What is the first‑line immunosuppressive agent and its dosing for interstitial lung disease associated with systemic autoimmune rheumatic diseases such as systemic sclerosis, inflammatory myopathy, rheumatoid arthritis, mixed connective tissue disease, and Sjögren’s syndrome?

First-Line Immunosuppressive Therapy for CTD-ILD

Mycophenolate is the preferred first-line immunosuppressive agent across all systemic autoimmune rheumatic disease-associated interstitial lung diseases (SARD-ILD), including systemic sclerosis, inflammatory myopathy, rheumatoid arthritis, mixed connective tissue disease, and Sjögren's syndrome. 1, 2

General Dosing for Mycophenolate

• Start at 500-1000 mg twice daily, titrating to a target dose of 1500 mg twice daily as tolerated 2
• This represents a conditional recommendation based on favorable adverse effect profile compared to cyclophosphamide and substantial clinical experience 1

Disease-Specific First-Line Regimens

Systemic Sclerosis-ILD (SSc-ILD)

Preferred agents (in hierarchical order):

• Mycophenolate (first choice) 1, 2
• Tocilizumab (conditionally recommended as preferred option) 1, 2
• Rituximab (preferred option) 1, 2

Additional options:

• Azathioprine 1, 2
• Cyclophosphamide 1, 2
• Nintedanib (may be used conditionally as first-line in progressive disease) 2

Critical contraindication:

• Glucocorticoids are strongly contraindicated as first-line therapy due to high risk of scleroderma renal crisis, particularly at doses >15 mg/day prednisone 1, 2, 3

Inflammatory Myopathy-ILD (IIM-ILD)

Preferred agents:

• Mycophenolate (first choice) 1, 2
• Short-term glucocorticoids (≤3 months) are conditionally recommended as part of initial regimen 2, 3

Additional first-line options specific to IIM-ILD:

• JAK inhibitors (conditionally recommended) 1, 2
• Calcineurin inhibitors (conditionally recommended) 1, 2
• Azathioprine 1, 2
• Rituximab 1, 2
• Cyclophosphamide 1, 2

Rheumatoid Arthritis-ILD (RA-ILD)

Preferred agents:

• Mycophenolate (first choice) 2, 4
• Rituximab (primary alternative, especially with active inflammatory arthritis) 2, 4
• Short-term glucocorticoids (≤3 months) conditionally recommended 2, 4

Additional options:

• Azathioprine 2, 4
• Cyclophosphamide 2, 4

Agents to avoid:

• Methotrexate (may worsen ILD) 4
• Leflunomide (pulmonary toxicity risk) 4
• TNF-α inhibitors (may exacerbate ILD) 4

Mixed Connective Tissue Disease-ILD (MCTD-ILD)

Preferred agents:

• Mycophenolate (first choice) 2
• Tocilizumab (conditionally recommended) 2
• Short-term glucocorticoids (≤3 months) conditionally recommended, but use cautiously in patients with SSc phenotype due to renal crisis risk 2

Additional options:

• Azathioprine 2
• Rituximab 2
• Cyclophosphamide 2

Sjögren's Disease-ILD (SjD-ILD)

Preferred agents:

• Mycophenolate (first choice) 1, 2
• Short-term glucocorticoids (≤3 months) conditionally recommended 2

Additional options:

• Azathioprine 2
• Rituximab 2
• Cyclophosphamide 2

Glucocorticoid Guidance Across All CTD-ILD

When glucocorticoids are used:

• Limit to ≤3 months duration 2, 3
• Keep dose ≤15 mg/day prednisone-equivalent when used 3, 4
• Serve as bridge therapy while initiating disease-modifying immunosuppression 2, 4
• Long-term glucocorticoids (>3-6 months) are strongly recommended against for maintenance therapy across all SARD-ILD types 2, 3

Rapidly Progressive ILD (RP-ILD) - Distinct Approach

For respiratory failure developing over days-to-weeks:

• IV pulse methylprednisolone 1000 mg daily for 3 days (conditionally recommended) 1, 2, 3
• Upfront combination therapy (2-3 agents) is conditionally recommended over monotherapy 2, 3
  • Triple-drug regimens for confirmed/suspected MDA-5-positive disease 2
  • Double or triple-drug regimens for MDA-5-negative disease 2

First-line combination options for RP-ILD:

• Rituximab + cyclophosphamide 2
• Mycophenolate + calcineurin inhibitor 2
• Other combinations using: IVIG, JAK inhibitors 2

Agents to avoid in RP-ILD:

• Methotrexate, leflunomide, azathioprine, TNF-α inhibitors, abatacept, tocilizumab, nintedanib, pirfenidone (all conditionally recommended against as first-line) 2

Critical Monitoring Requirements

Laboratory monitoring:

• CBC with differential at 2-3 weeks after starting any immunosuppressive agent, then every 3 months 2, 3
• Liver enzymes every 3 months 2
• Check thiopurine methyltransferase activity before prescribing azathioprine to prevent severe leukopenia 2, 3

Pulmonary monitoring:

• Serial PFTs (FVC, DLCO) every 3-6 months to assess disease trajectory 2, 4
• High-resolution CT at baseline, then annually or with significant PFT change 4

Infection prophylaxis:

• Pneumocystis jirovecii prophylaxis required when cyclophosphamide or other potent immunosuppressants are used 2, 3

Common Pitfalls to Avoid

• Never use glucocorticoids as first-line monotherapy for SSc-ILD - high risk of scleroderma renal crisis 1, 2, 3
• Exclude alternative causes (infection, lymphoproliferative disease) before initiating high-dose steroids 3
• Recognize drug-induced lung disease from TNF-α inhibitors, sulfasalazine, leflunomide, methotrexate, and sulfonamides 2, 3
• Avoid long-term glucocorticoid maintenance (>3 months) due to limited efficacy and significant toxicity 2, 3, 4
• Monitor for steroid complications including hyperglycemia, hypertension, osteoporosis, and opportunistic infections 3