Scleroderma Etiology
Scleroderma (systemic sclerosis) is an autoimmune disease of unknown cause, though multiple factors including genetic predisposition, immune system abnormalities, vascular dysfunction, and environmental triggers likely interact to produce the disease.
Pathogenic Mechanisms
The disease arises from a complex interplay of three primary pathogenic processes 1, 2, 3:
- Autoimmunity and inflammation: Immune system dysregulation leads to production of disease-specific autoantibodies and cell-mediated autoimmunity 4, 3
- Vasculopathy: Microvascular endothelial cell injury and small vessel fibroproliferative changes occur early in disease pathogenesis 2, 3
- Fibrosis: Fibroblast dysfunction generates excessive accumulation of collagen and other matrix components in skin and internal organs 2, 3
Contributing Factors
While no single "cause" has been identified, several factors are implicated in disease development 4:
- Genetic predisposition: Polymorphisms in critical molecules of the immune system and matrix homeostasis contribute to susceptibility 4
- Immune abnormalities: Cytokine and chemokine dysregulation, abnormal T cell signaling, and B cell dysfunction are present 4
- Environmental triggers: Infections or environmental toxins may trigger disease in genetically susceptible individuals 3
- Microchimerism: Fetal/maternal placental exchange of HLA-compatible cells has been proposed as a potential mechanism 4
Clinical Implications
The heterogeneous clinical presentation of scleroderma likely reflects different genetic or triggering factor influences on the immune system, vasculature, and connective tissue cells 3. This explains why approximately 80% of patients are female, with one-half presenting before age 40, and why some studies suggest higher incidence and severity in Black females compared to whites 5.
Key Diagnostic Features
The presence of characteristic autoantibodies supports the autoimmune nature of the disease 5, 6:
- Antinuclear antibodies (ANA)
- Anti-centromere antibodies
- Anti-topoisomerase I (Scl-70) antibodies 1, 5
- Anti-RNA polymerase III antibodies 1
These autoantibodies are helpful for classification and prognosis determination, though their exact role in pathogenesis remains unclear 6.
Important Caveats
Unlike other cutaneous autoimmune diseases (lupus, dermatomyositis), scleroderma does not cause epithelial injury despite being an autoimmune condition 4. This distinguishes it mechanistically from other autoimmune skin diseases and explains why the primary pathology is excessive collagen synthesis rather than tissue destruction 4, 7.
The disease remains chronic and progressive, with no definitive cure identified to date 4. Early diagnosis and intervention before significant tissue fibrosis occurs offers the best therapeutic window 7, 6.