What is the management of systemic sclerosis?

Management of Systemic Sclerosis

Systemic sclerosis requires organ-specific pharmacological treatment, with mycophenolate mofetil as first-line therapy for interstitial lung disease, combination therapy for pulmonary arterial hypertension, and calcium channel blockers for Raynaud's phenomenon. 1

Disease Overview and Treatment Approach

Systemic sclerosis is a rare autoimmune connective tissue disease characterized by vasculopathy, immune dysregulation, and progressive fibrosis affecting skin and internal organs. 1 The disease has the highest morbidity and mortality among rheumatic diseases, though survival has improved with organ-based treatment strategies. 1

Treatment is fundamentally organ-based rather than disease-modifying, targeting specific manifestations as they arise. 1

Early Diffuse Cutaneous SSc (dcSSc)

First-Line Immunosuppression

For early dcSSc with skin involvement, initiate mycophenolate mofetil as the preferred first-line agent, having surpassed cyclophosphamide due to better tolerability. 1, 2

Alternative immunosuppressive options include: 1

• Methotrexate
• Cyclophosphamide
• Rituximab
• Tocilizumab

Autologous Hematopoietic Stem Cell Transplantation (AHSCT)

For rapidly progressive early dcSSc at high risk of mortality, consider AHSCT as it improves survival. 1, 2 Eligible patients include those with: 1

• Very high modified Rodnan skin scores
• Moderate skin involvement with worsening interstitial lung disease
• Disease duration typically less than 5 years

AHSCT produces the largest effect on skin fibrosis, with approximately 20-point reductions in modified Rodnan skin score. 1 However, cardiac toxicity from high-dose cyclophosphamide conditioning remains a concern, requiring careful pre-transplant cardiac evaluation. 1

Limited Cutaneous SSc

Treatment for early limited cutaneous SSc remains uncertain and requires further research. 1 These patients should be monitored closely for organ involvement rather than receiving empiric immunosuppression.

Interstitial Lung Disease (ILD)

First-Line Therapy

Initiate mycophenolate mofetil as first-line treatment for SSc-ILD. 1, 2 This represents a major shift from previous cyclophosphamide-based approaches.

Progressive Fibrotic ILD

For fibrotic and progressing ILD, add nintedanib as anti-fibrotic therapy to the immunosuppressive regimen. 1, 2 Pirfenidone may be considered as an alternative, though evidence is less robust. 1

Alternative Immunosuppressive Options

If mycophenolate mofetil is ineffective or not tolerated: 2

• Cyclophosphamide
• Rituximab
• Tocilizumab

Supportive Care

• Ensure all vaccinations are current, including pneumococcal, influenza, and COVID-19 vaccines. 2
• Provide oxygen therapy if hypoxia is present to reduce dyspnea and potentially mitigate pulmonary hypertension development. 2
• Consider lung transplantation for end-stage lung fibrosis, with outcomes comparable to other chronic lung diseases. 2

Pulmonary Arterial Hypertension (PAH)

Initial Treatment Strategy

Start with initial combination therapy for newly diagnosed SSc-PAH, typically combining: 1

• Phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil)
• Endothelin receptor antagonists (e.g., bosentan, ambrisentan, macitentan)

This represents a significant update from sequential monotherapy approaches. 1

Second-Line Therapy

If inadequate response to initial combination therapy, add a prostacyclin analogue (e.g., epoprostenol, treprostinil, iloprost). 1

Pulmonary Hypertension Secondary to ILD

For pulmonary hypertension associated with ILD, consider inhaled treprostinil, which has demonstrated improved exercise capacity and reduced NT-proBNP levels. 2

Riociguat may also be considered in this context. 1

Raynaud's Phenomenon and Digital Ulcers

First-Line Treatment

Initiate dihydropyridine calcium channel blockers (especially nifedipine) as first-line therapy for Raynaud's phenomenon. 1, 2 Nearly all patients with SSc have Raynaud's phenomenon, making this a universal consideration. 1

Second-Line Options

If calcium channel blockers are insufficient: 1, 2

• Phosphodiesterase-5 inhibitors
• Intravenous iloprost

Fluoxetine may be considered for SSc-related Raynaud's phenomenon based on emerging evidence. 1, 2

Digital Ulcer Prevention

For prevention of new digital ulcers, use bosentan (endothelin receptor antagonist) after optimizing vasodilator therapy with calcium channel blockers and PDE-5 inhibitors. 1 Approximately half of SSc patients develop digital ulcers. 1

Gastrointestinal Involvement

Gastrointestinal involvement affects nearly 90% of patients with SSc, with the esophagus being the most commonly affected organ. 1 However, trial data for gastrointestinal manifestations are mostly lacking, and treatment remains largely supportive and symptom-based. 1

Scleroderma Renal Crisis

While specific preventive therapies are limited, ACE inhibitors remain the cornerstone of treatment for scleroderma renal crisis when it occurs. 1 Early recognition and aggressive blood pressure control are critical.

Screening and Monitoring

Essential Screening Protocols

Regular screening for organ complications is mandatory, as early intervention may prevent irreversible damage: 2, 3

• Annual pulmonary function tests and high-resolution CT to detect ILD progression 3
• Annual echocardiography to screen for pulmonary hypertension 3
• Right heart catheterization if echocardiography suggests PAH 1
• Cardiac evaluation for arrhythmias and heart failure 1
• Blood pressure monitoring for scleroderma renal crisis 1
• Nutritional assessment if malabsorption is suspected 1

Improved survival in dcSSc has been directly associated with better ascertainment of internal organ disease through systematic annual screening. 3

Critical Clinical Pitfalls

Combination therapies addressing multiple pathogenic mechanisms are likely needed to impact long-term survival, as single-agent approaches have shown limited disease-modifying effects. 2 The complexity and heterogeneity of SSc means that monotherapy rarely addresses all active disease processes. 4

Many SSc manifestations still lack evidence-based therapies, including specific treatments for gastrointestinal involvement, musculoskeletal complications, and calcinosis. 1, 2 This highlights ongoing research needs and the importance of supportive care.

Disease duration matters critically for treatment eligibility—most trials for skin disease only include patients with disease duration less than 2-5 years, meaning the majority of SSc patients would not qualify for these interventions. 1

Do not delay organ-specific screening—the shift from historical to contemporary cohorts shows that systematic screening has improved survival, particularly in dcSSc, by enabling earlier intervention for pulmonary complications. 3