What is scleroderma?

Scleroderma: Definition, Classification, and Management

Scleroderma is a rare autoimmune connective tissue disorder characterized by a pathogenic triad of vasculopathy, inflammation/autoimmunity, and fibrosis, leading to collagen deposition in the skin and internal organs with highly variable outcomes and the highest mortality rate among rheumatic diseases. 1

Classification

Scleroderma is classified into two main types:

1. Systemic Sclerosis (SSc)

SSc involves both skin and internal organs and is further divided into three clinical subsets:

• Diffuse Cutaneous Systemic Sclerosis (dcSSc):

  • Extensive skin involvement (distal and proximal)
  • More rapid disease progression
  • Higher risk of organ involvement
  • Often associated with anti-topoisomerase I (Scl-70) antibodies 2, 1

• Limited Cutaneous Systemic Sclerosis (lcSSc):

  • Skin fibrosis limited to distal extremities
  • Slower disease progression
  • Better overall prognosis
  • Higher risk of pulmonary hypertension
  • Frequently associated with anti-centromere antibodies 2, 1

• Systemic Sclerosis sine Scleroderma (ssSSc):

  • Internal organ involvement without skin fibrosis 2, 1

2. Localized Scleroderma (LS)

LS affects only the skin and occasionally subcutaneous tissues without internal organ involvement. It is more common in children and includes subtypes such as:

• Circumscribed morphoea
• Linear scleroderma
• Generalized morphoea
• Pansclerotic morphoea
• Mixed subtype 2, 3

Clinical Features

Skin Manifestations

• Skin thickening and hardening (scleroderma)
• Raynaud's phenomenon (present in almost all patients)
• Digital ulcers
• Calcinosis
• Telangiectasias 1, 4

Internal Organ Involvement (in Systemic Sclerosis)

• Gastrointestinal: Affects nearly 90% of patients
• Pulmonary: Interstitial lung disease (40-75% of patients)
• Cardiovascular: Pulmonary arterial hypertension (more common in lcSSc)
• Renal: Scleroderma renal crisis (more common with anti-RNA polymerase III antibodies)
• Musculoskeletal: Joint and muscle problems 1, 4

Diagnosis

Diagnosis requires:

• Assessment of skin fibrosis extent
• Specific autoantibody testing (anti-centromere, anti-topoisomerase I, anti-RNA polymerase III)
• Nailfold capillaroscopy
• Organ-specific evaluations:
  • Pulmonary function tests and HRCT for interstitial lung disease
  • Echocardiography for pulmonary hypertension
  • Regular monitoring of renal function in patients with dcSSc 1

Treatment

Systemic Sclerosis

Treatment targets three main pathways:

1. Vasculopathy:

   • For Raynaud's phenomenon and digital ulcers:

     • Dihydropyridine calcium channel blockers
     • Phosphodiesterase-5 inhibitors
     • IV iloprost
     • Bosentan 1

   • For Pulmonary Arterial Hypertension:

     • Combination therapy with phosphodiesterase-5 inhibitors and endothelin receptor antagonists
     • Addition of prostacyclin analogues if necessary 1

2. Inflammation/Autoimmunity:

   • For early diffuse skin fibrosis:
     • Mycophenolate mofetil
     • Rituximab
     • Tocilizumab 1

3. Fibrosis:

   • For Interstitial Lung Disease:
     • Mycophenolate mofetil (first-line)
     • Nintedanib
     • Cyclophosphamide
     • Rituximab
     • Tocilizumab 2, 1

Localized Scleroderma

Treatment options include:

• Topical treatments: Corticosteroids, vitamin D analogues 5
• Systemic treatments:
  • Methotrexate (15 mg/m²/week) for active, potentially disfiguring or disabling forms 2
  • Mycophenolate mofetil for severe or methotrexate-refractory cases 2
• Phototherapy: Medium-dose UVA1 phototherapy to improve skin softness 2, 6
• Immunomodulators: Topical imiquimod for circumscribed morphoea 2

Prognosis

• Prognosis is determined by the degree of internal organ involvement
• SSc-ILD and cardiac involvement are the main causes of death
• Systemic sclerosis has the highest individual mortality rate among rheumatic diseases 1
• Accurate classification is essential for determining prognosis, guiding follow-up, and selecting appropriate treatment 1

Important Considerations

• Early diagnosis and treatment are crucial for improving outcomes
• Regular monitoring for organ involvement is essential
• A multidisciplinary approach to care is recommended for optimal management
• For localized forms, treatment should be maintained for at least 12 months before tapering 2
• Despite advances in treatment, there is no definitive cure for scleroderma