What is the recommended dosing of mycophenolate mofetil (MMF) and other immunosuppressive drugs, such as corticosteroids, in a patient with systemic sclerosis?

Mycophenolate Mofetil and Other Drug Dosing in Systemic Sclerosis

For systemic sclerosis, mycophenolate mofetil should be dosed at 1000-1500 mg twice daily (2-3 g/day total), and glucocorticoids are strongly contraindicated as first-line therapy due to scleroderma renal crisis risk. 1

MMF Dosing for SSc-ILD and Skin Fibrosis

Target Dose and Titration:

• Start MMF at 500 mg twice daily and gradually increase to the therapeutic dose of 1000-1500 mg twice daily (mycophenolic acid 720-1080 mg twice daily) 1
• The 2025 EULAR guidelines recommend MMF (Level 1A evidence) as first-line therapy for both SSc-ILD and skin fibrosis 1
• Drug exposure varies up to 8-fold between patients, with lower levels in those using proton pump inhibitors, males, and anti-topoisomerase-1 positive patients 2

Critical Monitoring:

• Check CBC with differential and comprehensive metabolic panel at baseline, 2-3 weeks after starting, 2-3 weeks after any dose increase, and every 3 months on stable dosing 1
• Consider therapeutic drug monitoring with target MPA AUC of 20-60 µg·h/mL, especially if gastrointestinal intolerance develops 3
• Avoid concurrent antacids (aluminum/magnesium), cholestyramine, iron, and activated charcoal as they inhibit absorption 3

Treatment Duration

Long-term Maintenance:

• MMF should be continued for at least 2 years, as discontinuation or dose reduction below 1000 mg/day before this timeframe results in recurrence of progressive skin involvement in 26.3% of patients 4
• Continue MMF indefinitely if disease control is maintained, with withdrawal considered only after achieving remission for minimum 1 year off corticosteroids 5
• Premature discontinuation leads to average 35.9% increase in modified Rodnan skin score and potential worsening of pulmonary function 4

Glucocorticoid Use in SSc

Strong Contraindication:

• The 2025 EULAR guidelines provide a strong recommendation against glucocorticoids as first-line ILD treatment in SSc due to scleroderma renal crisis risk, particularly with doses >15 mg/day prednisone equivalent 1
• The 2023 ACR/CHEST guidelines echo this with a strong recommendation against glucocorticoids in SSc-ILD 1
• If glucocorticoids must be used in mixed connective tissue disease with SSc phenotype, use cautiously due to increased renal crisis risk 1

Alternative First-Line Immunosuppressants

Cyclophosphamide:

• Low-dose regimen: 0.5-0.75 g/m² monthly for 6 months (Euro-Lupus protocol) 1
• High-dose regimen: 0.5-1 g/m² every 4 weeks for 3-6 months, reserved for patients with adverse prognostic factors (crescents/necrosis in >25% of glomeruli, GFR 25-80 mL/min) 1
• Monitor CBC with differential and urinalysis every 1-2 weeks after dose increase, every 4 weeks on stable dosing; annual urine cytology after any cyclophosphamide exposure 1

Rituximab:

• Dose: 1 g IV every 2 weeks for 2 doses (or 375 mg/m² weekly × 4) 1
• Level 1A evidence for both SSc-ILD and skin fibrosis per 2025 EULAR guidelines 1
• Monitor CBC with differential at baseline and 2-4 month intervals; screen for hepatitis B/C and latent TB before initiation 1

Tocilizumab:

• Dose: 162 mg subcutaneously weekly 1
• Level 1B evidence for SSc-ILD; may be considered for skin fibrosis in early inflammatory dcSSc 1
• Monitor CBC, ALT/AST, alkaline phosphatase, total bilirubin at baseline, every 4-8 weeks for first 6 months, then every 3 months 1

Combination Therapy Options

MMF + Nintedanib:

• Nintedanib 100-150 mg PO every 12 hours can be added to MMF for progressive SSc-ILD (Level 1A evidence) 1
• Monitor liver function tests monthly for 3 months, then every 3 months; monitor for diarrhea and weight loss 1

Severe/Rapidly Progressive Disease:

• For rapidly progressive SSc-ILD, consider IV methylprednisolone 1 g daily for 3 days followed by MMF, though glucocorticoid use remains controversial 6
• Autologous hematopoietic stem cell transplantation may be considered for selected patients with early dcSSc and poor prognosis, absent advanced cardiorespiratory involvement (Level 1A evidence) 1

Common Pitfalls to Avoid

• Never discontinue MMF before 2 years of treatment or while disease is active, as this leads to disease flare in over one-quarter of patients 4
• Never use high-dose glucocorticoids (>15 mg/day prednisone) in SSc due to scleroderma renal crisis risk 1
• Never ignore proton pump inhibitor interactions - PPI use is associated with significantly lower MMF drug exposure and may require dose adjustment 2
• Never dose MMF without considering body weight - drug exposure is inversely related to body weight, and weight-based dosing may be more appropriate 2
• Never assume MMF is working without monitoring - 14% of patients show no effect on disease activity and require treatment change 7