What is Systemic Sclerosis?
Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease characterized by a triad of vasculopathy, inflammation/autoimmunity, and progressive fibrosis affecting both skin and internal organs, with an estimated prevalence of 30-120 cases per million. 1
Core Pathophysiology
The disease involves three fundamental pathogenic mechanisms that drive its clinical manifestations: 1, 2
- Vasculopathy: Microvascular damage and dysfunction affecting multiple organ systems 1
- Immune dysregulation: Autoimmune activation with production of disease-specific autoantibodies 1, 2
- Fibrosis: Excessive collagen deposition in skin and internal organs (lungs, heart, gastrointestinal tract, kidneys) 1
Clinical Classification
SSc is classified based on the extent and distribution of skin involvement: 1, 3
- Limited cutaneous SSc (lcSSc): Skin fibrosis restricted to areas distal to elbows/knees, though face and neck may be involved 1, 3
- Diffuse cutaneous SSc (dcSSc): Skin involvement both distal and proximal to elbows/knees, including truncal areas 1, 3
- SSc sine scleroderma: Absence of definite skin involvement despite major internal organ complications (affects 1.5-8% of patients) 1, 3
Cardinal Clinical Features
Vascular Manifestations
- Raynaud phenomenon: Present in nearly all patients (>95%) and typically the first disease manifestation 1, 2, 3
- Digital ulcers: Affect approximately 50% of patients 1, 2, 3
Organ Involvement Patterns
Pulmonary complications are the leading cause of morbidity and mortality: 1
- Interstitial lung disease (ILD) occurs in 40-75% of patients but is progressive in only 15-18% 3
- Pulmonary arterial hypertension develops with longer disease duration and older age 3
Gastrointestinal involvement affects nearly 90% of patients, with the esophagus most commonly affected, followed by small bowel, colon, and anorectum 1, 3
Renal involvement: Scleroderma renal crisis occurs predominantly in early dcSSc, particularly in patients with anti-RNA polymerase III antibodies 3
Cardiac manifestations can present as myocardial disease, pericardial disease, conduction abnormalities, or arrhythmias 4
Musculoskeletal features: Inflammatory arthritis and myositis/myopathy each affect approximately 15% of patients 3
Prognostic Significance
SSc remains the rheumatic disease with the highest individual mortality rate, with death primarily attributable to SSc-ILD and cardiac involvement. 1, 2 Despite recent therapeutic advances, mortality has not substantially changed over the past 40 years, reflecting the difficulty in counteracting the fibrotic process. 5
The modified Rodnan skin score (mRSS) measures skin thickness on a 0-3 scale at 17 anatomical sites (total range 0-51) and serves as a key disease severity marker. 2, 3
Autoantibody Profiles
Specific autoantibodies help predict disease subtype and organ involvement patterns: 2, 3
- Anti-topoisomerase I (Scl-70): Associated with higher frequency of ILD 3
- Anti-centromere antibodies: Considered protective against ILD development 1
- Anti-RNA polymerase III: High risk for scleroderma renal crisis and increased malignancy risk 3
Clinical Implications
The EULAR guidelines emphasize using the term "systemic sclerosis" rather than "scleroderma" because SSc encompasses the entire multisystem disease affecting both skin and internal organs, while scleroderma refers specifically to cutaneous manifestations. 2 Early detection and treatment of organ involvement significantly impacts prognosis, making comprehensive screening essential. 2, 3