eMedicine Specialties > Dermatology > Connective Tissue Diseases

Systemic Sclerosis

Author: Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Coauthor(s): Bozena Dziankowska-Bartkowiak, MD, PhD, Consulting Staff, Department of Dermatology, University Hospital, Medical University of Lodz, Poland; Anna Zalewska, MD, PhD, Assistant Professor, Adjunct Professor, Department of Dermatology and Venereology, Medical University of Lodz, Poland; Anna Sysa-Jedrzejowska, MD, PhD, Head, Professor, Department of Dermatology and Venereology, Medical University of Lodz, Poland
Contributor Information and Disclosures

Updated: May 5, 2009

Introduction

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.

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.

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.

Clinical

History

Systemic sclerosis can have 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. Systemic sclerosis 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 systemic sclerosis 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 College of Rheumatology (ACR), 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.
    • Systemic sclerosis is diagnosed when a patient has 1 major and 2 minor criteria.
Face of 65-year old woman with systemic sclerosis...

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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Face of 65-year old woman with systemic sclerosis...

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 pron...

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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Telangiectasias affecting the face: They are pron...

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.

  • Cutaneous involvement has 3 phases: (1) edematous, (2) indurative, and (3) atrophic. Skin becomes thickened and tight.
Puffy appearance of the woman's hand in the edema...

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

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Puffy appearance of the woman's hand in the edema...

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:
    • Generalized skin fibrosis of the chest and limbs
    • Areas of skin hyperpigmentation and hypopigmentation
In systemic sclerosis, skin hyperpigmentation of ...

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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In systemic sclerosis, skin hyperpigmentation of ...

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


    • Tendon friction rubs
    • Early involvement of the lungs, kidneys, digestive system, and heart
    • Antibodies against topoisomerase I DNA (Scl 70) in approximately 30% of patients3,4
    • Nail-fold capillary dilatation and capillary destruction


Raynaud phenomenon of the hands: Symmetrical acra...

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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Raynaud phenomenon of the hands: Symmetrical acra...

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

  • 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
In systemic sclerosis, ulceration at the tip of t...

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

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In systemic sclerosis, ulceration at the tip of t...

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...

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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Hand of a woman with scleroderma of several years...

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.

  • 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

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:

  • 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): A limited form of cutaneous systemic sclerosis has been described with paclitaxel in with the setting of breast cancer.5
  • Appetite suppressants (eg, phenylethylamine derivatives)
  • Substances used in cosmetic procedures (eg, silicone or paraffin implants)

More on Systemic Sclerosis

Overview: Systemic Sclerosis
Differential Diagnoses & Workup: Systemic Sclerosis
Treatment & Medication: Systemic Sclerosis
Follow-up: Systemic Sclerosis
Multimedia: Systemic Sclerosis
References
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Further Reading

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Keywords

systemic sclerosis, SSc, progressive systemic sclerosis, scleroderma, systemic connective tissue disease, diffuse systemic sclerosis, dSSc, limited systemic sclerosis, lSSc, transitory systemic sclerosis, dSSc/lSSc, systemic scleroderma sine scleroderma, malignant scleroderma

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Contributor Information and Disclosures

Author

Robert A Schwartz, MD, MPH, Professor and Head, Dermatology, Professor of Pathology, Pediatrics, Medicine, and Preventive Medicine and Community Health, UMDNJ-New Jersey Medical School
Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and Sigma Xi
Disclosure: Nothing to disclose.

Coauthor(s)

Bozena Dziankowska-Bartkowiak, MD, PhD, Consulting Staff, Department of Dermatology, University Hospital, Medical University of Lodz, Poland
Disclosure: Nothing to disclose.

Anna Zalewska, MD, PhD, Assistant Professor, Adjunct Professor, Department of Dermatology and Venereology, Medical University of Lodz, Poland
Disclosure: Nothing to disclose.

Anna Sysa-Jedrzejowska, MD, PhD, Head, Professor, Department of Dermatology and Venereology, Medical University of Lodz, Poland
Disclosure: Nothing to disclose.

Medical Editor

Mark W Cobb, MD, Consulting Staff, WNC Dermatological Associates
Mark W Cobb, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, and American Society of Dermatopathology
Disclosure: Nothing to disclose.

Pharmacy Editor

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Managing Editor

Jeffrey P Callen, MD, Professor of Medicine, Chief, Division of Dermatology, University of Louisville School of Medicine
Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American College of Physicians, and American College of Rheumatology
Disclosure: Amgen Honoraria Consulting; Abbott Honoraria Consulting; Electrical Optical Sciences Honoraria Consulting; Centocor Honoraria Consulting; Genetech Honoraria Consulting; Celgene Honoraria Consulting

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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