Systemic Sclerosis

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Background

Systemic sclerosis (SSc) is a systemic connective tissue disease. Characteristics of systemic sclerosis 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.

Also see Systemic Sclerosis for a pediatric focus.

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 systemic sclerosis. 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 systemic sclerosis. 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 systemic sclerosis 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 systemic sclerosis. Some data suggest that apoptosis and the generation of free radicals may be involved in the pathogenesis of systemic sclerosis.

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

Epidemiology

Frequency

United States

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

International

Systemic sclerosis is estimated to occur in 2.3-10 people per 1 million. Systemic sclerosis 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 systemic sclerosis. Pulmonary hypertension leads to 12% of systemic sclerosis–related deaths. Lung fibrosis and heart changes are responsible for 9% of systemic sclerosis – related deaths.

Race

No apparent racial predominance exists. However, systemic sclerosis is rare in the resident population of Japan and China. Diffuse systemic sclerosis (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 systemic sclerosis (lSSc) has a strong female predominance, with a female-to-male ratio of 10:1. Another analysis showed that men tend to have diffuse disease and women to have calcinosis.[2]

Age

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

History

Systemic sclerosis can have many different presentations. It involves the skin and many internal organs. Therefore, the presenting symptoms may differ among patients. Note the following history findings:

Physical

According to the American College of Rheumatology (ACR), features characteristic for scleroderma are divided into the following 2 groups (systemic sclerosis 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. Note the images below.


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Face of 65-year old woman with systemic sclerosis and skin thickening of 20 years' duration: Note the pinched nose, taut skin with numerous telangiect....


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Telangiectasias affecting the face: They are pronounced and numerous, especially in the atrophic phase of the disease. Radical furrowing around the mo....


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Puffy appearance of the woman's hand in the edematous phase of early scleroderma.

Systemic sclerosis 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:

lSSc is characterized by sclerotic changes of the hands, face, feet, and forearms in addition to the following features (note the images below):

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.

GI involvement can be serious.[8] Upper GI symptoms are generally more prominent than lower GI ones.

Pain is common those with systemic sclerosis and is independently associated with frequent episodes of Raynaud phenomenon, active ulcers, severe synovitis, and GI symptoms.[9]

Causes

Systemic sclerosis 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:

Laboratory Studies

The following findings may be found with laboratory studies:

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.[15] Manometric esophageal changes may be observed during invasive examination.

Cardiac and pulmonary vascular involvement in systemic sclerosis should be evaluated. Cardiac abnormalities may be assessed by Doppler echocardiography.[16] Left- and right-sided heart diseases were found to be common in persons with systemic sclerosis. A few patients had a restrictive mitral flow pattern, possibly due to primary cardiac involvement of systemic sclerosis.

Because cardiac involvement is one of the major problems in systemic sclerosis, evaluation of ventricular function using echocardiographic strain imaging should be considered, because it appears to be useful to detect subclinical cardiac involvement in systemic sclerosis patients with normal standard echocardiographic and tissue Doppler velocity findings.[17]

Since the initial changes in systemic sclerosis are believed to involve microcirculation, its evaluation using laser Doppler flowmetry in the distal portion of the upper extremity has been advocated.[18]

Other Tests

With bronchoalveolar lavage (BAL), abnormal numbers of granulocytes, particularly neutrophils and eosinophils are present in BAL fluid. In addition, the concentration of vascular endothelial growth factor may be low.[19]

Lung function tests reveal ventilation-perfusion changes, including the following:

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:

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 systemic sclerosis, but they are not characteristic. The following antinuclear antibodies (ANAs) are characteristic of scleroderma:

ANAs can be detected in the course of systemic sclerosis. 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 systemic sclerosis patients.[20, 21] The spectrum of systemic sclerosis-associated ANA differs in patients with and without cutaneous involvement.[22]

Elevated high-sensitivity C-reactive protein appears related to the occurrence of antimitochondrial antibody in these patients.[23]

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.

In one study, progressive systemic sclerosis histologic changes were systematically scored in skin biopsy specimens of dorsal forearm and upper inner arm in 53 consecutive patients and controls. The amount of hyalinized collagen, myofibroblasts, mean epidermal thickness, the mononuclear cellular infiltration, and the frequency of focal exocytosis varied significantly between those with and those without local clinical skin involvement.[24]

Medical Care

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

In pruritus, the following agents are sometimes helpful:

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.[25]

In patients with kidney involvement, ACE or angiotensin II 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.

Antifibrotic agents have been investigated, although results have varied and none is clearly shown to be of consistent benefit. These have included D-penicillamine, interferon alfa and interferon gamma, and immunomodulatory agents. Immunomodulatory agents have included the following:

Additionally, with its antifibrotic properties, imatinib mesylate may be a potential therapy.[35, 36]

Surgical Care

The cutaneous telangiectasias can be treated. The number of pulsed dye laser treatments required to effectively clear systemic sclerosis/CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) syndrome telangiectasia was approximately 2-fold higher than with sporadic telangiectasias, a finding attributed to thickened collagen fibers and blood vessels.[37] Pulsed dye laser (PDL) and intense pulsed light (IPL) may be used, both being effective, although the former produces a better cosmetic result but with more adverse effects than the latter.[38]

Consultations

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

Medication Summary

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 systemic sclerosis. The efficacy and safety of lidocaine in treating scleroderma has been questions, with an analysis showing a lack of efficacy.[39]

Prednisone (Deltasone, Meticorten, Orasone, Sterapred)

Clinical Context:  Immunosuppressant used for the treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes. Suppresses lymphocytes and antibody production.

Methotrexate (Rheumatrex)

Clinical Context:  Antimetabolite that inhibits dihydrofolate reductase, thereby hindering DNA synthesis and cell reproduction. Satisfactory response is observed in 3-6 wk after administration. Adjust dose gradually to achieve satisfactory response.

Chlorambucil (Leukeran, Leukeran)

Clinical Context:  Alkylates and cross-links strands of DNA, inhibiting DNA replication and RNA transcription.

Cyclosporine (Neoral, Sandimmune)

Clinical Context:  Helpful in a variety of skin disorders.

Tacrolimus (Prograf)

Clinical Context:  Suppresses humoral (T-lymphocyte) immunity.

Cyclophosphamide (Neosar, Cytoxan)

Clinical Context:  Chemically related to nitrogen mustards.

As an alkylating agent, the mechanism of action of the active metabolites may involve DNA cross-linking, which may interfere with growth of healthy and neoplastic cells.

Class Summary

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

Penicillamine (Cuprimine, Cuprimine, Depen)

Clinical Context:  Metal chelation agent used to treat arsenic poisoning. Forms soluble complexes with metals excreted in urine.

Colchicine

Clinical Context:  Decreases leukocyte motility and phagocytosis in inflammatory responses.

Class Summary

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

Nifedipine (Adalat, Procardia)

Clinical Context:  Relaxes coronary smooth muscle and causes coronary vasodilation, which, in turn, improves myocardial oxygen delivery. Sublingual administration generally is safe, despite theoretic concerns.

Class Summary

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

Aspirin (Bayer Buffered Aspirin, Bayer Aspirin, Anacin)

Clinical Context:  Inhibits prostaglandin synthesis, preventing the formation of platelet-aggregating thromboxane A2. May be used in low doses to inhibit platelet aggregation and improve complications of venous stases and thrombosis.

Class Summary

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

Reserpine

Clinical Context:  Depletes norepinephrine and epinephrine. This effect, in turn, depresses sympathetic nerve functions, decreasing the heart rate and lowering the arterial blood pressure.

Methyldopa (Aldomet)

Clinical Context:  Stimulates central alpha-adrenergic receptors, resulting in decreased sympathetic outflow. Results in inhibition of vasoconstriction.

Class Summary

These agents are used to reduce blood pressure.

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.[40]

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 systemic sclerosis (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. Pulmonary hypertension may be an important cause of mortality in these patients. Survival complicated by pulmonary hypertension remains poor despite currently available treatment options.[41] Pulmonary hypertension was documented 25% of elderly patients, yet only in 12% of the youngest ones in a large study that stressed the differences in early- versus late-onset systemic sclerosis.[42] Cigarette smoking has been found to reduce overall survival.[43]

Author

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, Rutgers New Jersey Medical School

Disclosure: Nothing to disclose.

Coauthor(s)

Anna Sysa-Jedrzejowska, MD, PhD, Head, Professor, Department of Dermatology and Venereology, Medical University of Lodz, Poland

Disclosure: Nothing to disclose.

Anna Zalewska, MD, PhD, Professor of Dermatology and Venereology, Psychodermatology Department, Chair of Clinical Immunology and Microbiology, Medical University of Lodz, Poland

Disclosure: Nothing to disclose.

Bozena Dziankowska-Bartkowiak, MD, PhD, Consulting Staff, Department of Dermatology, University Hospital, Medical University of Lodz, Poland

Disclosure: Nothing to disclose.

Specialty Editors

Mark W Cobb, MD, Consulting Staff, WNC Dermatological Associates

Disclosure: Nothing to disclose.

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

Disclosure: Nothing to disclose.

Jeffrey P Callen, MD, Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine

Disclosure: Auxillium Honoraria Consulting; Stiefel, a GSK company Honoraria Consulting; UpToDate Honoraria author/editor; JAMA Dermatology Honoraria Associate editor and intermittent author; Elsevier Royalty Book author/editor; Stock holdings in various trust accounts include some pharmaceutical companies and device makers I do not control these accounts, but have directed our managers to divest pharmaceutical stocks as is fiscally prudent I inherited these trust accounts

Catherine M Quirk, MD, Clinical Assistant Professor, Department of Dermatology, University of Pennsylvania

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Ackerman Academy of Dermatopathology, New York

Disclosure: Nothing to disclose.

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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.

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.

Puffy appearance of the woman's hand in the edematous phase of early scleroderma.

In systemic sclerosis, skin hyperpigmentation of the lower legs is surrounded by areas of hypopigmentation. The result is a salt-and-pepper appearance.

Raynaud phenomenon of the hands: Symmetrical acral vasospasm is present, with characteristic pallor, cyanosis, suffusion, and a sense of fullness and tautness.

In systemic sclerosis, ulceration at the tip of the finger is regarded to be secondary to ischemia.

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.

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.

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.

Raynaud phenomenon of the hands: Symmetrical acral vasospasm is present, with characteristic pallor, cyanosis, suffusion, and a sense of fullness and tautness.

Puffy appearance of the woman's hand in the edematous phase of early scleroderma.

In systemic sclerosis, ulceration at the tip of the finger is regarded to be secondary to ischemia.

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.

In systemic sclerosis, skin hyperpigmentation of the lower legs is surrounded by areas of hypopigmentation. The result is a salt-and-pepper appearance.