What is Scleroderma (Systemic Sclerosis)?

What is Scleroderma (Systemic Sclerosis)?

Scleroderma (Systemic Sclerosis) is a rare autoimmune connective tissue disorder characterized by a triad of pathogenic factors: 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 and Subtypes

Scleroderma is classified into three main clinical subsets based on the extent of skin fibrosis:

1. Diffuse Cutaneous Systemic Sclerosis (dcSSc)

   • Skin involvement both distal and proximal to elbows/knees and/or trunk
   • Higher risk of early internal organ involvement
   • Often associated with anti-topoisomerase I (Scl-70) or anti-RNA polymerase III antibodies
   • More rapid disease progression

2. Limited Cutaneous Systemic Sclerosis (lcSSc)

   • Skin involvement restricted to areas distal to elbows/knees (may include face/neck)
   • Slower disease progression
   • Often associated with anti-centromere antibodies
   • Higher risk of pulmonary hypertension

3. Systemic Sclerosis sine Scleroderma (ssSSc)

   • Absence of skin fibrosis despite SSc-related internal organ manifestations
   • Represents approximately 1.5-8% of SSc cases
   • Similar trajectory to lcSSc 1, 2

Clinical Manifestations

Cutaneous Manifestations

• Skin thickening and hardening (scleroderma)
• Raynaud's phenomenon (present in almost all patients)
• Digital ulcers (affecting approximately 50% of patients)
• Calcinosis
• Telangiectasias

Internal Organ Involvement

• Gastrointestinal: Affects nearly 90% of patients, with esophageal involvement being most common 1
• Pulmonary:
  • Interstitial lung disease (ILD) in 40-75% of patients, progressive in 15-18%
  • Pulmonary arterial hypertension (more common in lcSSc)
• Cardiac: Myocardial fibrosis, arrhythmias, conduction abnormalities
• Renal: Scleroderma renal crisis (more common in dcSSc)
• Musculoskeletal: Inflammatory arthritis, myopathy, myositis

Pathophysiology

The disease is characterized by:

• Microvascular damage and endothelial dysfunction
• Immune system dysregulation with autoantibody production
• Excessive collagen and extracellular matrix deposition leading to fibrosis
• Imbalance in cytokine production, including increased TGF-β1 3

Diagnostic Approach

Diagnosis requires a comprehensive evaluation including:

• Assessment of skin fibrosis extent (modified Rodnan skin score)
• Specific autoantibody testing (anti-centromere, anti-topoisomerase I, anti-RNA polymerase III)
• Nailfold capillaroscopy to detect microvascular abnormalities
• Organ-specific evaluations:
  • Pulmonary function tests and HRCT for ILD
  • Echocardiography for pulmonary hypertension
  • Gastrointestinal studies as indicated 2

Treatment Approaches

Treatment is primarily organ-based and aimed at managing complications:

1. Raynaud's phenomenon and digital ulcers:

   • Dihydropyridine calcium channel blockers (especially nifedipine)
   • Phosphodiesterase-5 inhibitors
   • IV iloprost
   • Bosentan to prevent new digital ulcers 1

2. Interstitial Lung Disease:

   • Mycophenolate mofetil as first-line therapy
   • Nintedanib for progressive fibrotic ILD
   • Cyclophosphamide, rituximab, or tocilizumab as alternatives 1

3. Pulmonary Arterial Hypertension:

   • Initial combination therapy (phosphodiesterase-5 inhibitors and endothelin receptor antagonists)
   • Addition of prostacyclin analogues if necessary 1

4. Skin Fibrosis:

   • Immunosuppressives and biologic agents for early diffuse disease
   • Mycophenolate mofetil, rituximab, and tocilizumab have shown efficacy 1

5. Scleroderma Renal Crisis:

   • Prompt initiation of ACE inhibitors
   • Avoidance of high-dose corticosteroids 4

Prognosis

Prognosis is determined by the degree of internal organ involvement, with SSc-ILD and cardiac involvement being the main causes of death. Despite improvements in survival, systemic sclerosis remains the rheumatic disease with the highest individual mortality rate 1.