Classification and Specific Forms
In clinical practice, two main forms of the disease are distinguished based on the rate and extent of organ involvement:
- Diffuse systemic sclerosis (dSSc): characterized by widespread skin involvement and very early visceral organ involvement.
- Limited systemic sclerosis (lSSc): specific changes are confined to the face, forearms, and fingers. Visceral complications develop much later.
There are also specific clinical variants, such as overlap syndrome, where the pathology coexists with features of other autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus (SLE), or dermatomyositis/polymyositis.
Etiology
The exact cause of the disease remains unknown, but several working hypotheses and proven predisposing factors exist:
- Microchimerism phenomenon (cellular theory). Fetal cells can cross the placental barrier and persist in maternal tissues. Being genetically foreign, they can trigger a chronic graft-versus-host-like reaction.
- Viral theory. Cytomegalovirus (CMV) is hypothesized to induce endothelial cell apoptosis.
- Genetics. Association with certain major histocompatibility complex antigens has been established. These include HLA-10, -B35, and -Cw4 generally, and HLA-B8 in patients with disease onset before age 30.
- Humoral immunity disorders. A spectrum of autoantibodies is synthesized, including antitopoisomerase (anti-Scl-70), anticentromere, anti-fibroblast membrane antibodies, and antibodies against type I and IV collagen.
- External triggers. Cold, trauma, vibration, infections, and chemical agents directly injure the vascular endothelium.
Pathogenesis: Development of Fibrosis
The fundamental mechanism can be summarized by a short sequence: unknown trigger $\rightarrow$ immune response $\rightarrow$ vascular wall injury and fibroblast activation $\rightarrow$ fibrosis.
Key links in this process include:
- Endothelial injury. Leads to platelet aggregation and activation.
- Vasospasm (Raynaud's phenomenon). Triggered by cold exposure, emotional stress, and release of serotonin and thromboxane $A_2$. Vasospasm affects both cutaneous and visceral vessels.
- Scleroderma renal crisis. Ischemia of the renal cortex due to vascular damage activates the juxtaglomerular apparatus. Stimulation of the renin-angiotensin system creates a vicious cycle of disease progression.
- Fibrogenesis mechanism. Proceeds via two pathways. The platelet pathway involves platelet adhesion to the basement membrane and release of factors stimulating perivascular fibrosis. The immune pathway is driven by an accumulation of sensitized CD4+ T cells, which stimulate macrophages and mast cells via cytokines. These cells in turn drive fibroblasts to actively synthesize collagen.
Morphogenesis: Three Phases of Tissue Changes
Pathomorphologically, the process represents sequential connective tissue disorganization. The inflammatory component is typically mild (low-cellular reaction). The ultimate outcome is always coarse sclerosis and hyalinosis.
Three developmental stages are recognized:
- Early (edematous) phase: capillaries and small arterioles are injured, increasing vascular permeability. Interstitial edema develops, and tissue hypoxia increases.
- Indurative phase: driven by hypoxia and edema, fibroblasts are activated, and massive, enhanced collagen synthesis begins.
- Terminal (atrophic) phase: parenchymal elements atrophy, while the stroma and vessels undergo irreversible sclerosis and hyalinosis.