DEFINITION AND ETIOLOGY

Scleroderma, or systemic sclerosis (SSc), is a chronic multisystem autoimmune disease characterized by a vasculopathy, diffuse fibrosis of skin and various internal organs, and immune abnormalities. The clinical manifestations of this disease are extremely heterogeneous and depend on the presence and degree of various internal organ involvement.

CLASSIFICATION

There are two major forms of scleroderma, localized scleroderma and systemic scleroderma (sclerosis). Diffuse (dcSSc) and limited (lcSSc) scleroderma are the two main types of systemic sclerosis.

Localized Scleroderma

The more common form of the disease, localized scleroderma, only affects the skin without any internal organ involvement. It often appears in the form of waxy patches (morphea) (Fig. 1A), or streaks on the skin (linear scleroderma). It is not uncommon for this less-severe form of scleroderma to regress or stop progressing without treatment (Box 1). Localized scleroderma can be disfiguring and sometimes requires systemic therapy to control disease activity.

Figure 1 Clinical manifestations of scleroderma.

A, Generalized morphea. B, Diffuse edema of hands. C, Firm, thickened skin. D, Flexion contractures of fingers. E, Raynaud’s phenomenon (pallor phase). F, Ischemic digital ulcer. G, Telangectasias on the face (a), dorsum of the hand (b), mucosa (c). H, Calcinosis cutis.

Box 1
Classification of Scleroderma

Localized Scleroderma (Localized cutaneous fibrosis)

Limited or generalized morphea: Circumscribed patches of sclerosis

Linear scleroderma: Linear lesions seen in childhood

En coup de sabre: Linear lesions of the scalp or face

Systemic Scleroderma (Cutaneous and noncutaneous involvement)

Limited cutaneous systemic sclerosis (lcSSc), formerly called CREST syndrome (calcinosis of the digits, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias)

Diffuse cutaneous systemic sclerosis (dcSSc): Sclerosis of proximal extremities, trunk, and face

Systemic sclerosis sine scleroderma (ssSSc): Organ fibrosis only; no skin thickening

EPIDEMIOLOGY

Systemic scleroderma is a rare disorder, with an annual incidence in the United States of about 20 cases per 1 million adults.² Several studies have estimated the prevalence of systemic sclerosis in the United States to be around 240 cases per 1 million adults.³ International reports from Britain and Japan suggest a lower prevalence of around 35 cases per 1 million adults.³ Women are roughly four times more likely than men to develop systemic scleroderma. African Americans are at greater risk for diffuse disease.^2,3 Most patients with systemic scleroderma present in the third or fourth decade of life.

Age- and gender-adjusted mortality rates for patients with dcSSc are approximately five to eight times greater than those of the general population.³ Survival, which is strongly dependent on the degree of internal organ involvement, has improved over the past few decades due to the advent of newer classes of drugs. The average 10-year survival rate is now 70% to 80%.⁴ Diffuse disease has a variable disease course, but it still carries a relatively poor prognosis. Progressive pulmonary fibrosis, pulmonary hypertension, severe gastrointestinal involvement, and scleroderma heart disease are the main causes of death. Limited disease has a relatively better prognosis except when pulmonary hypertension develops as a late complication. In a large cohort of patients in metropolitan Detroit, the poor prognostic markers were found to be older age at onset, male gender, African American race, and involvement of certain organ systems (heart, interstitial lung disease, pulmonary hypertension, and severe gastrointestinal disease).²

PATHOPHYSIOLOGY AND PATHOGENESIS

Scleroderma is characterized by immune system activation, endothelial dysfunction, and enhanced fibroblast activity.⁵

The earliest stage in the development of the scleroderma lesion is endothelial cell activation and vascular damage, the precise inciting events of which are unknown. This is followed by the extravasation of inflammatory cells, which initially are of the monocytic lineage. Later, there is a lymphocyte-predominant infiltrate. Eventually, a population of fibroblasts is activated. The autonomous activated fibroblasts continue to produce the excessive extracellular matrix that underlies the ultimate fibrotic pathology of scleroderma. Within the advanced lesional skin, there is very little visible evidence of ongoing inflammation, suggesting that this is a self-perpetuating fibrotic process.

The endothelium contributes to the regulation of the contraction and relaxation of vascular smooth muscle cells through the production and release of endothelium-derived vasoactive substances including prostacyclin (prostaglandin [PG]I₂), endothelium-derived relaxing factor (EDRF or nitric oxide), and endothelin. The impairment of endothelium-dependent vascular smooth muscle relaxation has been confirmed by the evidence of reduced serum levels of nitric oxide and prostacyclin in scleroderma. This state is probably worsened by increased endothelin levels that contribute to vasospasm and smooth muscle hypertrophy.

Vascular injury occurs before clinically evident fibrosis. There is an altered functional state of the endothelium characterized by increased permeability, enhanced vasoreactivity, enhanced expression of adhesion molecules, altered balance between hemostatic and fibrinolytic factors, platelet activation, and altered vascular wall growth. Most damage occurs at the level of the cutaneous circulation and in the microvasculature of various internal organs.⁴ Small arteries and capillaries constrict. Fibroproliferative changes in the vasculature ensue later, eventually leading to obliteration of the vascular lumen, resulting in ischemia.

Endothelin-1 plays an important role in the pathogenesis of scleroderma. Elevated plasma endothelin is seen in scleroderma-associated pulmonary hypertension. During an episode of Raynaud’s phenomenon, endothelin release is augmented. Increased endothelin-1 is also found in the bronchoalveolar lavage fluid from scleroderma patients and in prescleroderma skin and early diffuse skin lesions. Scleroderma lung fibroblasts shows elevated endothelin-1 expression and increases in endothelin-1 binding sites.

There are many other potent mediators of tissue fibrosis that are believed to play an important role in the pathogenesis of scleroderma. One of the key factors that has received the most attention as a very potent profibrotic factor, indirectly implicated very strongly in the pathogenesis of systemic sclerosis, is transforming growth factor (TGF)-β1. A number of studies have shown that TGF-β1 is a potent profibrotic factor in vitro and that TGF-β1 ligand expression is upregulated in the skin and the lungs of scleroderma patients. In very early lesional skin, immunostaining shows TGF-β1 ligand expression. There is also disruption of TGF-β1 receptor expression leading to modulation of TGF-β activity.

Other key growth factors that have also been implicated in the pathogenesis are connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF) and the beta chemokines monocyte chemoattractant protein (MCP)-1 and MCP-3. There may be a sequential interplay between these growth factors as the disease develops. Chemokine expression is an early feature of skin sclerosis, and fibroblasts are producers of these chemokines. Data suggest that PDGF receptor and ligand expression, and tumor necrosis factor (TNF)-α expression also occur. All of these factors are considered to be important early in the pathogenesis of scleroderma. Connective tissue growth factor was originally speculated to be an important downstream mediator of TGF-β1, but now it seems more likely to be a cofactor in TGF-β1–mediated activation of fibroblasts.

CLINICAL MANIFESTATIONS

Clinical manifestations of systemic sclerosis are heterogeneous and vary as a result of type of disease (limited or diffuse) and organ involvement (Box 3). Patients with diffuse disease (dcSSc) are at risk of developing rapidly progressive skin fibrosis and widespread, severe, internal organ involvement. Patients with lcSSc have a disease course characterized by slowly progressive skin changes not extending beyond the elbows and knees into the proximal extremities or trunk, along with varying degrees of internal organ involvement.

Raynaud’s phenomenon is present in most patients with systemic sclerosis and is often the earliest manifestation of disease. In patients with limited disease, it may be present for years before clinically significant skin changes or internal organ involvement develops. Although some patients with Raynaud’s phenomenon may not develop the entire spectrum of triphasic color changes (pallor, dusky cyanosis, and red engorgement),⁴ most have digital pallor in response to cold or stress.

Cutaneous changes usually begin with an early phase of skin edema, manifested as swollen fingers and hands (see Fig. 1B). In dcSSc, these changes are followed by the development of firm, thickened skin over the extremities (see Fig. 1C), trunk, and face. The patients in whom these changes develop more rapidly are at greater risk for serious internal organ involvement such as pulmonary fibrosis and renal failure. Skin thickening typically peaks in the first 3 to 5 years.⁶ As a result of skin thickening, flexion contractures can develop over joints (see Fig. 1D). Skin thickening may then begin to regress slowly over time. In patients with lcSSc, early symptoms include Raynaud’s phenomenon (see Fig. 1E) and ischemic digital ulceration (see Fig. 1F). Skin thickening and digital edema are confined to the distal extremities (distal to the elbows and the knees). As the disease progresses, there may be an increase in cutaneous telangiectasias on the face and hands (see Fig. 1G[a] and [b]), calcinosis cutis (see Fig. 1H), and ischemic digital ulcers. Sometimes mucosal telangiectasias also develop (see Fig. 1G[c]).

Patients may complain of dyspnea or a nonproductive cough as a manifestation of underlying pulmonary disease. Some patients may be asymptomatic but have changes on physical examination (basilar rales) or on chest radiography (lower-lobe interstitial infiltrates). Shortness of breath, fatigue, chest pain, and occasionally syncope may be warning signs of pulmonary arterial hypertension. In this situation, physical examination can reveal a loud pulmonary second sound (P₂), left parasternal heave, lower-extremity edema, and other signs of right-sided heart failure. Pulmonary function tests may be abnormal and can reveal restrictive changes even in the absence of radiographic changes or exertional dyspnea. Patients with dcSSc often develop interstitial lung disease, and about 20% to 30% of patients with lcSSc later develop pulmonary arterial hypertension without interstitial lung disease. Patients with dcSSc and rapidly progressive skin changes or those with antitopoisomerase-1 anti-bodies (anti-Scl-70) are at risk for earlier onset of severe pulmonary disease.⁷

Scleroderma renal crisis is characterized by the development of severe hypertension, renal failure, and microangiopathic hemolytic anemia. A small subset (10%) of patients develop normotensive renal crisis.⁸ Patients with rapidly progressive diffuse skin fibrosis, antecedent use of glucocorticoids, presence of RNA polymerase III antibody, or those with a new onset pericardial effusion are at greatest risk. The development of renal crisis is not seen in patients with lcSSc. Most cases occur in the first few years of dcSSc. Renal failure can follow a rapidly progressive course, and early recognition and control of hypertension with angiotensin-converting enzyme inhibitors are critical.

Gastrointestinal involvement is common in both forms of systemic sclerosis. Atrophy of the muscularis mucosa and submucosal fibrosis result in varying degrees of esophageal and other gastrointestinal dysfunction. Complaints of dysphagia and heartburn are common and often signal the development of esophageal dysmotility. Esophageal disease results in reflux esophagitis, esophageal strictures, and eventual development of an atonic esophagus. Gastric antral vascular ectasias (GAVE or watermelon stomach) can lead to chronic upper gastrointestinal bleeding and iron-deficiency anemia (Fig. 2). Gastric dysmotility is not rare and can lead to postprandial bloating and early satiety. Small intestinal motility may also be affected, resulting in constipation, varying degrees of malabsorption, and bacterial overgrowth (causing episodes of diarrhea). Severe constipation may develop from colonic hypomotility. Gastrointestinal bleeding is infrequent, but may occur from erosive esophagitis, GAVE, and wide-mouth diverticula in the colon. Pneumatosis cystoides intestinalis can manifest as an acute abdomen, leading to unnecessary laparotomy. Fecal incontinence may develop due to fibrosis of the anal sphincter. Patients with lcSSc sometimes develop primary biliary cirrhosis.

Figure 2 Watermelon stomach (gastric antral vascular ectasias [GAVE]).

From Miller ML: Winners of the 2002 American College of Rheumatology Annual Slide Competition [submitted by April Chang-Miller and Mark V. Larson]. Arthritis Rheum 2003;48(10):2737-2738.

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