Classification and special forms
In clinical practice, two basic forms of the disease are distinguished, differing in the rate and extent of involvement:
- Diffuse systemic sclerosis (dSSc): characterized by widespread skin involvement and very early engagement of internal organs in the pathological process.
- Limited systemic sclerosis (lSSc): specific changes affect only the face, forearms, and fingers. Visceral disorders (organ damage) develop much later.
There are also specific clinical variants. For example, overlap syndrome, where the pathology is combined with signs of other autoimmune diseases: rheumatoid arthritis, systemic lupus erythematosus (SLE), or dermatomyositis/polymyositis.
Etiology: where does the disease come from?
The exact cause of the disease has not yet been established, but there are several working hypotheses and proven predisposing factors:
- Microchimerism phenomenon (cellular theory). Embryonic cells can cross the placental barrier and persist in maternal tissues. Being genetically foreign, they are capable of provoking a chronic graft-versus-host-like reaction.
- Viral theory. It is hypothesized that cytomegalovirus (CMV) can trigger endothelial cell apoptosis.
- Genetics. A link with specific major histocompatibility complex antigens has been proven. In the general patient group, these are HLA-10, -B35, -Cw4, and in disease onset before age 30, HLA-B8.
- Humoral immunity disorders. A whole spectrum of autoantibodies is synthesized in the body: against topoisomerase (anti-Scl70), centromeres, fibroblast cell membranes, as well as type I and type IV collagen.
- External triggers. Cold, trauma, vibration, infections, and chemicals directly damage the vascular endothelium.
Pathogenesis: how fibrosis develops
The fundamental mechanism can be described by a short chain: unknown trigger $\rightarrow$ immune response $\rightarrow$ vascular wall damage and fibroblast activation $\rightarrow$ fibrosis.
Key links in this process:
- Endothelial damage. Leads to platelet aggregation and activation.
- Vasospasm (Raynaud's phenomenon). Triggered by cold, negative emotions, release of serotonin and thromboxane $A_2$. Vessels of both the skin and internal organs spasm.
- Scleroderma kidney. Ischemia of the cortical layer due to renal vascular damage activates the juxtaglomerular apparatus. Stimulation of the renin-angiotensin system occurs, which closes the vicious cycle of disease progression.
- Fibrogenesis mechanism. Proceeds in two ways. The platelet pathway is associated with platelet adhesion to the basement membrane and the release of factors stimulating perivascular fibrosis. The immune pathway is due to the accumulation of sensitized CD4+ T cells, which stimulate macrophages and mast cells via cytokines. These, in turn, force fibroblasts to actively synthesize collagen.
Morphogenesis: three phases of changes
Pathomorphologically, the process represents sequential connective tissue disorganization. The inflammatory component is weakly expressed (mild cellular reaction). The outcome is always the same: severe sclerosis and hyalinosis.
Three stages of change development are distinguished:
- Early (edematous) phase: capillaries and small arterioles are damaged, and their permeability increases. Interstitial edema develops, and tissue hypoxia worsens.
- Indurative phase: against the background of oxygen starvation and edema, fibroblasts are activated, and massive enhanced collagen synthesis begins.
- Final (atrophic) phase: parenchymal elements of organs atrophy, while the stroma and vessels undergo irreversible sclerosis and hyalinosis.
Briefly: answers to topical questions
Which internal organs are most frequently affected in systemic sclerosis, besides the kidneys?
Besides the kidneys, systemic sclerosis most frequently affects the gastrointestinal tract, lungs, and heart.
- Gastrointestinal tract — involved in 90% of patients; the most pronounced changes occur in the esophagus: sclerosis of the muscular layer and motility disorders.
- Lungs — affected in more than 50% of cases; alveolitis and subsequent basal diffuse interstitial pneumosclerosis are possible.
- Heart — affected in 30% of patients; "scleroderma heart" develops with productive vasculitis and small- and large-focal cardiosclerosis.
How does the skin macroscopically change in the indurative stage of systemic sclerosis?
In the induration stage, the skin becomes rigid, smooth, acquires a waxy color, and cannot be gathered into a fold. Macroscopic changes depend on the location:
- Face — becomes expressionless and mask-like, the nose and auricles thin out, and radial "purse-string" wrinkles form around the narrowed oral aperture.
- Hands — acquire a cast-like appearance; fingers do not close into fists due to circulatory disorders and muscle atrophy.
- Fingers — sclerodactyly develops (symmetric thickening, enlargement, and induration of the skin).
The abbreviation CREST is an ideal cheat sheet for remembering a special syndrome: Calcinosis, Raynaud's, Esophageal dysmotility, Sclerodactyly, Telangiectasia.
Class and exam questions
What is the essence of the cellular theory of systemic sclerosis development?
It is based on the phenomenon of fetal microchimerism. Fetal cells cross the placental barrier, persist in maternal tissues, and trigger an immune conflict resembling a graft-versus-host reaction.
Which autoantibodies are specific to this disease?
Antitopoisomerase (anti-Scl70), anticentromere, and antinuclear antibodies, as well as antibodies to fibroblast membranes and type I and IV collagen, are detected in the patients' blood.
How does the "scleroderma kidney" form?
Damage to renal vessels leads to ischemia of the cortical layer. This stimulates the juxtaglomerular apparatus and the renin-angiotensin system, which exacerbates systemic vascular spasm.
What else to study on this topic
- The relationship between HLA antigens and the age of disease onset.
- Mechanisms of endothelial cell apoptosis induced by cytomegalovirus antibodies.
- The role of serotonin and thromboxane A2 in the development of vasospastic reactions.
- Differences of overlap syndromes with rheumatoid arthritis and systemic lupus erythematosus.
- Dynamics of tissue hypoxia during the transition from the edematous to the indurative phase of morphogenesis.
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