AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Systemic sclerosis (SSc) is a systemic connective tissue disease. Characteristics of SSc include essential vasomotor disturbances; fibrosis; subsequent atrophy of the skin, subcutaneous tissue, muscles, and internal organs (eg, alimentary tract, lungs, heart, kidney, CNS); and immunologic disturbances accompany these findings.

Pathophysiology

Excessive collagen deposition causes skin and internal organ changes. Many factors, including environmental factors, can lead to immunologic system disturbances and vascular changes. Endothelial alterations may lead to a cascade of stimulatory changes that involve many cells, including fibroblasts, T lymphocytes, macrophages, and mast cells. In turn, the activated cells secrete a variety of substances, including cytokines and their soluble receptors and enzymes and their inhibitors. These substances lead to changes in the extracellular matrix compounds, including fibronectin; proteoglycans; and collagen types I, III, V, and VII. Increased collagen deposition in tissues is a characteristic feature of SSc. Increased collagen production or disturbances in its degradation can cause excessive collagen deposition in tissues.

Fibrosis can be caused by profibrotic cytokines, including transforming growth factor-beta (TGF-beta), interleukin-4 (IL-4), platelet-derived growth factor (PDGF), and connective-tissue growth factor.¹ The vasculopathy may be linked to TGF-beta and PDGF, while the diminution of lesional cutaneous blood vessels can be attributed to antiendothelial cell autoantibodies. The activation of the immune system is of paramount importance in the pathogenesis of SSc. Antigen-activated T cells, activated infiltrate early, infiltrate the skin, and produce the profibrotic cytokine IL-4. B cells may contribute to fibrosis, as deficiency of CD19, a B-cell transduction molecule, results in decreased fibrosis in animal models.

Different factors, including genetic, environmental, vascular, autoimmunologic, and microchimeric factors are involved in SSc pathogenesis. One theory states that antigens from the human leukocyte antigen (HLA) histocompatability complex, including HLA-B8, HLA-DR5, HLA-DR3, HLA-DR52, and HLA-DQB2, are involved in SSc. Some data suggest that apoptosis and the generation of free radicals may be involved in the pathogenesis of SSc.

In SSc, affected organs and systems include the skin, lungs, heart, digestive system, kidneys, muscles, joints, and nervous system.

Frequency

United States

SSc is a rare disease. SSc is diagnosed in approximately 67 male patients and 265 female patients per 100,000 people each year.

International

SSc is estimated to occur in 2.3-10 people per 1 million. SSc is rare in the resident population of Japan and China.

Mortality/Morbidity

The mortality rate is increasing in the United States and Europe; as many as 3.08 persons are affected per 1 million.

• Generally, renal and lung changes are responsible for death in patients with SSc.
• Pulmonary hypertension leads to 12% of SSc-related deaths.
• Lung fibrosis and heart changes are responsible for 9% of SSc-related deaths.

Race

No apparent racial predominance exists. However, SSc is rare in the resident population of Japan and China. Diffuse SSc (dSSc) occurs more often in black women than in white women.

Sex

Overall, a substantial female predominance exists, with a female-to-male ratio of 3-6:1. However, dSSc occurs equally in males and females. The limited form of SSc (lSSc) has a strong female predominance, with a female-to-male ratio of 10:1.

Age

SSc usually appears in women aged 30-40 years, and it occurs in slightly older men. In approximately 85% of cases, SSc develops in individuals aged 20-60 years. Cases also are observed in children and in the elderly population.

CLINICAL

Section 3 of 11  

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History

SSc is a disease with many different presentations. It involves the skin and many internal organs. Therefore, the presenting symptoms may differ among patients.

• Cutaneous pruritus is common.
• Raynaud phenomenon, or whitening of the hands on exposure to cold, is a common finding. Pain in the affected digits, blanching, cyanosis, and hyperemia can follow.
• Difficulty in swallowing solid foods can be followed by difficulty with swallowing liquids and subsequent nausea, vomiting, weight loss, abdominal cramps, blotting diarrhea, and fecal incontinence.
• The patient can have shortness of breath on exertion and, subsequently, at rest.
• Palpitations may occur without characteristic pain in thoracic cavity.
• The patient may have a nonproductive cough.
• Atypical chest pain, fatigue, dyspnea, and hypertension may be present.
• Joint pain, limitation of movement, joint swelling, and muscle pain may be present. SSc begins as joint pain in 15% of patients. It begins as inflammatory myopathy in 10% of patients.
• Weakness is present in 80% of patients.
• Medical signs and symptoms associated with disability, pain, and psychosocial adjustment in SSc were assessed.² In one study, 114 patients underwent examination, including a determination of skin thickening. Signs and symptoms were a significant correlate of all outcomes. Patient-reported dependent edema significantly correlated with all outcomes. For disability, significant correlates were (1) physician-determined joint tenderness and number of tender points and (2) patient-reported joint pain with motion, joint contracture, extremity ulcers other than digital, and dyspnea.

Physical

• According to the American Rheumatism Association (ARA), features characteristic for scleroderma are divided into 2 groups:
• • Major features include centrally located skin sclerosis that affects the arms, face, and/or neck.
  • Minor features include sclerodactyly, erosions, atrophia of the fingertips, and bilateral lung fibrosis.
  • SSc is diagnosed when a patient has 1 major and 2 minor criteria.
• Cutaneous involvement has 3 phases: (1) edematous, (2) indurative, and (3) atrophic. Skin becomes thickened and tight.
• SSc is divided into 5 forms: (1) dSSc, (2) lSSc, (3) transitory form (dSSc/lSSc), (4) systemic scleroderma sine scleroderma, and (5) malignant scleroderma. The principal forms are dSSc and lSSc.
• In addition to the following features, dSSc is characterized by Raynaud phenomenon that precedes the development of skin changes by approximately 1 year:
• • Generalized skin fibrosis of the chest and limbs
  • Areas of skin hyperpigmentation and hypopigmentation
  • Tendon friction rubs
  • Early involvement of the lungs, kidneys, digestive system, and heart
  • Antibodies against topoisomerase I DNA (Scl 70) in approximately 30% of patients^{3, 4}
  • Nail-fold capillary dilatation and capillary destruction
• lSSc is characterized by sclerotic changes of the hands, face, feet, and forearms in addition to the following features:
• • Atrophic changes of the ala nasi and lips, facial amimia
  • Telangiectasia of the skin
  • Late involvement of the lungs and late development of pulmonary hypertension
  • Anticentromere antibodies in approximately 70-80% of patients
  • Dilated capillary loops in nail folds
  • Cutaneous calcification
• dSSc and/or lSSc are described in a few cases in which internal organ changes preceded or simultaneously occurred with cutaneous changes.
• Systemic scleroderma sine scleroderma is difficult to diagnose because only internal organs are involved. Systemic scleroderma sine scleroderma usually is diagnosed after the patient's death.
• Malignant scleroderma most often occurs in men, usually in elderly men. An accelerated course of malignant scleroderma leads to death.

Causes

SSc is an autoimmunologic disease, but the pathogenesis is only partially understood. Certain factors are well known to trigger occurrence of the disease or create a similar clinical appearance. Environmental factors include exposure to the following:

• Vibration injury (similar vascular changes)
• Silica
• Organic solvents (eg, toluene, benzene, xylene)
• Aliphatic hydrocarbons (eg, hexane, vinyl chloride, trichloroethylene)
• Epoxy resin
• Amino acid compound L-5-hydroxytryptophan
• Pesticides
• Drugs (eg, bleomycin, carbidopa, pentazocine, cocaine, penicillamine, vitamin K)
• Appetite suppressants (eg, phenylethylamine derivatives)
• Substances used in cosmetic procedures (eg, silicone or paraffin implants)

DIFFERENTIALS

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Other Problems to be Considered

• Spider angiomas in person with alcoholism
• Hereditary hemorrhagic telangiectasia
• Taxane-induced scleroderma: Scleroderma due to taxanes may mimic SSc. Taxane chemotherapy for metastatic breast cancer may show marked edema first, followed by skin sclerosis occurring mainly at the distal ends of the extremities 6-12 months after the administration of taxane, in all patients. Although skin biopsy samples may show (1) full-layer dermal fibrosis with thickened collagen bundles and (2) perivascular monocytic cell infiltration, resembling SSc in clinical course and histological findings, Raynaud phenomenon, pulmonary fibrosis, and immunological abnormalities associated with SSc may not be detected.⁵

WORKUP

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Lab Studies

• Increased erythrocyte sedimentation rate
• Thrombocytopenia
• Hypergammaglobulinemia
• Microangiopathic hemolytic anemia
• Increased creatine phosphokinase levels in patients with muscle involvement
• Increased urea and creatinine levels in patients with kidney involvement

Imaging Studies

• Chest radiographs may show normal findings in 5-10% of the patients, even when the patients have respiratory tract symptoms.
• • In approximately 30-60% of patients, fibrosis of the basal parts of the lungs is observed.
  • Occasionally, pictures of diffuse ground-glass and honeycomb lung patterns are observed. In patients with honeycomb lung patterns, changes are irreversible. These changes can be an important feature of patient's response to treatment.
• Bone radiography reveals generalized osteopenia, which most commonly affects the hands. Intra-articular calcifications often are observed.
• High-resolution computed tomography (HRCT) and scintigraphy reveal thickening of the alveolar walls and intestinal tissue and honeycomb-appearing lungs.
• Gastrointestinal tract changes may be depicted.
• • Scintigraphy of the esophagus may reveal a disturbance of the esophageal passage.⁶
  • Manometric esophageal changes may be observed during invasive examination.
• Cardiac and pulmonary vascular involvement in SSc should be evaluated. Cardiac abnormalities may be assessed by Doppler echocardiography.⁷ Left- and right-sided heart diseases were found to be common in persons with SSc. A few patients had a restrictive mitral flow pattern, possibly due to primary cardiac involvement of SSc.
• Because cardiac involvement is one of the major problems in SSc, evaluation of ventricular function using echocardiographic strain imaging should be considered, because it appears to be useful to detect subclinical cardiac involvement in SSc patients with normal standard echocardiographic and tissue Doppler velocity findings.⁸

Other Tests

• With bronchoalveolar lavage (BAL), abnormal numbers of granulocytes, particularly neutrophils and eosinophils are present.
• Lung function tests reveal ventilation-perfusion changes, including the following:
• • Reduced carbon monoxide diffusion capacity
  • A reduced partial pressure of oxygen, with a normal or low partial pressure of carbon dioxide
  • Restrictive ventilatory defect, with reductions in pulmonary compliance, vital capacity, and total lung capacity
  • Decreased diffusion capacity of carbon monoxide transfer factor (DLCO) levels, which is a measure of diffusion capacity
• The gas transfer measurement (KCO), adjusted for alveolar volume, is also reduced.
• Heart changes, including myocardial disease, pericardial problems, conduction system disease, and arrhythmias, can be observed with the following tests:
• • Electrocardiography (ECG)
  • Holter 24-hour monitoring
  • Doppler ultrasonography (US)
• Exophthalmos, macroglossia, and/or gigantism may be present, with increased polyphasic potentials of normal or decreased amplitude.
• Antihistone antibodies can be observed in the course of SSc, but they are not characteristic. The following antinuclear antibodies (ANAs) are characteristic of scleroderma:
• • Antibodies against topoisomerase I DNA (Scl 70) are detected in the serum of patients with SSc. The antibodies are detected in two thirds of patients with dSSc and interstitial lung fibrosis.
  • Anticentromere antibodies (ACAs) are most commonly detected in patients with lSSc; in these patients, changes in the heart, kidneys, and lungs (without fibrosis) are observed less frequently than in other patients.
• ANAs can be detected in the course of SSc. ANAs include antibodies against fibrillarin, a 34-kd protein of ribonucleoprotein U3 RNP; antibodies against the ribonucleoprotein nucleolar 7-2 RNA protein particle Th RNP; and antibodies to 20-110-kd proteins related to preribosomes (PM-Scl). Anti-PM/Scl antibodies are seen in roughly 24% of patients with polymyositis/systemic sclerosis overlap syndrome. They are also found in 3-10% of SSc patients.^{9, 10}
• Elevated high-sensitivity C-reactive protein appears related to the occurrence of antimitochondria antibody in these patients.¹¹
• With capillary microscopy, enlarged capillaries are observed in all 3 portions of the capillary nail fold–arterial, apical, and venous– and especially at the edge of the nail fold. Adjacent areas are avascular.
• Spirometry demonstrates functional lung disturbances. In approximately 70% of patients, the DLCO is decreased.

Histologic Findings

In the active indurative phase, a loss of rete ridges occurs, epidermal skin appendages atrophy, and collagen fibers in the reticular dermis appear broad and hyalinized. A loss of space between collagen bundles is noted. Mononuclear cells, mostly T cells, form a variable perivascular infiltrate in the deep dermis and subcutis. Later, sclerotic changes predominate. The number of adnexal structures is reduced, and a loss of periadnexal fat is noted.

TREATMENT

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Medical Care

Different treatment regimens for SSC exist. The therapeutic approach depends on the presentation of the disease and complexity of symptoms.

• In pruritus, the following agents are sometimes helpful:
• • Camphor and menthol
  • Topical emollients
  • Psoralen UV-A (PUVA) treatment
• In patients with calcinosis, surgery may be of some benefit, but healing time is often prolonged.
• When Raynaud phenomenon is present, the most effective nonpharmacologic method of preventing Raynaud episodes is avoiding exposure to cold temperature and wearing layers of warm, loose-fitting clothing, including socks and gloves. Also, smoking cessation is advised. In the pharmacologic regimen, consider the use of agents such as calcium-channel blockers, vasodilating drugs, intravenous prostaglandins, prostacyclin analogs, or aspirin.
• In patients with kidney involvement, ACE inhibitor therapy is indicated.
• In patients with GI tract involvement, proton pump inhibitors (eg, omeprazole) and H2 blockers can help to control reflux symptoms.
• In patients with lung involvement, calcium-channel blockers (eg, nifedipine), prostaglandins (eg, prostacyclin), and cyclophosphamide have been used with variable success. When inflammatory myositis is present, the use of high doses of corticosteroids (eg, prednisolone with a starting dose of 1 mg/kg/d) is suggested.
• The following antifibrotic agents have been investigated, although results have varied and none is clearly shown to be of consistent benefit:
• • D-penicillamine
  • Interferon alfa and interferon gamma
  • Immunomodulatory agents
  • • Photopheresis¹²
    • Corticosteroids (in inflammatory myositis, pericarditis, refractory arthritis, or alveolitis)
    • Methotrexate (15 mg/wk)¹³
    • Chlorambucil
    • Cyclosporine¹⁴
    • FK506 (tacrolimus)
    • Thalidomide
    • Low-dose intravenous cyclophosphamide^{15, 16}
    • Statins¹⁷
    • Immunosuppressive drugs with autologous peripheral hematopoietic stem cell transplantation¹⁸

Consultations

The symptoms of SSc are diverse; therefore, consider consultations with the following specialists, if applicable:

• Dermatologist
• Pulmonologist
• Nephrologist
• Radiologist
• Cardiologist
• Orthopedic surgeon

MEDICATION

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Treatment regimens have enormous diversity. Currently, no standard therapy is available for skin sclerosis. Raynaud phenomenon often responds to calcium channel blockers, and scleroderma kidney disease often responds to angiotensin-converting enzyme and angiotensin II inhibitors. The treatment depends on the presentation of SSc.

Drug Category: Immunomodulatory agents

These agents are used to stop disease progression. They act on the host's immune system; they suppress the immune system to prevent fibrosis.

Drug Category: Antifibrotic agents

These agents are used to decrease fibrosis by interference with collagen metabolism.

Drug Category: Vasoactive agents

These agents are used to modify disease with its vasoactive actions.

Drug Category: Antiplatelet agents

These agents inhibit the cyclo-oxygenase system, decreasing the level of thromboxane A₂, which is a potent platelet activator.

Drug Category: Antihypertensive agents

These agents are used to reduce blood pressure.

FOLLOW-UP

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Further Inpatient Care

Female patients should be evaluated for breast cancer. Epidemiologic studies have suggested that patients with scleroderma have an increased risk of cancer. However, large-scale case-control studies are needed to substantiate a possible association between scleroderma—both cutaneous and systemic—and breast cancer.¹⁹

Complications

• Neoplastic diseases may complicate the disease course.
• Examples include breast carcinoma; multiple myeloma; lymphoma; and cancer of the ovary, esophagus, colon, or rectum.

Prognosis

• The prognosis depends on the type of SSc.
• In lSSc, a patient's condition can be stable for years.
• However, in dSSc, the disease can rapidly lead to death, if it is not treated promptly.

Patient Education

• The most effective method for preventing a Raynaud episode is to avoid exposure to cold temperatures.
• Smoking cessation should be discussed with patients and their families, as applicable.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• Capillary nail fold changes are one of the earliest signs of SSc.

Special Concerns

• ANA serum levels in patients with SSc are not correlated with disease activity.
• The undeniable impact of SSc on quality of life underscores the need for a biopsychosocial approach to the clinical management. Timely detection of psychosocial difficulties and appropriate psychological or psychiatric intervention are also important steps toward better adherence to medical treatment.²⁰

MULTIMEDIA

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Media file 1:  Face of 65-year old woman with systemic sclerosis and skin thickening of 20 years' duration: Note the pinched nose, taut skin with numerous telangiectasias, and retraction of the lips.
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Media file 2:  Telangiectasias affecting the face: They are pronounced and numerous, especially in the atrophic phase of the disease. Radical furrowing around the mouth is also characteristic in the later stage of the disease.
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Media file 3:  Raynaud phenomenon of the hands: Symmetrical acral vasospasm is present, with characteristic pallor, cyanosis, suffusion, and a sense of fullness and tautness.
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Media file 4:  Puffy appearance of the woman's hand in the edematous phase of early scleroderma.
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Media file 5:  In systemic sclerosis, ulceration at the tip of the finger is regarded to be secondary to ischemia.
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Media file 6:  Hand of a woman with scleroderma of several years' duration: The thickened, tight, thin skin over the fingers is the result of self-amputation of the distal phalanx due to ischemia. Moderately severe flexion contractures of the fingers are present.
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Media file 7:  In systemic sclerosis, skin hyperpigmentation of the lower legs is surrounded by areas of hypopigmentation. The result is a salt-and-pepper appearance.
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Media type:  Photo

REFERENCES

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Article Last Updated: Mar 11, 2008