What is the treatment for diffuse scleroderma?

Treatment of Diffuse Scleroderma

For early diffuse cutaneous systemic sclerosis (dcSSc), initiate immunosuppressive therapy with mycophenolate mofetil as first-line treatment, and reserve autologous hematopoietic stem cell transplantation for rapidly progressive disease with high mortality risk (very high modified Rodnan skin scores or moderate skin involvement with worsening interstitial lung disease). 1

Disease-Modifying Therapy for Skin and Systemic Disease

First-Line Immunosuppression

• Mycophenolate mofetil (MMF) is the preferred initial immunosuppressive agent for early dcSSc based on the most recent 2023 guidelines, which have shifted away from cyclophosphamide as first-line therapy 1
• Methotrexate (15 mg/m²/week oral or subcutaneous) combined with systemic corticosteroids during the initial inflammatory phase is an alternative first-line option, particularly for skin disease 1
• Cyclophosphamide should be considered but is no longer the automatic first choice, given its known toxicity profile 1
• Rituximab and tocilizumab are additional immunosuppressive options that can soften skin and change the natural history of early dcSSc 1

Autologous Hematopoietic Stem Cell Transplantation (HSCT)

• HSCT should be considered for selected patients with rapidly progressive early dcSSc at risk of organ failure, specifically those with:
  • Very high modified Rodnan skin scores (mRSS), OR
  • Moderate skin involvement with worsening interstitial lung disease (ILD) 1
• Two randomized controlled trials have demonstrated that HSCT improves event-free survival and can improve survival compared to cyclophosphamide 1
• Critical caveat: HSCT carries high risk of treatment-related side effects and early treatment-related mortality, requiring careful patient selection and an experienced medical team 1

Organ-Specific Complications

Interstitial Lung Disease (ILD)

• Mycophenolate mofetil has surpassed cyclophosphamide as the initial treatment for SSc-ILD 1
• Cyclophosphamide remains an option for progressive ILD, particularly in patients with more severe disease (baseline FVC <70% predicted showed mean improvement of 4.62% at 12 months and 6.8% at 18 months) 1
• For fibrotic and progressing ILD, add anti-fibrotic therapy: nintedanib (and possibly pirfenidone) 1

Raynaud Phenomenon and Digital Ulcers

• First-line: Dihydropyridine calcium channel blockers, especially nifedipine (10-20 mg three times daily) 1
• Second-line: Phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil) or intravenous iloprost 1
• Bosentan can reduce the development of new digital ulcers 1

Scleroderma Renal Crisis (SRC)

• Immediate use of ACE inhibitors is mandatory for treatment of SRC 1
• Monitor blood pressure and renal function carefully in patients treated with glucocorticoids, as retrospective studies suggest glucocorticoids are associated with higher risk of SRC 1
• Patients with anti-RNA polymerase III antibodies require particularly vigilant blood pressure monitoring 1

Gastrointestinal Involvement

• Proton pump inhibitors (PPIs) for gastroesophageal reflux disease and prevention of esophageal ulcers and strictures 1
• Prokinetic drugs for symptomatic motility disturbances (dysphagia, GERD, early satiety, bloating, pseudo-obstruction) 1
• Intermittent or rotating antibiotics for symptomatic small intestinal bacterial overgrowth 1
• Critical pitfall: Malnutrition is the leading cause of mortality from GI involvement; monitor closely and consider enteral or parenteral nutrition when needed 1, 2

Pulmonary Arterial Hypertension (PAH)

• Initial combination therapy with phosphodiesterase-5 inhibitors and endothelin receptor antagonists 1
• Add prostacyclin analogue if necessary 1
• Screen regularly with echocardiography and pulmonary function tests (DLCO) 1

Treatment Duration and Monitoring

• Continue immunosuppressive therapy for at least 12 months after achieving clinical improvement before tapering 1
• Use the modified Rodnan skin score (mRSS) to monitor skin disease progression 1
• Screen for ILD and PAH regularly given their high frequency (ILD in 40-75%, progressive in 15-18%) 1

Key Nuances in the Evidence

The 2023 Nature Reviews Rheumatology guidelines 1 represent the most current evidence and show a clear shift toward mycophenolate mofetil as first-line therapy, moving away from the 2017 EULAR recommendations 1 that still positioned cyclophosphamide more prominently. The European Scleroderma Observational Study (ESOS) 3 showed modest benefit from immunosuppressants overall, with no statistically significant differences between methotrexate, MMF, and cyclophosphamide in reducing skin scores at 12 months (all groups showed -2.2 to -4.1 unit reductions in mRSS), though survival was poorest in the no immunosuppressant group (84.0% at 24 months).

Common Pitfalls

• Underestimating disease severity: Early aggressive treatment is essential before irreversible organ damage occurs 1
• Inadequate screening: Failure to screen regularly for ILD and PAH can miss opportunities for early intervention 1
• Glucocorticoid overuse: High-dose steroids increase SRC risk; use cautiously and monitor blood pressure closely 1
• Premature treatment discontinuation: Maintain therapy for at least 12 months after improvement to prevent relapse 1