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.
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.
SSc is a rare disease. SSc is diagnosed in approximately 67 male patients and 265 female patients per 100,000 people each year.
SSc is estimated to occur in 2.3-10 people per 1 million. SSc is rare in the resident population of Japan and China.
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.
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.
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.
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.
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.
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 patients3, 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
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.
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)
Organic solvents (eg, toluene, benzene, xylene)
Aliphatic hydrocarbons (eg, hexane, vinyl chloride, trichloroethylene)
Amino acid compound L-5-hydroxytryptophan
Drugs (eg, bleomycin, carbidopa, pentazocine, cocaine, penicillamine, vitamin K)
Appetite suppressants (eg, phenylethylamine derivatives)
Substances used in cosmetic procedures (eg, silicone or paraffin implants)