Systemic Scleroderma
Disease Details
Family Health Simplified
- Description
- Systemic scleroderma, also known as systemic sclerosis, is a chronic autoimmune disease characterized by hardening and tightening of the skin and connective tissues, often affecting internal organs such as the heart, lungs, and kidneys.
- Type
- Systemic scleroderma, also known as systemic sclerosis, is an autoimmune connective tissue disease. The type of genetic transmission for systemic scleroderma is complex and not fully understood. It is believed to involve a combination of genetic predisposition and environmental triggers, but it does not follow a straightforward Mendelian pattern of inheritance. Cases tend to cluster in families, suggesting a hereditary component, but no single gene has been identified as the cause.
- Signs And Symptoms
- Calcinosis, Raynaud's phenomenon, Esophageal dysfunction, Sclerodactyly, and Telangiectasia (CREST syndrome) are associated with limited scleroderma. Other symptoms include:
- Prognosis
- A 2018 study placed 10-year survival rates at 88%, without differentiation based on subtype. Diffuse systemic sclerosis, internal organ complications, and older age at diagnosis are associated with worse prognoses.
- Onset
- Systemic scleroderma, or systemic sclerosis, typically manifests in adults between the ages of 30 and 50. The onset can vary widely among individuals. Symptoms often begin gradually and may include fatigue, Raynaud's phenomenon (where fingers and toes turn white or blue in response to cold or stress), and skin thickening or tightening, among others. Early diagnosis and management are crucial to mitigate potential complications.
- Prevalence
- Systemic scleroderma, also known as systemic sclerosis, is a rare autoimmune connective tissue disease. The prevalence of systemic scleroderma varies by population and geographic location. Generally, it is estimated to affect approximately 50 to 300 individuals per million globally. This means it is considered an uncommon condition.
- Epidemiology
- Systemic scleroderma is a rare disease, with an annual incidence that varies in different populations. Estimates of incidence (new cases per million people) range from 3.7 to 43 in the United Kingdom and Europe, 7.2 in Japan, 10.9 in Taiwan, 12.0 to 22.8 in Australia, 13.9 to 21.0 in the United States, and 21.2 in Buenos Aires. The interval of peak onset starts at age 30 and ends at age 50.Globally, estimates of prevalence vary from 31.0 to 658.6 affected people per million. Systemic sclerosis has a female:male ratio of 3:1 (8:1 in mid- to late childbearing years). Incidence is twice as high among African Americans. Full-blooded Choctaw Native Americans in Oklahoma have the highest prevalence in the world (469 per 100,000).The disease has some hereditary association. It may also be caused by an immune reaction to a virus (molecular mimicry) or by toxins.
- Intractability
- Systemic scleroderma, also known as systemic sclerosis, is currently considered an intractable or chronic disease. There is no known cure for systemic scleroderma, and treatment primarily focuses on managing symptoms and slowing disease progression. Therapies may include medications to control immune system function, manage symptoms, and address specific organ involvement, as well as lifestyle modifications and supportive care.
- Disease Severity
- The severity of systemic scleroderma can vary significantly among individuals. It can range from mild to life-threatening, depending primarily on the extent and organs involved. Severe cases can lead to significant complications in the skin, lungs, heart, kidneys, and gastrointestinal system. Early diagnosis and appropriate management are crucial in addressing potential complications and improving patient outcomes.
- Healthcare Professionals
- Disease Ontology ID - DOID:418
- Pathophysiology
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Overproduction of collagen is thought to result from an autoimmune dysfunction, in which the immune system starts to attack the kinetochore of the chromosomes. This would lead to genetic malfunction of nearby genes. T cells accumulate in the skin; these are thought to secrete cytokines and other proteins that stimulate collagen deposition. Stimulation of the fibroblast, in particular, seems to be crucial to the disease process, and studies have converged on the potential factors that produce this effect.
A significant player in the process is transforming growth factor (TGFβ). This protein appears to be overproduced, and the fibroblast (possibly in response to other stimuli) also overexpresses the receptor for this mediator. An intracellular pathway (consisting of SMAD2/SMAD3, SMAD4, and the inhibitor SMAD7) is responsible for the secondary messenger system that induces transcription of the proteins and enzymes responsible for collagen deposition. Sp1 is a transcription factor most closely studied in this context. Apart from TGFβ, connective tissue growth factor (CTGF) has a possible role. Indeed, a common CTGF gene polymorphism is present at an increased level in systemic sclerosis.Damage to endothelium is an early abnormality in the development of scleroderma, and this, too, seems to be due to collagen accumulation by fibroblasts, although direct alterations by cytokines, platelet adhesion, and a type II hypersensitivity reaction similarly have been implicated. Increased endothelin and decreased vasodilation have been documented.Jimenez and Derk describe three theories about the development of scleroderma:
The abnormalities are primarily due to a physical agent, and all other changes are secondary or reactive to this direct insult.
The initial event is fetomaternal cell transfer causing microchimerism, with a second summative cause (e.g. environmental) leading to the actual development of the disease.
Physical causes lead to phenotypic alterations in susceptible cells (e.g. due to genetic makeup), which then effectuate DNA changes that alter the cells' behavior. - Carrier Status
- Systemic scleroderma, also known as systemic sclerosis, is an autoimmune disease and not an inherited genetic disorder. It does not have a "carrier status" as seen in genetic conditions. The exact cause is unknown, but it involves the immune system attacking the body's own tissues, leading to fibrosis and vascular abnormalities. Environmental factors, genetic predisposition, and immune system irregularities are thought to play roles in its development.
- Mechanism
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Systemic scleroderma, also known as systemic sclerosis, is an autoimmune connective tissue disease characterized by fibrosis (thickening and hardening of the skin), vascular abnormalities, and immune system dysregulation.
**Mechanism:**
The pathogenesis of systemic scleroderma involves three main processes:
1. **Fibrosis**: Excessive deposition of collagen and other extracellular matrix components in the skin and internal organs.
2. **Vascular Damage**: Endothelial cell damage and dysfunction lead to narrowing of the blood vessels, reduced blood flow, and vascular complications.
3. **Autoimmunity**: Dysregulation of the immune system with production of autoantibodies and inflammation.
**Molecular Mechanisms:**
1. **Fibrogenic Pathways**:
- **TGF-β (Transforming Growth Factor-beta)**: A key cytokine driving fibrosis. It promotes the differentiation of fibroblasts into myofibroblasts, which produce excessive collagen.
- **Connective Tissue Growth Factor (CTGF)**: Works in conjunction with TGF-β to enhance fibrosis.
- **Wnt Pathway**: Contributes to fibroblast activation and matrix production.
2. **Vascular Pathways**:
- **Endothelin-1**: A potent vasoconstrictor that also stimulates fibroblast proliferation and collagen synthesis.
- **Vascular Endothelial Growth Factor (VEGF)**: Initially increased to counteract vascular damage but may eventually contribute to abnormal vessel formation and dysfunction.
- **Nitric Oxide (NO)**: Reduced levels due to endothelial cell dysfunction, contributing to vasoconstriction and impaired blood flow.
3. **Immune System Dysregulation**:
- **Autoantibodies**: Presence of autoantibodies such as anti-topoisomerase I (Scl-70) and anti-centromere antibodies, which are associated with various disease phenotypes.
- **Cytokine Production**: Elevated levels of pro-inflammatory cytokines (e.g., IL-6, IL-1, TNF-α) which perpetuate immune dysregulation.
- **B cells and T cells**: Abnormal activation and interaction of B cells and T cells that contribute to autoantibody production and chronic inflammation.
Understanding these mechanisms highlights the complex interplay between fibrosis, vascular damage, and immune dysregulation in systemic scleroderma. This knowledge is crucial for developing targeted therapies aimed at modulating these pathogenic pathways. - Treatment
- No cure for scleroderma is known, though treatments exist for some of the symptoms, including drugs that soften the skin and reduce inflammation. Some patients may benefit from exposure to heat. Holistic care of patients comprising patient education tailored to patients' education level is useful in view of the complex nature of the disease symptoms and progress.
- Compassionate Use Treatment
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Compassionate use treatment for systemic scleroderma typically involves access to experimental drugs that are not yet approved but show promise in clinical trials. These treatments are provided when conventional therapies have failed or are not suitable.
Off-label or experimental treatments often considered for systemic scleroderma include:
1. **Rituximab**: An off-label use to target B-cells, potentially reducing immune system activity that drives the disease.
2. **Imatinib**: Typically used for certain cancers, it has shown some promise in reducing skin thickening and improving lung function.
3. **Nintedanib**: Originally approved for idiopathic pulmonary fibrosis, sometimes used experimentally for scleroderma-related lung disease.
4. **Tocilizumab**: An IL-6 receptor inhibitor, usually for rheumatoid arthritis, studied for its effects on systemic scleroderma.
5. **Hematopoietic stem cell transplantation (HSCT)**: An aggressive approach aimed at resetting the immune system, considered in severe, refractory cases. - Lifestyle Recommendations
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Systemic scleroderma is a chronic connective tissue disease characterized by changes in the skin, blood vessels, muscles, and internal organs. Lifestyle recommendations for managing systemic scleroderma include:
1. **Regular Medical Check-ups**: Frequent visits to healthcare providers are essential for monitoring the progression of the disease and adjusting treatments as necessary.
2. **Skin Care**: Use moisturizers regularly to keep the skin supple and prevent dryness and cracking. Protect your skin from cold and injury.
3. **Healthy Diet**: Eat a balanced diet rich in fruits, vegetables, lean proteins, and whole grains. Maintain a healthy weight to reduce stress on the body.
4. **Exercise**: Engage in low-impact exercises like walking, swimming, or yoga to maintain flexibility and muscle strength. Consult with a physical therapist for an appropriate exercise regimen.
5. **Smoking Cessation**: Avoid smoking, as it can worsen vascular problems and exacerbate symptoms.
6. **Stress Management**: Practice stress-reducing techniques such as meditation, deep breathing exercises, or hobbies that you enjoy to help manage the emotional aspects of the disease.
7. **Protect Extremities**: Keep hands and feet warm, particularly in cold weather, to prevent Raynaud's phenomenon, a common condition linked with scleroderma.
8. **Monitor Gastrointestinal Health**: Eat smaller, more frequent meals, and avoid foods that trigger reflux. Elevate the head of your bed to reduce nighttime reflux symptoms.
9. **Adequate Sun Protection**: Use sunscreen and protective clothing to shield the skin from ultraviolet light.
10. **Hydrate Well**: Drink plenty of fluids unless otherwise directed by your healthcare provider, especially if there are kidney or heart issues.
Following these recommendations can help manage symptoms and improve the quality of life for individuals with systemic scleroderma. Always consult with healthcare providers for personalized advice. - Medication
- For systemic scleroderma, treatment focuses on managing symptoms and slowing disease progression. Common medications include immunosuppressants like methotrexate or mycophenolate mofetil, corticosteroids, and drugs to manage symptoms like calcium channel blockers for Raynaud’s phenomenon. Each treatment plan is individualized based on specific symptoms and disease severity.
- Repurposable Drugs
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There are currently no well-established repurposable drugs specifically for systemic scleroderma. However, drugs originally developed for other conditions have been explored for their potential in treating systemic scleroderma. Some of these include:
1. **Methotrexate** - Originally for rheumatoid arthritis and certain cancers.
2. **Mycophenolate Mofetil** - Used in organ transplant patients.
3. **Cyclophosphamide** - Used in cancer chemotherapy.
4. **Rituximab** - A monoclonal antibody used for non-Hodgkin's lymphoma and rheumatoid arthritis.
5. **Nintedanib** - Initially used for idiopathic pulmonary fibrosis.
It’s important to consult with a healthcare provider for personalized medical advice and treatment options. - Metabolites
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Systemic scleroderma, also known as systemic sclerosis, can involve altered metabolism of several biomarkers. Some of the key metabolic changes observed include:
1. **Amino Acids**: Alterations in levels of amino acids such as taurine, tryptophan, and histidine have been noted.
2. **Lipids**: Abnormal lipid profiles, including changes in phospholipids and free fatty acids, are observed.
3. **Carbohydrates**: Variations in glucose metabolism, including insulin resistance, have been reported.
4. **Oxidative Stress Markers**: Elevated levels of oxidative stress markers, such as malondialdehyde (MDA), are common.
5. **Nitric Oxide**: Decreased bioavailability of nitric oxide, contributing to vascular dysfunction.
These metabolite imbalances can offer insights into disease mechanisms and potential therapeutic targets. - Nutraceuticals
- There is limited scientific evidence supporting the use of nutraceuticals specifically for systemic scleroderma. Common approaches focus on controlling symptoms and preventing complications primarily through medications and other medical therapies. Patients are encouraged to consult healthcare providers before starting any new supplement regimen.
- Peptides
- Systemic scleroderma, also known as systemic sclerosis, is a chronic autoimmune disease characterized by fibrosis, vascular alterations, and autoantibodies. Peptide-based therapies are an area of research interest for this condition, aiming to modulate immune responses or target fibrotic pathways. Although not widely used in standard treatment, peptides can potentially serve as therapeutic agents or biomarkers. Nanotechnology also holds promise in systemic scleroderma for improved drug delivery, diagnostic imaging, and biomarker detection. Nanoparticles can be engineered to enhance the stability, bioavailability, and targeted delivery of treatments, potentially improving efficacy and reducing side effects.