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Published: August, 2010

Systemic Scleroderma

Soumya Chatterjee

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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.

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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) (Figure 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.

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

Systemic Scleroderma

Systemic scleroderma always leads to some internal organ involvement. It is further divided into two subsets of disease, limited or diffuse (see Box 1). According to LeRoy and colleagues, limited or diffuse disease is based on the extent of skin tightening.1 In limited disease (formerly called CREST [calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias] syndrome), skin tightening is confined to the fingers, hands, and forearms distal to the elbows, with or without tightening of skin of the feet and of the legs distal to the knees. Proximal extremities and the trunk are not involved. In diffuse disease or diffuse cutaneous systemic sclerosis (dcSSc), the skin of the proximal extremities and trunk is also involved. Both dcSSc and lcSSc are associated with internal organ involvement; however, patients with dcSSc are at greater risk for clinically significant major organ dysfunction (Box 2). Systemic sclerosis sine scleroderma (ssSSc) is a rare disorder in which patients develop vascular and fibrotic damage to internal organs (phenotypically similar to that in limited scleroderma), in the absence of cutaneous sclerosis.

Box 2: Subsets of Systemic Sclerosis
Diffuse Cutaneous Systemic Sclerosis (dcSSc)
  • Onset of Raynaud's within 1 year of onset of skin changes (puffy or hidebound skin)
  • Truncal and acral skin involvement
  • Presence of tendon friction rubs
  • Early and significant incidence of interstitial lung disease, oliguric renal failure, diffuse gastrointestinal disease, and myocardial involvement
  • Absence of anticentromere antibodies
  • Nailfold capillary dilation and capillary destruction
  • Antitopoisomerase antibodies (30% of patients)
Limited Cutaneous Systemic Sclerosis (LcSSc)
  • Raynaud's phenomenon for years (occasionally decades)
  • Skin involvement limited to hands, face, feet, and forearms (acral) or absent
  • A significant late incidence of pulmonary hypertension, with or without interstitial lung disease, trigeminal neuralgia, skin calcifications, telangiectasias
  • A high incidence of anticentromere antibodies (70%-80%)
  • Dilated nailfold capillary loops, usually without capillary dropout

Adapted from LeRoy EC, Black C, Fleischmajer R, et al: Scleroderma (systemic sclerosis): Classification, subsets and pathogenesis. J Rheumatol 1988;15:202-205.

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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

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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.

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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.

Box 3: Major Clinical Manifestations of Systemic Sclerosis
Cutaneous
  • Diffuse edema of hands and feet (early stages)
  • Progressive skin tightening
  • Sclerodactyly
  • Calcinosis
  • Telangiectasias
  • Digital ulcers and pits
  • Contractures
  • Hyperpigmentation, hypopigmentation, salt and pepper skin
  • Characteristic facies
Vascular
  • Raynaud's phenomenon
  • Nailfold capillary changes
  • Digital ischemia and ulcers
  • Vasculitic leg ulcers (rare)
Pulmonary
  • Interstitial lung disease, including alveolitis and interstitial fibrosis
  • Pulmonary hypertension
  • Recurrent aspiration pneumonitis caused by esophageal reflux and dysmotility
  • Chest wall restriction (decreased thoracic compliance)
  • Respiratory muscle weakness
Cardiac
  • Cardiomyopathy (systolic and diastolic dysfunction): Congestive heart failure
  • Conduction defects
    • Septal infarction pattern
    • Ventricular conduction abnormalities
    • Arrhythmias
    • Heart blocks
  • Pericarditis or pericardial effusion (impending renal crisis)
Renal
  • Scleroderma renal crisis (hypertension, renal failure MAHA)
Musculoskeletal and Rheumatologic
  • Arthralgia
  • Tendon friction rubs (relatively specific for diffuse scleroderma)
  • Inflammatory arthritis, erosive arthropathy (rare)
  • Myopathy, myositis
Gastrointestinal
  • Gastroesophageal reflux
  • Esophageal dysmotility, aperistaltic esophagus
  • Esophageal stricture
  • Adenocarcinoma arising in Barrett's esophagus (occasionally)
  • Watermelon stomach (gastric antral vascular ectasias [GAVE]): Iron-deficiency anemia
  • Decreased peristalsis throughout the GI tract, leading to bloating, early satiety, stasis, and pseudo-obstruction
  • Bacterial overgrowth and malabsorptive diarrhea, alternating diarrhea and constipation
  • Megacolon (rare)
  • Colonic wide-mouth diverticuli (usually asymptomatic)
  • Pneumatosis cystoides intestinales
  • Primary biliary cirrhosis
  • Anal incontinence
Endocrine
  • Hypothyroidism
Neurologic
  • Carpal tunnel syndrome
  • Trigeminal neuralgia

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 Figure 1B). In dcSSc, these changes are followed by the development of firm, thickened skin over the extremities (see Figure 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 Figure 1D). Skin thickening may then begin to regress slowly over time. In patients with lcSSc, early symptoms include Raynaud's phenomenon (see Figure 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 Figure 1G[a] and [b]), calcinosis cutis (see Figure 1H), and ischemic digital ulcers. Sometimes mucosal telangiectasias also develop (see Figure 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 (Figure 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.

Although subclinical cardiac involvement is common (in autopsy studies), clinical manifestations of cardiac involvement are fortunately rare. Myocardial fibrosis may develop in patients with dcSSc, resulting in cardiac failure, arrhythmias, and conduction defects. Other features of systemic scleroderma include dry eyes and mouth (due to secondary Sjögren's syndrome) and hypothyroidism. Musculoskeletal involvement is common and can manifest as nonspecific myalgias and arthralgias. True arthritis is rare. Muscle weakness may also occur, associated with elevation of serum levels of muscle enzymes. A true scleroderma-polymyositis overlap syndrome occurs in some cases, and is more commonly seen in children. Erectile dysfunction in men is common and is partly attributed to impaired local circulation.

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Diagnosis

The diagnosis of systemic scleroderma is usually made on the basis of the characteristic cutaneous finding of skin thickening, in association with Raynaud's phenomenon and varying degrees of internal organ involvement. In early disease, Raynaud's phenomenon may be the only manifestation. Nailfold capillaroscopy (Figure 3) may be helpful in determining whether Raynaud's phenomenon is primary (Raynaud's disease) (see Figure 3A) or is secondary to a systemic autoimmune disorder such as scleroderma (see Figure 3B to D).9 Other disorders associated with scleroderma-like skin changes, such as eosinophilic fasciitis and nephrogenic systemic fibrosis, are not associated with Raynaud's phenomenon or nailfold vascular changes.

Diagnostic criteria for scleroderma have been proposed by the American College of Rheumatology (Box 4).10 However, there are limitations regarding their usefulness, especially for lcSSc, and experts have recommended some modifications to the original criteria.9

Box 4: American College of Rheumatology Diagnostic Criteria for Systemic Sclerosis
Major Criterion
  • Proximal sclerodermatous skin changes (proximal to the metacarpophalangeal joints)
Minor Criteria*
  • Sclerodactyly
  • Digital pitting scars of fingertips or loss of substance of the distal finger pads
  • Bibasilar pulmonary fibrosis

*The patient should fulfill the major criterion or two of the three minor criteria.
Adapted from Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum 1980;23:581-590.


A complete blood count, complete metabolic panel, muscle enzymes, thyroid function test, and urinalysis are indicated in all patients. Serologic testing for autoantibodies can be helpful in diagnosing and classifying systemic sclerosis.11 However, none of the serologic tests is sensitive enough to independently exclude disease. Antinuclear antibody (ANA) is positive in 60% to 80% of patients with scleroderma. Anticentromere antibodies (ACAs) are found in roughly 60% to 80% of patients with lcSSc and only rarely in patients with dcSSc. Antibodies to topoisomerase-1 (Scl-70 antibodies) are present in about 30% of patients with dcSSc. The presence of either ACA or anti-Scl-70 is highly specific (95%-99%) for the diagnosis of lcSSc and dcSSc, respectively. These antibodies are only rarely present in healthy subjects and in patients with other rheumatologic diseases. The presence of ACA or anti-Scl-70 antibodies is also highly specific for underlying systemic sclerosis in patients presenting initially with isolated Raynaud's phenomenon and therefore may be helpful when Raynaud's phenomenon is the initial manifestation.12

Once the diagnosis has been established, the clinician must determine whether the disease is diffuse or limited, based on the extent of skin tightening. The initial evaluation on the physical examination should include a skin score. The modified Rodnan skin score (MRSS) is the most widely used. The total skin surface area is arbitrarily divided into 17 different areas: fingers, hands, forearms, arms, feet, legs, and thighs (in pairs), and face, chest, and abdomen (Figure 4). In each of these areas, the skin score is evaluated by manual palpation. The skin score is 0 for uninvolved skin, 1 for mild thickening, 2 for moderate thickening, and 3 for severe thickening (hidebound skin). The total skin score is the sum of the skin scores of the individual areas, the maximum possible score being 51. The skin score tends to correlate with the extent of dermal fibrosis, which in turn correlates with the extent of fibrosis and dysfunction of the internal organs, such as pulmonary fibrosis, scleroderma heart disease, renal disease, and gastrointestinal involvement. With the onset of diffuse scleroderma, the skin score tends to rise rapidly, but it usually reaches a plateau in the first 3 to 5 years and then may start regressing slowly over the years (Figure 5). The skin score in limited scleroderma, on the other hand, does not progress that fast, and the total skin score is never as high as in diffuse disease (see Figure 5). The extent of skin thickening must be carefully documented in all follow-up visits. The degree of organ involvement must also be determined by history, physical examination, laboratory markers, and various other studies as appropriate.

Complaints of dysphagia, heartburn, early satiety, nausea and vomiting can be investigated with endoscopy and esophageal manometry (although in practice these invasive studies are often not routinely performed unless there is a reason to suspect esophageal stricture, Barrett's esophagus, or adenocarcinoma). Pulmonary function studies, including spirometry for forced vital capacity (FVC) and diffusion capacity for carbon monoxide (DLCO), may suggest the presence of interstitial lung disease (ILD), when both FVC and DLCO are reduced. Chest radiography and high-resolution computed tomography of the chest may suggest the presence of ILD and help differentiate active alveolitis (ground-glass opacification) from established pulmonary fibrosis (coarse reticulation and honeycombing) (Figure 6).

Bronchoscopy with bronchoalveolar lavage (BAL) may be indicated to evaluate for alveolitis (>3% neutrophils, >2% eosinophils, or both, in BAL fluid). Transbronchial or open lung biopsy may rarely be necessary to characterize the nature of the ILD histologically. Nonspecific interstitial pneumonitis (NSIP) is the most common histologic subtype of ILD in scleroderma; less common types are usual interstitial pneumonitis (UIP) or cryptogenic organizing pneumonia (COP).

An isolated or disproportionate reduction in DLCO relative to the forced vital capacity and total lung capacity can raise the suspicion of pulmonary hypertension. Surface echocardiography followed by right-heart catheterization are necessary to evaluate and confirm the presence of pulmonary hypertension.

In all newly diagnosed patients with scleroderma, a baseline pulmonary function test (spirometry and DLCO) and an echocardiogram are recommended, for early diagnosis of ILD and pulmonary hypertension. These tests should be repeated at least annually, even in asymptomatic patients. An annual 6-minute walk distance assessment is also recommended in all patients. This is a simple way of evaluating severity and response to therapy in patients with pulmonary hypertension and is found to correlate with survival.

To investigate the possibility of renal crisis, monitoring of blood pressure, tests of renal function, urinalysis, and peripheral blood smear are necessary in all patients with new onset or worsening hypertension, renal insufficiency, or new anemia (microangiopathic hemolytic anemia) in the absence of blood loss.

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Differential diagnosis

Some conditions associated with scleroderma-like skin changes and included in the differential diagnosis of systemic sclerosis are listed in Box 5. Readers can refer to appropriate texts for detailed descriptions of these entities.

Box 5: Differential Diagnosis of Systemic Sclerosis
Mixed connective tissue disease
Graft-versus-host disease
Nephrogenic systemic fibrosis (formerly known as nephrogenic fibrosing dermopathy)
Diabetic scleredema
Diffuse fasciitis with eosinophilia (Shulman's syndrome)
Toxic oil syndrome
Eosinophilia-myalgia syndrome
Lichen sclerosus et atrophicus
Sclerodermiform acrodermatitis chronica atrophicans (Lyme disease)
Scleromyxedema (lichen myxedematosus) associated with paraproteinemia
Drugs and toxins (l-tryptophan, bleomycin, pentazocine, carbidopa, vinyl chloride, silica)

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Treatment

In addition to taking prescribed medications correctly and regularly, a person with scleroderma can take many steps to better manage the disease.

Exercise

Regular exercise not only helps improve overall physical and spiritual well-being but it also helps keep the joints flexible and improves circulation. Physical therapy is often helpful in patients with diffuse disease with widespread skin involvement, muscle weakness, and joint contractures.

Skin Protection

Taking proper precautions and care of the skin can be beneficial for symptoms of Raynaud's phenomenon and for the dry, thick patches of skin that result from localized scleroderma. During the colder months, patients should dress appropriately. Keeping the body warm and protected from the cold weather with a hat, gloves, and a scarf will help keep the blood vessels in the extremities open and the circulation flowing. Patients should be advised to wear multiple thin layers and wear loose-fitting boots or shoes to keep the blood supply moving to the feet. A humidifier in the house helps keep the air moist. Patients should use soaps and creams that are designed especially for dry skin.

Diet

Aside from eating healthy foods to get the proper amounts of vitamins and nutrients, it is important to eat foods that do not aggravate existing stomach problems. Patients should avoid excess alcohol use, smoking, and foods that cause heartburn. Water or another liquid helps soften food further. High-fiber foods decrease constipation. Eating frequent, smaller meals as opposed to three large meals enables the body to digest the food more easily. After a large meal, patients should wait at least 4 hours before lying down. Raising the head end of the bed about 15 cm (6 in) by placing wooden blocks underneath it helps reduce acid reflux while sleeping.

Dental Care

For patients with scleroderma who also have Sjögren's syndrome, proper dental care is essential. Sjögren's syndrome increases the risk of developing cavities and tooth decay.

Stress Management

Because the effects of stress can play a part in reducing blood flow and can affect many other aspects of emotions and health, it is important to learn to manage or reduce stress. This can be done by getting proper sleep and rest, avoiding stressful situations when possible, eating a healthy diet, learning methods to control anxiety, and exercising regularly.

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Assessment of disease activity and treatment

Institution of therapy is predicated on proper assessment of disease activity and organ involvement. The extent of skin thickening is useful for assessing overall disease activity, disease subset (lcSSc or dcSSc), prognosis, and risk of internal organ involvement.6

Although no therapy is proved to reverse the vascular and fibrotic damage in patients with scleroderma, several therapies are available in an effort to slow down disease progression, improve vascular function, limit mortality, and provide supportive symptomatic care.

Patients with Raynaud's phenomenon are advised to stop smoking, avoid cold exposure, wear warm clothing and gloves, and avoid vasoconstrictive substances (clonidine, sympathomimetics, cocaine, ergot alkaloids). Various pharmacologic agents are aimed at reversing digital vasospasm. The dihydropyridine calcium channel blockers (amlodipine and long-acting preparations of nifedipine) are first-line agents for the treatment of scleroderma-associated Raynaud's phenomenon.13 Sustained-release preparations are preferred, and the dose should be adjusted to reduce the severity and frequency of attacks. Patients should be monitored for dose-limiting side effects such as worsening of acid reflux symptoms, lower extremity edema, headache, flushing, and hypotension. For patients who do not respond to calcium channel blockers, other drugs such as topical nitrates, and α-adrenergic blockers (such as prazosin or tamsulosin) may be tried.

The role of antiplatelet and anticoagulant therapy is unclear, although in the absence of contraindications, most experts would recommend low dose aspirin to patients with Raynaud's phenomenon. Phosphodiesterase-5 (PDE5) inhibitors like sildenafil, tadalafil or vardenafil, have been found to be particularly useful in ameliorating refractory digital ischemia and ulceration, presumably because of their vasodilative properties, although they have not yet received regulatory approval for this indication.14 Endothelin receptor antagonists (such as bosentan) are proved effective for the prevention of ischemic digital ulcers.13,15 Intravenous prostanoids (e.g., epoprostenol, alprostadil, or iloprost) have also been shown to ameliorate severe digital ischemia and improve digital ulceration. Patients with critical digital ischemia require hospitalization, pain relief, intravenous prostanoid therapy,13 and, in the presence of concomitant infection, systemic antibiotics. Angiographic assessment may be necessary to evaluate the extent of vascular disease. When medical therapy fails, digital sympathectomy may be tried to inhibit sympathetic-mediated vasoconstriction.

Because of its anticollagen and immune-modulating effects, d-penicillamine has been used in patients with dcSSc in an effort to slow skin fibrosis. Although small observational studies had demonstrated a small benefit in 5-year mortality and a decrease in development of visceral disease, the role of d-penicillamine remains unclear. Clements and colleagues did not show an advantage of high-dose d-penicillamine over low-dose d-penicillamine therapy, and patients in the high-dose arm had a higher withdrawal rate as a result of adverse events.16

Cyclophosphamide may be beneficial in patients with interstitial lung disease associated with scleroderma.4 Multiple uncontrolled studies had suggested that cyclophosphamide might slow the loss of, or even improve, lung function (specifically FVC) in the setting of early scleroderma with declining FVC and progressive dyspnea.17 Based on these earlier studies, the NIH conducted a randomized double-blind, placebo controlled, multicenter study to determine the effects of oral cyclophosphamide on lung function and health-related symptoms in patients with evidence of active alveolitis from scleroderma-related interstitial lung disease. The results showed that 1 year of oral cyclophosphamide had a statistically significant but clinically modest beneficial effect on the FVC. There were improvements in the dyspnea score, skin score, and health-related quality of life. More toxicity (especially leukopenia) was seen in the cyclophosphamide arm. The effects on lung function were maintained through the 24 months of the study.18 Follow-up was continued in these patients for the second year, and the results were published recently.19 It was found that although the dyspnea scores remained better in the cyclophosphamide arm, the benefit from cyclophosphamide on pulmonary function, health status, and skin score was not sustained until the end of the 24 months of follow-up.

Methotrexate has been shown to improve skin scores, but the effects were modest.19 Corticosteroids may be useful in the treatment of myositis and alveolitis, but their use is limited by the observation that high doses can precipitate renal crisis.8 Immunoablation combined with autologous stem cell rescue is still considered experimental, but one report documented improved skin scores.20 However, 1-year mortality was high after transplantation.21

Gastroesophageal reflux usually responds to proton pump inhibitors, and motility disorders are treated with prokinetic agents such as metoclopramide and domperidone. For significant small bowel hypomotility and intestinal pseudo-obstruction, octreotide 50 to 100 µg subcutaneous injection daily may be beneficial.22,23 Small bowel malabsorption and diarrhea caused by bacterial overgrowth might respond to chronic, alternating regimens of antibiotics (e.g., doxycycline, metronidazole, or ciprofloxacin). Endoscopy-directed dilation may be necessary in cases of esophageal stricture leading to dysphagia, and argon plasma coagulation (APC) may be indicated for gastric bleeding from ectatic vessels (GAVE).

Angiotensin-converting enzyme inhibitors should be used at the first sign of renal crisis (severe hypertension, renal failure, and microangiopathic hemolytic anemia). Their early use is critical in preserving renal function, controlling hypertension, and improving survival during renal crisis. In the hope that control of reninmediated hypertension can result in renal recovery, therapy with angiotensin-converting enzyme inhibitors should be continued even in the face of renal insufficiency requiring dialysis.24

Hypoxia from pulmonary hypertension is treated with oxygen. Epoprostenol is an intravenous prostacyclin analogue delivered by continuous central infusion. In clinical trials, it has been shown to improve functional status.25 Iloprost and treprostinil are synthetic prostacyclins; iloprost is delivered by inhalation, and treprostinil is delivered subcutaneously or intravenously. Bosentan is an oral endothelin receptor antagonist that can improve functional status in patients with pulmonary arterial hypertension associated with systemic sclerosis.26 Ambrisentan, an endothelin-A receptor antagonist,27 and sildenafil, a PDE5 inhibitor,28 have also received FDA approvals for the treatment of pulmonary hypertension. Long-term anticoagulation is preferably avoided for patients with scleroderma-associated pulmonary hypertension because of the risk of serious bleeding from ulcerative esophagitis or GAVE.

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Future directions

The central role of TGF-β in inducing endothelial damage and fibroblast activation has led investigators to target this molecule as a promising site for future therapies. Indeed, anti–TGF-β drugs and other cytokine-based therapies could theoretically provide true disease modification, especially in patients with early disease, before cutaneous and internal fibroses result in significant irreversible damage.29

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Conclusion

Although no cure has been found for scleroderma, the disease is often slowly progressive and manageable, and people who have it can lead healthy and productive lives. Like many other conditions, education about scleroderma and local support groups can be the greatest tools for managing the disease and reducing the risk of further complications.

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Summary

  • The initial presentation in most scleroderma patients is Raynaud's phenomenon.
  • Nailfold capillary microscopy can help differentiate primary Raynaud's phenomenon from that secondary to an underlying connective tissue disease.
  • Although not specific, ANA has high sensitivity in scleroderma (60%-80%) and is useful as a screening test.
  • Limited and diffuse diseases have different disease courses and prognoses. The nature and extent of organ system involvement also determine the prognosis.
  • Therapeutic modalities now include ACE inhibitors for scleroderma renal crisis; parenteral prostanoids, oral endothelin receptor antagonists, and PDE5 inhibitors for pulmonary hypertension; cyclophosphamide for interstitial lung disease in early scleroderma; and octreotide for intestinal pseudo-obstruction.

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References

  1. LeRoy EC, Black C, Fleischmajer R, et al: Scleroderma (systemic sclerosis): Classification, subsets and pathogenesis. J Rheumatol. 1988, 15: 202-205.
  2. Mayes MD, Lacey JV Jr, Beebe-Dimmer J, et al: Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 2003, 48: 2246-2255.
  3. Mayes MD. Scleroderma epidemiology. Rheum Dis Clin North Am. 2003, 29: 239-254.
  4. Korn JH. Scleroderma: A treatable disease. Cleve Clin J Med. 2003, 70: 954, 956, 958.
  5. Kurasawa K, Hirose K, Sano H, et al: Increased interleukin-17 production in patients with systemic sclerosis. Arthritis Rheum. 2000, 43: 2455-2463.
  6. Medsger TA Jr. Natural history of systemic sclerosis and the assessment of disease activity, severity, functional status, and psychologic well-being. Rheum Dis Clin North Am. 2003, 29: 255-273.
  7. Steen VD, Powell DL, Medsger TA Jr. Clinical correlations and prognosis based on serum autoantibodies in patients with systemic sclerosis. Arthritis Rheum. 1988, 31: 196-203.
  8. Kohno K, Katayama T, Majima K, et al: A case of normotensive scleroderma renal crisis after high-dose methylprednisolone treatment. Clin Nephrol. 2000, 53: 479-482.
  9. Lonzetti LS, Joyal F, Raynauld JP, et al: Updating the American College of Rheumatology preliminary classification criteria for systemic sclerosis: Addition of severe nailfold capillaroscopy abnormalities markedly increases the sensitivity for limited scleroderma. Arthritis Rheum. 2001, 44: 735-736.
  10. Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee: Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum. 1980, 23: 581-590.
  11. Spencer-Green G, Alter D, Welch HG. Test performance in systemic sclerosis: Anti-centromere and anti-Scl-70 antibodies. Am J Med. 1997, 103: 242-248.
  12. Kallenberg CG, Wouda AA, Hoet MH, van Venrooij WJ. Development of connective tissue disease in patients presenting with Raynaud's phenomenon: A six year follow up with emphasis on the predictive value of antinuclear antibodies as detected by immunoblotting. Ann Rheum Dis. 1988, 47: 634-641.
  13. Hummers LK, Wigley FM. Management of Raynaud's phenomenon and digital ischemic lesions in scleroderma. Rheum Dis Clin North Am. 2003, 29: 293-313.
  14. Levien TL. Phosphodiesterase inhibitors in Raynaud's phenomenon. Ann Pharmacother. 2006, 40: 1388-1393.
  15. Korn JH, Mayes M, Matucci CM, et al: Digital ulcers in systemic sclerosis: Prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum. 2004, 50: 3985-3993.
  16. Clements PJ, Furst DE, Wong WK, et al: High-dose versus low-dose d-penicillamine in early diffuse systemic sclerosis: Analysis of a two-year, double-blind, randomized, controlled clinical trial. Arthritis Rheum. 1999, 42: 1194-1203.
  17. White B, Moore WC, Wigley FM, et al: Cyclophosphamide is associated with pulmonary function and survival benefit in patients with scleroderma and alveolitis. Ann Intern Med. 2000, 132: 947-954.
  18. Tashkin DP, Elashoff R, Clements PJ, et al: Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006, 354: 2655-2666.
  19. Tashkin DP, Elashoff R, Clements PJ, et al: Scleroderma Lung Study Research Group. Effects of 1-year treatment with cyclophosphamide on outcomes at 2 years in scleroderma lung disease. Am J Respir Crit Care Med. 2007, 176: 1026-1034.
  20. Pope JE, Bellamy N, Seibold JR, et al: A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum. 2001, 44: 1351-1358.
  21. Binks M, Passweg JR, Furst D, et al: Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure related mortality and impact on skin disease. Ann Rheum Dis. 2001, 60: 577-584.
  22. Perlemuter G, Cacoub P, Chaussade S, et al: Octreotide treatment of chronic intestinal pseudoobstruction secondary to connective tissue diseases. Arthritis Rheum. 1999, 42: 1545-1549.
  23. Verne GN, Eaker EY, Hardy E, Sninsky CA. Effect of octreotide and erythromycin on idiopathic and scleroderma-associated intestinal pseudoobstruction. Dig Dis Sci. 1995, 40: 1892-1901.
  24. Steen VD, Medsger TA Jr. Long-term outcomes of scleroderma renal crisis. Ann Intern Med. 2000, 133: 600-603.
  25. Badesch DB, Tapson VF, McGoon MD, et al: Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med. 2000, 132: 425-434.
  26. Rubin LJ, Badesch DB, Barst RJ, et al: Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002, 346: 896-903.
  27. Cerinic Matucci M, Del Rosso A, Federico P, et al: Therapeutic challenges for systemic sclerosis: facts and future targets. Ann N Y Acad Sci. 2007, 1110: 448-454.
  28. Badesch DB, Hill NS, Burgess G, et al: SUPER Study Group. Sildenafil for pulmonary arterial hypertension associated with connective tissue disease. J Rheumatol. 2007, 34: 2417-2422.
  29. Simms RW, Korn JH. Cytokine directed therapy in scleroderma: Rationale, current status, and the future. Curr Opin Rheumatol. 2002, 14: 717-722.

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Suggested Readings

  • Badesch DB, Tapson VF, McGoon MD, et al: Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med. 2000, 132: 425-434.
  • In: Clements PJ, Furst DE (eds): Systemic Sclerosis. 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 2004.
  • Korn JH, Mayes M, Matucci CM, et al: Digital ulcers in systemic sclerosis: Prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum. 2004, 50: 3985-3993.
  • LeRoy EC, Black C, Fleischmajer R, et al: Scleroderma (systemic sclerosis): Classification, subsets and pathogenesis. J Rheumatol. 1988, 15: 202-205.
  • Mayes MD, Lacey JV Jr, Beebe-Dimmer J, et al: Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large U.S. population. Arthritis Rheum. 2003, 48: 2246-2255.
  • Medsger TA Jr. Natural history of systemic sclerosis and the assessment of disease activity, severity, functional status, and psychologic well-being. Rheum Dis Clin North Am. 2003, 29: 255-273.
  • Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum. 1980, 23: 581-590.
  • Rubin LJ, Badesch DB, Barst RJ, et al: Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002, 346: 896-903.
  • Simms RW, Korn JH. Cytokine directed therapy in scleroderma: Rationale, current status, and the future. Curr Opin Rheumatol. 2002, 14: 717-722.
  • Tashkin DP, Elashoff R, Clements PJ, et al: Cyclophosphamide versus placebo in scleroderma lung disease. N Engl JMed. 2006, 354: 2655-2666.

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