What is the initial treatment approach for patients with scleroderma?

Initial Treatment Approach for Scleroderma

Mycophenolate mofetil (MMF) at 2-3g per day is the first-line therapy for patients with early diffuse cutaneous systemic sclerosis, particularly when there is concern for skin fibrosis or interstitial lung disease, based on superior tolerability compared to cyclophosphamide and strong evidence for efficacy. 1

Treatment Algorithm by Disease Manifestation

Early Diffuse Cutaneous Systemic Sclerosis (dcSSc)

For skin fibrosis and/or interstitial lung disease:

• First-line: MMF 2-3g/day is the preferred initial therapy 2, 1
• Alternative first-line: Methotrexate 15-25mg/week (orally or intramuscularly) if MMF is contraindicated or unavailable 2, 1, 3
• Second-line (if inadequate response after 6-12 months): Rituximab 375mg/m² IV weekly for 4 weeks 1, 4 or tocilizumab 162mg subcutaneously weekly 2, 1

The 2023 Nature Reviews Rheumatology guidelines emphasize that MMF has become the most common first-line drug in practice, even though mRSS change was not a primary outcome in RCTs, because of its positive benefits for ILD 2. The ESOS study demonstrated modest improvement in mRSS across all immunosuppressants with no significant difference between treatments, but the no-immunosuppressant group had the smallest improvement and highest mortality 2.

Raynaud's Phenomenon (First Manifestation in Most Patients)

Treatment escalation:

• First-line: Dihydropyridine calcium channel blockers, specifically nifedipine 2
• Second-line: Phosphodiesterase-5 inhibitors (e.g., sildenafil) 2
• Third-line: Intravenous iloprost for severe Raynaud's 2

Digital Ulcers

Active ulcers:

• Intravenous prostanoids (particularly iloprost) for healing active digital ulcers 2

Prevention of recurrent ulcers:

• Bosentan for patients with multiple digital ulcers after failure of calcium antagonists and prostanoid therapy 2

Interstitial Lung Disease (SSc-ILD)

Initial therapy:

• First-line: MMF 2-3g/day has surpassed cyclophosphamide as the preferred initial treatment 2, 1
• Alternative: Cyclophosphamide 1-2mg/kg/day orally for 12 months or 600mg/m²/month IV for 6 months 2, 1
• For progressive fibrotic ILD: Add nintedanib (and possibly pirfenidone) to immunosuppressive therapy 2

The SLS II trial demonstrated that MMF over 2 years was comparable to cyclophosphamide for 1 year in improving lung function, with better tolerability 2.

Gastrointestinal Manifestations

Gastroesophageal reflux (affects ~90% of patients):

• Proton pump inhibitors (PPIs) for prevention of reflux, esophageal ulcers, and strictures 2
• Prokinetic drugs for symptomatic motility disturbances (dysphagia, early satiety, bloating) 2

Scleroderma Renal Crisis

Emergency treatment:

• ACE inhibitors should be initiated immediately despite lack of RCT evidence 2

Critical Monitoring Requirements

• Modified Rodnan Skin Score every 3-6 months to assess skin thickness 1, 4
• Pulmonary function tests (FVC, DLCO) every 3-6 months to monitor for ILD progression 1, 4
• Blood pressure and renal function monitoring, especially in patients on corticosteroids 2

Common Pitfalls and Caveats

Avoid high-dose corticosteroids: Four retrospective studies demonstrate association with increased risk of scleroderma renal crisis; patients on steroids require careful blood pressure and renal function monitoring 2, 1

Early aggressive treatment is essential: Long-term follow-up studies show that skin disease is associated with high morbidity both physically and psychologically, and ILD has become the most common cause of SSc-related death 2

Patients with more severe baseline disease (higher skin scores or more extensive lung involvement) may show greater response to immunosuppressive therapy 1

Do not delay treatment in early dcSSc: The first 3 years are critical, as 50% of early SSc patients in the EUSTAR database showed significant or moderate progression of ILD 2

Special Consideration: Autologous Hematopoietic Stem Cell Transplantation (AHSCT)

For patients with rapidly progressive early dcSSc at high risk of mortality (very high modified Rodnan skin scores or moderate skin involvement with worsening ILD), AHSCT can improve survival 2. The SCOT trial demonstrated significantly higher overall survival and event-free survival at 54-72 months compared to cyclophosphamide, though with higher frequency of severe adverse events in the first year 2.