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| DEPARTMENT OF DERMATOLOGY AND CUTANEOUS BIOLOGY |
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Scleroderma Center
Basic Information About
Scleroderma (Systemic Sclerosis)
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What is Scleroderma (Systemic Sclerosis)?
What is fibrosis?
Who is most likely to get Scleroderma?
Kinds of Scleroderma
Diagnosing Scleroderma
The Course and Prognosis of the Disease
Current Research
Frequency of Organ Involvement
DEFINITION OF SYSTEMIC SCLEROSIS OR SCLERODERMA
- Systemic sclerosis, also known as Scleroderma, is an autoimmune disorder of unknown cause which affects the connective tissue
that is present in all organs of the body.
- It is clinically heterogeneous, ranging from limited skin induration with limited internal organ alterations to diffuse skin sclerosis with severe internal
organ involvement.
- Raynaud's phenomenon (abrupt spasm of the arteries in the hands), swelling of the extremities, and pain in multiple joints often are the first
symptoms of systemic sclerosis and usually precede the onset of skin tightness and induration.
- Visceral (internal organ) involvement with fibrosis, alterations in the small arteries and arterioles (microvasculature), and chronic inflammation and damage of the gastrointestinal
tract, lungs, heart, and kidneys is present to a variable extent in most patients.
- Autoantibodies, some with very high specificity for the diagnosis of systemic sclerosis such as anti-centromere and anti-Scl70 antibodies,
are present almost universally.
- The severity of the disease and its outcome are directly related to the extent of the fibrosis and alterations in the microvasculature.
- The mechanisms involved in the development of systemic sclerosis are extremely complex, and at present, there is no single
unifying hypothesis to explain all aspects of this complex disorder.
- Fundamental abnormalities in at least 3 types of cells are intimately involved in the development of the clinical and pathologic
manifestations of the disease. These cells are:
- fibroblasts, the cells responsible for production of scar tissue;
- endothelial cells, the cells lining the lumen of arteries and arterioles; and
- cells of the immune system, in particular macrophages and T and B lymphocytes.
- The profound functional alterations in these various types of cells result in the characteristic triad of pathologic changes
present in the disease: severe and often progressive cutaneous and visceral fibrosis; obliteration of the lumen of small arteries
and arterioles; and immunologic abnormalities, which include the production of autoantibodies and the chronic inflammation
and damage of affected tissues.
- A better understanding of the pathogenesis of this incurable disorder and further research to unravel the mechanisms of tissue damage will help to design effective therapies in the future.
- Scleroderma is the most common chronic disease characterized by hardening and thickening of the skin.
- The name Scleroderma is derived from scleros (hard) and derma (skin).
- Three processes responsible for the symptoms of Scleroderma:
- Excessive accumulation of scar tissue (fibrosis) and chronic inflammation of the skin and internal organs (e.g. lungs, heart,
kidneys, gastrointestinal tract);
- Severe alterations in the microvasculature (small vessels, e.g. capillaries);
- Immunologic abnormalities of the cells and bodily fluids (e.g. lymph).
- Scleroderma is an autoimmune disease of unknown etiology (very little is known about its causes).
- It is the third most common autoimmune connective tissue disease (following in frequency rheumatoid arthritis and systemic
lupus erythematosus).
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FIBROSIS
- Fibrosis is a complex process involving the development of scar tissue.
- Fibroblasts are specialized cells present in almost all organs of the body which are responsible for the production of fibrous
tissue.
- The organs and tissues of our bodies are made up of individual cells, held together by a connective tissue also known as extracellular
matrix. In normal tissue, extracellular matrix production is balanced by its degradation (its being broken down). When this
balance is disrupted and there is excessive production or defective breakdown, or a combination of both, the result is tissue
fibrosis.
- A crucial component in the tissue fibrosis and damage in systemic sclerosis is the persistent and unregulated activation of
genes encoding various proteins which are components of scar tissue such as collagens.
- Alterations in the production of inflammatory substances and growth factors which are capable of modulating the function of
fibroblasts play a relevant role in tissue fibrosis.
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WHO GETS SCLERODERMA
- Scleroderma affects all racial groups and all ages.
- It is more common in females (4-8:1 female to male).
- Scleroderma most often develops in people 40-60 years old, although it can occur at any age.
- Familial Scleroderma is rare.
- There is no evidence of genetic inheritance.
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KINDS OF SCLERODERMA
- Scleroderma is a clinically heterogeneous disease, meaning the symptoms and complications can vary widely across patients
and over time, depending upon which organs are involved and to what extent.
- The least severe kind of Scleroderma is called Limited Scleroderma (also known as CREST). Patients with Limited Scleroderma
develop thickened skin which is usually confined to the face, fingers, and hands. They also usually have long-standing Raynaud phenomenon, esophageal dysfunction, and multiple dilated small vessels (telangiectasias).This kind of Scleroderma is most likely to
progress slowly and has the best prognosis.
- The most severe kind of Scleroderma is called Diffuse Scleroderma. Patients with Diffuse Scleroderma have extensive and rapidly
progressive fibrosis which affects the thighs, chest and abdomen and is often associated with severe derangement of internal
organs.
- There are several clinical and laboratory studies that distinguish between these two extremes.
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DIAGNOSIS
- The diagnosis is generally made on clinical grounds, e.g. the appearance of the skin and other symptoms.
- Laboratory studies help in defining the type, extent, and severity of internal organ involvement.
- Immunological Tests:
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- 90% or more Scleroderma patients have a positive blood test for antinuclear antibodies, and there is a different specific
pattern for the diffuse and limited forms of Scleroderma. Patients with diffuse Scleroderma harbor Scl-70 antibodies, whereas,
patients with limited Scleroderma harbor anti-centromere antibodies.
- The anti-Scl-70 antibody is highly specific for diffuse Scleroderma. However, Scl-70 antibody is present in only in 30-40%
of patients with diffuse Scleroderma, and is rare in patients with limited Scleroderma and other connective tissue diseases.
The absence of anti-Scl-70 antibody does NOT exclude the diagnosis of Scleroderma.
- There are numerous other antibodies which are also helpful in predicting the chance of developing certain organ involvements.
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TREATMENT AND PROGNOSIS
- Scleroderma is a progressive disease, meaning that it tends to get worse over time. For some patients the progression is gradual,
and for others more rapid.
- There is currently no cure for Scleroderma, but there has been remarkable improvement in the treatment and management of Scleroderma
in recent years. In some cases, the progression of the disease can be slowed, halted, or even reversed. In many cases, treatment
effectively and successfully manages the disease, resulting in increased survival and improvement in quality of life.
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CURRENT RESEARCH
Systemic sclerosis, or Scleroderma, is a systemic autoimmune disease characterized by widespread fibroproliferative vascular
damage and progressive tissue fibrosis leading to severe multi-organ dysfunction. The fibroproliferative process occurs essentially
in all organs but is often particularly evident and aggressive in the skin, kidneys and lungs, causing severe skin tightening
and induration, Scleroderma Renal Crisis or Pulmonary Fibrosis and Arterial Hypertension (PAH), respectively.These serious
clinical events combined represent the major cause of symptoms and mortality in Scleroderma patients. The following are some
of the research projects currently being pursued at the Scleroderma Center and the Jefferson Institute of Molecular Medicine.
- Role of the novel protein "caveolin-1" in the pathogenesis of tissue fibrosis and organ damage in systemic sclerosis. Recent studies on idiopathic PAH and idiopathic pulmonary fibrosis have identified caveolins, a family of membrane proteins,
as important participants in the pathogenesis of both diseases. Caveolin-1 (cav-1), the most important member of this family, is involved in numerous important biological functions including the regulation
of two pathways universally accepted to play a crucial role in the pathogenesis of systemic sclerosis, namely the transforming growth factor β (TGF-β) and endothelin (ET-1) pathways. Thus, the hypothesis to be tested in these studies is that cav-1 reduction plays a critical role in the pathogenesis
of systemic sclerosis and that restoration of cav-1 levels may be a novel approach for the treatment of the fibroproliferative
vascular damage and the tissue fibrosis of systemic sclerosis.
- Vascular and biochemical alterations in scleroderma. Although the mechanisms involved in the development of Scleroderma are not completely known, it is clear that skin, visceral,
and vascular fibrosis are responsible for the most severe clinical manifestations and the mortality of the disease. The overall
objective of this study is to identify the important molecular events involved in the exaggerated production of collagen and in the vascular abnormalities in Scleroderma. Several novel areas of investigation have been identified during our previous research studies, including
the significant association of Scleroderma with the gene encoding Allograft Inflammatory Factor 1 (AIF-1). AIF-1 is a protein which plays a crucial role in graft rejection, a process that resembles many features of Scleroderma.
Furthermore, we demonstrated that high levels of this protein are present in inflammatory and endothelial cells in Scleroderma-affected
vasculature. Based on these results, we propose to test the hypothesis that this protein plays an important role in the pathogenesis
of the vascular abnormalities characteristic of Scleroderma.
- Identification of biomarkers of Scleroderma disease severity and progression employing cDNA microarrays and proteomics. At the present time there are no available biomarkers that can be used as litmus tests to provide information regarding the severity, progression, or response to therapy for a
particular Scleroderma patient. Currently only clinical parameters, which are remarkably inaccurate and fraught with biases
and variability, are employed. This project will attempt to identify valuable biomarkers by employing global gene expression
microarray studies, and proteomics followed by mass spectrometry analysis.
- Assessment of severity of cutaneous fibrosis in Scleroderma and its response to treatment by confocal laser immunofluorescent
microscopy. The extent and severity of skin fibrosis in Scleroderma are currently only assessed by cutaneous examination and palpation
(a physican looks at the skin and feels its texture and thickness), a method which is non-quantitative, highly subjective,
and usually not very reproducible. There is a great need to develop an accurate and reliable method of quantifying the severity
of fibrotic skin involvement. These studies employ highly sophisticated methods of confocal immunomicroscopy to develop a
quantitative method of assessment of the biochemical content and location of molecular components of the fibrous tissues.
- Identification of novel intracellular cascades involved in the regulation of fibrosis. Some of the intracellular signaling pathways involved fibrotic processes have been identified and at least partially characterized,
but we are still far from a complete picture. By employing state of the art molecular and genetic approaches to identify and
characterize more of the complex intracellular pathways involved in the exaggerated production of fibrous tissue by scleroderma
cells, we locate the key events that pose the best new targets for intervention and may lead to the development of novel effective treatments.
- Inhibition of exaggerated production of fibrotic tissue by Scleroderma fibroblasts involving novel therapeutic agents including
rottlerin, CellCept, statins, biologics, and others. These studies are based on extensive prior experimental results from numerous research laboratories, including our own,
and are aimed at testing potentially effective therapeutic agents in the laboratory by employing human skin cells in culture to identify the most
promising candidate drugs with the potential to be developed into effective treatments for Scleroderma.
- Creation of an animal model of Scleroderma by injection of cells from Scleroderma patients into mice lacking a functional
immune system (Rag mice). At present there is no animal model which reproduces the clinical and pathologic features of Scleroderma. Such an animal
model would be an extremely valuable resource to study the mechanisms involved in the organ damage in Scleroderma and to test
potential therapeutic agents. We are employing a novel concept in attempts to develop a model for the disease by taking advantage
of a genetic strain of mice which is unable to mount an effective immune response. In these studies we inject various types
of cells obtained from the blood of Scleroderma patients into the immune deficient mice to identify which particular cells
types are involved in the production of Scleroderma-like alterations and to test potentially effective therapeutic agents.
- Treatment of pulmonary fibrosis in mice by an aerosol delivering cell permeable peptides capable of entering cells without
a requirement for viral vectors. This study takes an innovative approach to treatment of one of the most serious and often lethal complications of Scleroderma
by employing small molecules that are capable of being shuttled inside cells without using viral vectors. These studies have
the potential to develop an inhaler to deliver the effective drugs directly into the lung cells for the treatment of pulmonary fibrosis.
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FREQUENCY OF ORGAN SYSTEM INVOLVEMENT
| SKIN |
95% |
| RAYNAUD'S PHENOMENON |
90% |
| GASTROINTESTINAL TRACT |
90% |
| LUNGS |
60-65% |
| BONES/JOINTS |
40-50% |
| MUSCLES |
35% |
| HEART |
30-40% |
| KIDNEYS |
15% |
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CUTANEOUS (SKIN) INVOLVEMENT
- 95% of Scleroderma patients have skin sclerosis.
- 5% have typical visceral (internal organ) involvement without skin sclerosis (called "Scleroderma sine Scleroderma").
- Thickened and hidebound skin first appears distally (at the extremities), typically with Sclerodactyly (involving fingertips
and hands), and progresses proximally (toward the center of the body).
- Facial involvement leads to an expressionless appearance with loss of wrinkles, beaked nose, thin lips with radial wrinkling
and furrowing, and reduction in the size of the mouth opening (microstomia).
- Diffuse darkening (hyperpigmentation) or hyperpigmented hair follicles surrounded by areas with loss of pigment ("salt-and-pepper"
pattern) may also occur.
- There may be chronic dilation of groups of capillaries causing red blotches (telangiectasia) on the hands, face, lips, tongue,
or mucosal membranes. Mucosal telangiectasia may lead to gastrointestinal bleeding.
- The more severe skin complications include the development of painful ulcerations at the fingertips and other areas where
the skin is tightly stretched, and calcifications (bone spurs and calcium crystals) at the fingertips, along the top of the
forearms, and around the joints.
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RAYNAUD'S PHENOMENON
- Raynaud's phenomenon is a distinctive sudden blood vessel spasm causing a particular series of discolorations.
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- White: The digits involved initially blanch white because the spasm constricts blood vessels and sharply diminishes the blood
supply.
- Blue: If the spasm lasts long enough, the digits next turn purple or blue due to the prolonged lack of oxygen.
- Red: When the spasm ends, the blood vessels reopen and flush the digits with blood, turning them red (erythema).
- Most frequently occurs in the fingers, toes, tip of the nose, tongue, or ears.
- Numbness, tingling, and loss of sensation in the affected parts is common.
- Typically occurs following exposure to cold temperatures, stress and anxiety, or exposure to tobacco smoke.
- Raynaud's phenomenon is common among premenopausal women.
- Most people who experience Raynaud's phenomenon do not develop a connective tissue disease, but those who do most commonly
develop Scleroderma.
- For most Scleroderma patients, Raynaud's phenomenon is the initial symptom.
- It usually precedes the onset of other Scleroderma features and it ultimately develops in virtually all Scleroderma patients.
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SKELETAL INVOLVEMENT
- Symmetrical pain in multiple joints (polyarthralgia) is common, but true arthritis and joint inflammation (synovitis) are
rare for Scleroderma patients.
- Contracture of the fingers and wrists with loss of hand function is very common.
- Carpal tunnel syndrome often occurs at the onset of the disease and may resolve spontaneously.
- Coarse leathery crepitus (tendon friction rub) are detected in rare instances, but when present are virtually always specific
to diffuse Scleroderma.
- X-rays may show resorption and complete dissolution of the distal end of the phalanx (loss of bone at the end of the fingertip).
- Indolent muscle involvement (slow-growing and causing little or no pain) caused by muscle fibrosis and fiber atrophy is not
uncommon.
- Some patients develop typical inflammation of the muscles (myositis) with elevation in muscle enzymes in blood tests and abnormalities
in electromyography testing.
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GASTROINTESTINAL (GI) TRACT
- The digestive system is the internal organ system most frequently involved in Scleroderma.
- Abnormalities of the esophagus develop in up to 90% of patients.
- Failure of the lower esophageal sphincter and decreased or absent contractions in the lower two-thirds can cause difficulty
swallowing.
- Chronic reflux can cause esophageal inflammation (esophagitis), Barrett`s esophagus, and lower esophageal stricture.
- Reflux of gastric contents can cause hoarseness, cough and aspiration pneumonia.
- When there are problems with contraction of the stomach and intestinal muscles, food cannot move through the GI tract properly.
Food is poorly digested and absorbed, and bacteria can overgrow. Symptoms of this include bloating, diarrhea, and weight loss.
- Colon disease with large sacculations, similar to diverticulitis, is typical of Scleroderma.
- "Watermelon stomach" (large dilated capillaries in the lining of the stomach wall) can cause severe GI bleeding in some Scleroderma
patients.
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RESPIRATORY SYSTEM
- Lung (pulmonary) involvement is currently the leading cause of mortality in Scleroderma.
- Lung involvement results in pulmonary fibrosis (scarring of the lung tissue) or pulmonary hypertension (thickening and narrowing
of the pulmonary vasculature) or a combination of both.
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- Pulmonary fibrosis in Scleroderma is gradual at onset and often progressive.
- Pulmonary hypertension may develop abruptly in patients with limited Scleroderma, even in the absence of pulmonary tissue
involvement.
- Tests:
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- Chest roentgenograms are insensitive for detection of early lesions.
- Pulmonary function studies are more sensitive and can show reduction in diffusion capacity and total lung capacity.
- High resolution CAT scan is highly sensitivity, allowing the detection of inflammation and early fibrosis.
- Echocardiography is of crucial importance to detect early pulmonary hypertension.
- In advanced cases there is not enough transfer of oxygen through the lungs into the bloodstream and supplemental oxygen may
be needed.
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RENAL (KIDNEY) INVOLVEMENT
- Renal involvement is considered to be the most deadly complication of Scleroderma.
- Renal crisis develops in 15-20% of patients and usually occurs abruptly.
- Scleroderma renal crisis is characterized by malignant hypertension, acute cardiac failure, myocardial infarction, stroke,
and rapidly progressive renal insufficiency.
- Progression to renal failure may occur rapidly unless the diagnosis of renal crisis is established and aggressive treatment
instituted promptly.
- Patients with diffuse and rapidly progressive skin involvement are at the highest risk.
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CARDIAC (HEART) INVOLVEMENT
- Heart involvement develops in 30-40% percent of patients, but clinically significant cardiac failure is less common.
- Abnormal heart rhythm, premature contractions, and cardiac conduction disturbances are common.
- Pericardial fluid is found by echocardiography in many patients, but is not symptomatic.
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OTHER ORGAN INVOLVEMENT
- Peripheral neuropathy (trigeminal neuralgia and carpal tunnel syndrome) can occur but the brain is spared.
- Erectile dysfunction develops in many male patients, and can precede other Scleroderma manifestations.
- Dry eyes and mouth and dryness of other mucosal surfaces (sicca syndrome) are frequently found.
- Hypothyroidism is detected in a third of the patients, but is generally mild.
- Primary biliary cirrhosis has been documented in a few Scleroderma cases.
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