Systemic Sclerosis/Scleroderma: A Treatable Multisystem Disease

Epidemiology and Classification

Patients who have systemic sclerosis can be classified into distinct clinical subsets with different patterns of skin and internal organ involvement, autoantibody production, and patient survival.4  The most common subsets are limited cutaneous (approximately 60 percent of patients with systemic sclerosis) and diffuse cutaneous (approximately 35 percent of patients with systemic sclerosis). Table 1 includes the clinical features of limited and diffuse cutaneous systemic sclerosis, and Table 23,4 presents the clinical associations between subtypes and autoantibodies. The limited cutaneous subset is diagnosed when skin thickening is limited to areas distal to the elbows and knees. CREST (calcinosis cutis, Raynaud phenomenon, esophageal dysfunction, sclerodactyly, telangiectasia) syndrome is a variant of limited cutaneous systemic sclerosis. Systemic sclerosis sine scleroderma is a less common subset (approximately 5 percent of patients with systemic sclerosis) that is associated with the characteristic internal organ manifestations of the disease without skin thickening.

Localized forms of scleroderma, such as linear scleroderma and morphea, primarily affect children and, in contrast to systemic sclerosis, are not associated with Raynaud phenomenon or significant internal organ manifestations. Scleroderma mimics are uncommon conditions that are associated with skin induration, but lack Raynaud phenomenon, internal organ involvement, and autoantibodies. Other diseases, such as mixed or undifferentiated connective tissue disease and overlap syndrome, should be considered before establishing a diagnosis (Table 3).

Clinical Presentation

A systemic sclerosis diagnosis is based on clinical findings, which have substantial heterogeneity and varying manifestations. The classic clinical presentation is a young or middle-age woman with Raynaud phenomenon and skin changes accompanied by musculoskeletal discomfort and gastrointestinal symptoms. Table 4 summarizes the systemic manifestations of the disease.

RAYNAUD PHENOMENON

Cold-induced Raynaud phenomenon is the most common manifestation of systemic sclerosis, occurring in more than 95 percent of patients. Patients' fingers may change from white (vasospasm) to blue-purple (ischemia) to red (hyperemia); this is precipitated by exposure to cold temperature or emotional stress. Idiopathic or primary Raynaud phenomenon typically occurs in female adolescents, and is not associated with ischemic complications. In contrast, secondary Raynaud phenomenon tends to occur later in life and often leads to tissue damage. Table 5 presents the characteristics of primary and secondary Raynaud phenomenon. Physical findings of secondary Raynaud phenomenon include cyanosis and signs of ischemic damage to the fingers, such as digital pitting (Figure 1A), visible capillaries on the nail bed, ischemic ulcerations (Figure 1B), and pterygium inversus unguis (i.e., distal nail bed adherence to the ventral surface of the nail plate).

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Figure 1.

Dermatologic signs of vascular abnormalities in a patient with systemic sclerosis. (A) Digital pitting. (B) Healing digital ulcer.

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Figure 1.

Dermatologic signs of vascular abnormalities in a patient with systemic sclerosis. (A) Digital pitting. (B) Healing digital ulcer.

SKIN MANIFESTATIONS

The degree of skin thickening depends on the subtype and duration of disease. Early in the disease, diffuse swelling of the fingers and hands (Figure 2A) may precede skin thickening and lead to an initial undifferentiated arthritis diagnosis. Other early dermatologic changes include shiny skin (Figure 2B) or pigment changes ( Online Figure A1). As the skin thickens on the fingers (sclerodactyly), hands and forearms (limited cutaneous systemic sclerosis), or trunk (diffuse cutaneous systemic sclerosis), the systemic sclerosis diagnosis becomes increasingly apparent.

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Figure 2.

Early dermatologic manifestations of systemic sclerosis. (A) Diffusely puffy hands are a common initial presentation. (B) Shiny skin suggests impending skin thickening.

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Figure 2.

Early dermatologic manifestations of systemic sclerosis. (A) Diffusely puffy hands are a common initial presentation. (B) Shiny skin suggests impending skin thickening.

Facial thickening, which can occur with the limited cutaneous and diffuse cutaneous subsets, often leads to difficulty opening the mouth ( Online Figure A2). Other cutaneous manifestations include hair loss on involved skin; telangiectasia on the face, buccal mucosa, chest, and hands; and calcinosis cutis ( Online Figures B1 and B2). With disease progression, ulcerations over joints and flexion contractures of the fingers, wrists, and elbows may occur.

MUSCULOSKELETAL MANIFESTATIONS

Musculoskeletal involvement is common in early systemic sclerosis and often prompts patients to seek medical evaluation. Puffy hands with arthralgia and myalgia may lead to difficulty making a fist. Palpable or audible friction rubs may be noted over the extensor and flexor tendons of the hands, knees, and ankles. Because friction rubs are highly associated with diffuse cutaneous systemic sclerosis,5 the presence of friction rubs should prompt early diagnosis and screening for characteristic internal organ involvement.

GASTROINTESTINAL MANIFESTATIONS

Symptoms related to gastroesophageal reflux disease (GERD) and dysphagia or changes in bowel habits secondary to intestinal dysmotility are common in patients with early systemic sclerosis. Esophageal disease is virtually universal in patients with the limited cutaneous subset and can cause considerable pathology, even in asymptomatic patients. Bacterial overgrowth in the small bowel (blind loop syndrome) with concomitant nutritional deficiencies (folate and vitamin B₁₂), malabsorption (steatorrhea), and pseudo-obstruction may be a presenting condition, but it is more likely to complicate established disease. Anemia may be a sign of gastric antral vascular ectasia (watermelon stomach). Watermelon stomach refers to the characteristic endoscopic finding of longitudinal rows of sacculated and ectatic mucosal vessels in the antrum of the stomach, which resemble the stripes on a watermelon.

Complications

Internal organ complications are common in patients with systemic sclerosis but are seldom symptomatic until the late stages of the disease; thus, routine screening for internal organ complications is essential.

PULMONARY

Dyspnea is a late manifestation of systemic sclerosis–related lung disease; however, lung involvement is common and is the leading cause of death in patients with systemic sclerosis.3,6 Systemic sclerosis can affect the lung parenchyma (interstitial lung disease) and the pulmonary blood vessels (pulmonary arterial hypertension). Thus, routine screening with pulmonary function tests and Doppler echocardiography in all patients is essential for the early detection of interstitial lung disease and pulmonary arterial hypertension, respectively.7,8

Interstitial Lung Disease

Interstitial lung disease, which is more common with diffuse cutaneous disease, may be preceded by alveolitis that leads to parenchymal fibrosis with destruction of lung architecture and impairment of gas exchange. Interstitial lung disease is suggested when pulmonary function tests reveal restrictive physiology (i.e., a reduction in forced expiratory volume in one second [FEV₁] and forced vital capacity [FVC], with a normal FEV₁/FVC ratio). Patients with systemic sclerosis who have severe restrictive changes (FVC less than 50 percent) have a 10-year mortality rate of 42 percent.9 Because interstitial lung disease and pulmonary arterial hypertension are both associated with restrictive defects, the FVC/carbon monoxide diffusion in the lung (DLCO) ratio should be calculated. A proportionate reduction in FVC and DLCO, yielding an FVC/DLCO ratio of less than 1.6, suggests interstitial lung disease rather than pulmonary arterial hypertension.9 Reticular or ground-glass opacification in lower lung zones on computed tomography (CT) suggests active alveolitis. Honeycombing, bronchiectasis, and subpleural fibrosis generally occur later in the disease course. Unilateral or upper-lobe abnormalities on high-resolution CT suggest possible infection or malignancy and require further evaluation.

Pulmonary Arterial Hypertension

Elevations in pulmonary arterial pressure are not only secondary to interstitial lung disease and left ventricular dysfunction (secondary pulmonary hypertension), but also to primary obliterative pulmonary arteriopathy (pulmonary arterial hypertension).10 Patients with limited cutaneous systemic sclerosis have the greatest risk of pulmonary arterial hypertension.10 Risk factors for severe pulmonary arterial hypertension include limited cutaneous subset, older age, and elevated pulmonary artery pressures at the initial evaluation.10 Routine screening with Doppler echocardiography and pulmonary function tests may detect pulmonary arterial hypertension before the onset of corpulmonale, when treatment is less effective. However, neither test has sufficient sensitivity or specificity to diagnose or exclude the condition. Other causes of increased pulmonary pressure, such as cardiac valvular disease, embolic disease, obstructive sleep apnea, and hypertensive heart disease, must be excluded. A mean pulmonary artery pressure greater than 25 mm Hg on right heart catheterization is diagnostic for pulmonary arterial hypertension.

RENAL

Before the introduction of angiotensin-converting enzyme (ACE) inhibitors, scleroderma renal crisis was the most fatal complication of systemic sclerosis. Scleroderma renal crisis develops in 3 to 10 percent of all patients with systemic sclerosis and in 10 to 20 percent of those with rapidly progressive diffuse cutaneous systemic sclerosis; the greatest risk occurs within the first three years of the disease.11,12 Other risk factors include high-dose corticosteroid use (greater than 15 mg of prednisone daily),13 the presence of tendon friction rubs, asymptomatic pericardial effusion, new-onset anemia, older age, and pregnancy.11,14 Although antitopoisomerase-1 (anti-Scl-70) antibodies are a marker of diffuse cutaneous systemic sclerosis, their presence does not increase the risk of renal crisis.15 Patients with scleroderma renal crisis characteristically present with sudden-onset accelerated hypertension that is often associated with progressive oliguric renal failure with proteinuria, microangiopathic anemia, and microscopic hematuria. Ten to 15 percent of patients with scleroderma renal crisis are normotensive, but hypertensive when compared with their baseline blood pressure measurements.16 Thus, regular blood pressure monitoring is essential for early detection of scleroderma renal crisis.

CARDIAC

Increasing evidence suggests that systemic sclerosis commonly affects the heart. Cardiac involvement in systemic sclerosis includes myocardial disease, conduction system defects, arrhythmias, or pericardial disease. Scleroderma renal crisis and pulmonary disease can also lead to cardiac dysfunction.17 Single-photon emission CT of asymptomatic patients can detect abnormal microcirculation and vasoreactivity of myocardial vessels.18 Cardiac fibrosis can now be assessed using cardiac magnetic resonance imaging, but no long-term studies have assessed the incidence and outcomes of patients with cardiac fibrosis.

DIFFERENTIAL DIAGNOSIS

The initial evaluation of patients with suspected systemic sclerosis includes a complete blood count; a comprehensive chemistry panel; and serologic studies, including antinuclear, anticentromere, and antitopoisomerase antibodies. Creatine kinase measurements, erythrocyte sedimentation rate, and C-reactive protein measurements may be useful; elevated results suggest myositis, vasculitis, malignancy, or overlap of systemic sclerosis with another autoimmune disease. Table 3 includes scleroderma spectrum disorders.

Treatment

Because of the heterogeneity of systemic sclerosis and potential treatment toxicity, therapy must be individualized to each patient's clinical presentation and needs. No disease-modifying agent has been proven to prevent or reverse fibrosis, although retrospective studies and case series show that d-penicillamine (Cuprimine), mycophenolate mofetil (Cellcept), and cyclophosphamide (Cytoxan) may be effective in some patients. There has been significant improvement in treatments for organ-specific complications (Table 6), especially Raynaud phenomenon, scleroderma renal crisis, and gastrointestinal and pulmonary complications.

RAYNAUD PHENOMENON

Digital amputation because of ischemic complications usually is not necessary if aggressive oral vasodilator therapy is initiated in patients with frequent or severe episodes of Raynaud phenomenon. Commonly used agents include long-acting calcium channel blockers (e.g., nifedipine [Procardia])19 and angiotensin-II receptor blockers (e.g., losartan [Cozaar]).20 There are limited data on the use of phosphodiesterase-5 inhibitors (e.g., sildenafil [Revatio]) for treating secondary Raynaud phenomenon.21 Patients with recurrent ischemic ulcers may benefit from bosentan (Tracleer), an oral endothe-lin-1 receptor inhibitor. In one recent study, patients with ischemic ulcers who were treated with bosentan had a 48 percent reduction in new ulcer formation; however, there was no improvement in existing ulcers.22 Autonomic nervous system modulation with sympatholytic agents (e.g., prazosin [Minipress]) is modestly beneficial and may be associated with adverse effects.23 Patients with symptomatic relief from sympathetic ganglionic blockade may benefit from surgical digital sympathectomy, although there are no controlled trials of its effectiveness.

GASTROINTESTINAL COMPLICATIONS

In addition to therapies to control gastrointestinal symptoms and prevent GERD complications, patients with systemic sclerosis and gastric antral vascular ectasia may require endoscopic laser coagulation to decrease the risk of bleeding. Intestinal pseudo-obstruction often is diagnosed at the time of laparotomy, although conservative nonsurgical management with bowel rest, antibiotics to treat bacterial overgrowth, and judicious use of promotility agents may be effective. Antibiotics, including rifaximin (Xifaxan), and correction of nutritional deficiencies are the mainstays of therapy for intestinal overgrowth.24

PULMONARY COMPLICATIONS

Results from two recent randomized trials suggest that oral or intravenous cyclophosphamide is beneficial in patients with early and progressive interstitial lung disease.25–27 Lung physiology (FVC) and health-related outcomes (dyspnea, skin thickening, quality of life, and function) improved modestly after one year of cyclophosphamide therapy with or without subsequent treatment with azathioprine (Imuran) and prednisone.25–27 It is important to note that although cyclophosphamide has modest benefits for lung function, there is a risk of hemorrhagic cystitis and bladder cancer, bone marrow suppression, infection, infertility, and possibly late hematologic malignancies. Although several small studies suggest a potential role for the immunomodulatory, antifibrotic drug mycophenolate mofetil in the treatment of interstitial lung disease, controlled trials are lacking.28 Oral bosentan, sildenafil, parenteral epoprostenol (Flolan) and treprostinil (Remodulin), and inhaled iloprost (Ventavis) are used to treat symptomatic pulmonary arterial hypertension.29–34 In patients with hypoxemia, continuous oxygen may be needed.

RENAL COMPLICATIONS

All patients with systemic sclerosis should be advised to check their blood pressure at home on a regular basis. Any persistent elevations should prompt a medical evaluation and treatment with ACE inhibitors if scleroderma renal crisis is suspected. ACE inhibitors should be used to control hypertension despite rising serum creatinine levels or the initiation of dialysis because they are essential for preserving and restoring renal function.35

Prognosis

Life expectancy in patients with systemic sclerosis is determined based on the extent and severity of internal organ involvement. Proper management requires regular monitoring and judicious use of organ-specific therapies. Patients may benefit from referral to specialty centers with expertise in treating the various complications of the disease. Self-help resources are available from the Scleroderma Foundation (http://www.scleroderma.org) and the Scleroderma Research Foundation (http://www.sclerodermaresearch.org).