What is Systemic Sclerosis?

Systemic Sclerosis: A Comprehensive Overview

Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease characterized by a triad of vasculopathy, inflammation/autoimmunity, and fibrosis affecting the skin and internal organs, with the highest mortality rate among rheumatic diseases. 1, 2

Classification and Subtypes

SSc is classified into three main subtypes:

1. Diffuse Cutaneous SSc (dcSSc):

   • Extensive skin involvement (distal and proximal to knees/elbows and/or truncal)
   • Rapid disease progression
   • Higher risk of organ involvement
   • Often associated with anti-topoisomerase I (Scl-70) antibodies
   • Higher risk of interstitial lung disease (ILD) 1, 2

2. Limited Cutaneous SSc (lcSSc):

   • Skin fibrosis limited to distal extremities (distal to elbows/knees)
   • Slower disease progression
   • Higher risk of pulmonary hypertension
   • Often associated with anti-centromere antibodies 1, 2

3. SSc sine scleroderma (ssSSc):

   • Internal organ involvement without skin fibrosis
   • Similar trajectory to lcSSc
   • Represents 1.5-8% of SSc cases 1, 2

Pathophysiology

SSc involves three key pathogenic mechanisms:

• Vasculopathy: Vascular damage and dysfunction
• Inflammation and autoimmunity: Immune system dysregulation
• Fibrosis: Excessive collagen deposition in skin and internal organs 1, 2

Clinical Manifestations

Skin Involvement

• Skin thickening and hardening (scleroderma)
• Raynaud's phenomenon (often the earliest manifestation)
• Digital ulcers
• Calcinosis 1, 2

Internal Organ Involvement

1. Pulmonary:

   • Interstitial lung disease (ILD) - most common cause of death
   • Pulmonary arterial hypertension 1, 2, 3

2. Cardiac:

   • Myocardial fibrosis
   • Pericardial disease
   • Conduction abnormalities
   • Arrhythmias 2, 4

3. Gastrointestinal:

   • Esophageal dysmotility and reflux
   • Gastric antral vascular ectasia
   • Small intestinal bacterial overgrowth
   • Malabsorption
   • Motility disorders throughout the GI tract 2, 4

4. Renal:

   • Scleroderma renal crisis (less common with ACE inhibitor use)
   • Chronic kidney disease 2, 4

5. Musculoskeletal:

   • Inflammatory arthritis
   • Tendon friction rubs
   • Muscle weakness/myositis 2, 4

6. Neurological:

   • Peripheral neuropathy
   • Autonomic dysfunction 4

Diagnosis

Diagnosis requires a comprehensive evaluation including:

• Assessment of skin fibrosis extent
• Specific autoantibody testing (anti-centromere, anti-Scl-70, anti-RNA polymerase III)
• Nailfold capillaroscopy
• Organ-specific evaluations:
  • Pulmonary function tests and HRCT for ILD
  • Echocardiography for pulmonary hypertension
  • GI studies as indicated 2

Treatment Approaches

Treatment targets the three main pathophysiological pathways:

1. Vasculopathy Treatment

• Raynaud's phenomenon and digital ulcers:
  • First-line: Dihydropyridine calcium channel blockers (especially nifedipine)
  • Second-line: Phosphodiesterase-5 inhibitors or IV iloprost
  • Bosentan to reduce new digital ulcer development 1, 2

2. Inflammation/Autoimmunity and Fibrosis Treatment

• Early diffuse cutaneous SSc:
  • Immunosuppressives: Mycophenolate mofetil, methotrexate, cyclophosphamide
  • Biologics: Rituximab, tocilizumab
  • Autologous hematopoietic stem cell transplantation for rapidly progressive cases 1, 2

3. Organ-Specific Treatments

• Interstitial Lung Disease:

  • First-line: Mycophenolate mofetil
  • Alternatives: Cyclophosphamide, rituximab, tocilizumab
  • Anti-fibrotic therapy (nintedanib, possibly pirfenidone) for progressive fibrotic ILD 1, 2

• Pulmonary Arterial Hypertension:

  • Initial combination therapy: Phosphodiesterase-5 inhibitors and endothelin receptor antagonists
  • Add prostacyclin analogues if necessary 1, 2

• Scleroderma Renal Crisis:

  • ACE inhibitors (prompt initiation)
  • Avoid high-dose corticosteroids 2, 5

• Gastrointestinal Manifestations:

  • Proton pump inhibitors for GERD
  • Prokinetics for dysmotility
  • Antibiotics for bacterial overgrowth 2

Prognosis and Monitoring

• Prognosis is determined by the degree of internal organ involvement
• ILD and cardiac involvement are the main causes of death
• Regular monitoring for organ involvement is essential
• Early diagnosis and treatment are crucial for improving outcomes 1, 2

Common Pitfalls and Caveats

1. Delayed diagnosis: Early recognition is critical for better outcomes
2. Underestimating organ involvement: Internal organ damage may be present despite minimal skin changes
3. Corticosteroid use: High-dose corticosteroids may trigger scleroderma renal crisis
4. Comorbidities: Cardiovascular disease, infections, cancer, and psychological disorders are common and require monitoring 2, 6
5. Incomplete assessment: Comprehensive evaluation of all potentially affected organ systems is necessary 2

SSc remains a complex, multisystem disease requiring a multidisciplinary approach to care, with treatment tailored to the specific subtype and organ involvement patterns.