophenolate is preferred first-line 1
• Short-term glucocorticoids (≤3 months) are conditionally recommended, but use cautiously in patients with SSc phenotype due to renal crisis risk 1, 2
• Tocilizumab is conditionally recommended as a first-line option 1
• Additional options include azathioprine, rituximab, and cyclophosphamide 1

Sjögren's Disease-ILD (SjD-ILD)

• Mycophenolate is preferred first-line 1
• Short-term glucocorticoids (≤3 months) are conditionally recommended 2
• Additional first-line options include azathioprine, rituximab, and cyclophosphamide 1

Treatment of Progressive Disease Despite First-Line Therapy

General Approach

• Strongly avoid long-term glucocorticoids for SSc-ILD progression; conditionally avoid for other SARD-ILD 1, 2
• Mycophenolate, rituximab, cyclophosphamide, and nintedanib are conditionally recommended as second-line options across most SARD-ILD subtypes 1

Disease-Specific Second-Line Options

SSc-ILD, MCTD-ILD, or RA-ILD progression:

• Tocilizumab is conditionally recommended 1
• Consider referral for stem cell transplantation and/or lung transplantation for SSc-ILD 1

RA-ILD progression:

• Pirfenidone is conditionally recommended as an add-on therapy 1

IIM-ILD progression:

• CNIs are conditionally recommended 1
• JAK inhibitors are conditionally recommended 1
• IVIG is conditionally recommended as an add-on therapy 1

MCTD-ILD progression:

• IVIG is conditionally recommended as an add-on therapy 1

Rapidly Progressive ILD (RP-ILD)

Initial Management

• Pulse intravenous methylprednisolone (1000 mg daily for 3 days) is conditionally recommended as first-line therapy 1, 2
• Upfront combination therapy is conditionally recommended over monotherapy 1, 2
  • Triple therapy for confirmed or suspected MDA-5 positive disease 1
  • Double or triple therapy for MDA-5 negative disease 1

First-Line Immunosuppressive Options for RP-ILD

• Rituximab, cyclophosphamide, IVIG, mycophenolate, CNIs, and JAK inhibitors are all conditionally recommended 1
• Typical combinations include rituximab + cyclophosphamide or mycophenolate + CNI 2

Agents to Avoid in RP-ILD

• Conditionally recommend against methotrexate, leflunomide, azathioprine, TNF inhibitors, abatacept, tocilizumab, nintedanib, pirfenidone, and plasma exchange as first-line options 1

Transplant Considerations

• Early referral for lung transplantation is conditionally recommended over later referral after progression on optimal medical management 1
• Conditionally recommend against stem cell transplantation as first-line therapy 1

Agents Generally Not Recommended as First-Line

Across all SARD-ILD subtypes, the following are conditionally recommended against as first-line therapy:

• Leflunomide, methotrexate, TNF inhibitors, and abatacept 1
• Pirfenidone 1
• IVIG or plasma exchange 1
• Upfront combination of nintedanib or pirfenidone with mycophenolate over mycophenolate alone 1

Critical Pitfalls to Avoid

• Never use glucocorticoids as first-line therapy for SSc-ILD due to scleroderma renal crisis risk 1, 2
• Avoid long-term glucocorticoids (>3 months) for maintenance therapy in all SARD-ILD types 1, 2
• Rule out alternative etiologies (infections, lymphoproliferative disorders) before initiating high-dose steroids 2
• Provide Pneumocystis jirovecii prophylaxis when using cyclophosphamide or significant immunosuppression 2, 3
• Be aware of drug-induced lung disease from TNF-alpha inhibitors, sulfasalazine, leflunomide, methotrexate, and sulfonamides 2
• Check thiopurine methyltransferase activity before using azathioprine to prevent life-threatening leukopenia 2

Monitoring Recommendations

• Serial pulmonary function tests every 3-6 months 2
• CBC with differential 2-3 weeks after starting immunosuppression, then every 3 months 2
• Liver function tests with same frequency 2
• Monitor for steroid-related complications including hyperglycemia, hypertension, osteoporosis, and opportunistic infections 2