Scleroderma (Systemic Sclerosis)

General Considerations

Scleroderma (systemic sclerosis) is a rare chronic disorder characterized by diffuse fibrosis of the skin and internal organs.

The causes of scleroderma are not known, but autoimmunity, endothelial cell damage, and increased production of extracellular matrix appear to play key pathogenic roles.

Symptoms usually appear in the third to fifth decades, and women are affected two to three times as frequently as men.

Two forms of scleroderma are generally recognized: limited (80% of patients) and diffuse (20%).

In limited scleroderma, which is also known as the CREST syndrome (representing calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia), the hardening of the skin (scleroderma) is limited to the face and hands.

In contrast, in diffuse scleroderma, the skin changes also involve the trunk and proximal extremities.

In general, patients with limited scleroderma have better outcomes than those with diffuse disease, largely because kidney disease or interstitial lung disease rarely develops in patients with limited disease.

Cardiac disease is also more characteristic of diffuse scleroderma.

Clinical FindingsSymptoms and Signs

Raynaud phenomenon is usually the initial manifestation and can precede other signs and symptoms by years in cases of limited scleroderma.

Polyarthralgia, weight loss, and malaise are common early features of diffuse scleroderma but are infrequent in limited scleroderma

Cutaneous disease usually, but not always, develops before visceral involvement and can manifest initially as non-pitting subcutaneous edema associated with pruritus.

With time the skin becomes thickened and hidebound, with loss of normal folds.

Telangiectasia, pigmentation, and

depigmentation are characteristic.

Ulceration about the fingertips and supbcutaneous calcification are seen.

Dysphagia and symptoms of reflux due to esophageal dysfunction are common and result from abnormalities in motility and later from fibrosis.

Fibrosis and atrophy of the gastrointestinal tract cause hypomotility. Large-mouthed diverticuli occur in the jejunum, ileum, and colon

Diffuse pulmonary fibrosis and pulmonary vascular disease are reflected in restrictive lung physiology and low diffusing capacities. Cardiac abnormalities include

pericarditis, heart block, myocardial fibrosis, right heart failure secondary to

pulmonary hypertension

Scleroderma renal crisis, resulting from intimal proliferation of smaller renal arteries and usually associated with hypertension, is a marker for a poor outcome even though many cases can be treated effectively with angiotensin-converting enzyme inhibitors.

Laboratory FindingsMild anemia is often present. In scleroderma

renal crisis, the peripheral blood smear shows findings consistent with a microangiopathic hemolytic anemia (due to mechanical damage to red cells from diseased small vessels).

Elevation of the ESR is unusual. Proteinuria and cylindruria appear in

association with renal involvement.

Antinuclear antibody tests are nearly always positive, frequently in high titers

The scleroderma antibody (anti-SCL-70), directed against topoisomerase III, is found in one-third of patients with diffuse systemic sclerosis and in 20% of those with CREST syndrome

. Although present in only a small number of patients with diffuse scleroderma, anti-SCL-70 antibodies may portend a poor prognosis, with a high likelihood of serious internal organ involvement (eg, interstitial lung disease).

Anticentromere antibodies are seen in 50% of those with CREST syndrome and in 1% of individuals with diffuse scleroderma Anticentromere antibodies are highly specific for limited scleroderma, but they also occur occasionally in overlap syndromes.

Other scleroderma autoantibodies include those directed against RNA polymerases (anti-RNAP I, II, III), and B23.

.

Although present in only a small number of patients with diffuse scleroderma, anti-SCL-70 antibodies may portend a poor prognosis, with a high likelihood of serious internal organ involvement (eg, interstitial lung disease).

Differential Diagnosis

Early in its course, scleroderma can cause diagnostic confusion with other causes of Raynaud phenomenon,

particularly SLE,

mixed connective tissue disease,

inflammatory myopathies.

Scleroderma can be mistaken for other disorders characterized by skin hardening. Eosinophilic fasciitis is a rare disorder presenting with skin changes that resemble diffuse scleroderma

poorly controlled diabetes can mimic sclerodactyly.

Nephrogenic fibrosing dermopathy produces thickening and hardening of the skin of the trunk and extremities in patients with chronic kidney disease; exposure to gadolinium may play a pathogenic role.

TreatmentTreatment of scleroderma is

symptomatic and supportive and focuses on the organ systems involved.

There is no effective therapy for the underlying disease process.

However, interventions for management of specific organ manifestations of this disease have improved substantially.

Severe Raynaud syndrome may respond to calcium channel blockers, eg, long-acting nifedipine, 30–120 mg/d orally, or to losartan, 50 mg/d orally, or to sildenafil 50 mg orally twice daily.

Patients with esophageal disease should take medications in liquid or crushed form.

Esophageal reflux can be reduced and the risk of scarring diminished by avoidance of late-night meals and by the use of proton pump inhibitors (eg, omeprazole, 20–40 mg/d orally), which achieve near-complete inhibition of gastric acid production and are remarkably effective for refractory esophagitis.

Patients with delayed gastric emptying maintain their weight better if they eat small, frequent meals and remain upright for at least 2 hours after eating.

Long-term octreotide (0.1 mg subcutaneously twice daily), a somatostatin analog, helps some patients with bacterial overgrowth and pseudoobstruction.

Malabsorption due to bacterial overgrowth also responds to antibiotics, eg, tetracycline, 500 mg four times orally daily, often prescribed cyclically

The hypertensive crises associated with systemic sclerosis renal crisis must be treated early and aggressively (in the hospital) with angiotensin-converting enzyme inhibitors, eg, captopril, initiated at 25 mg orally every 6 hours and titrated up as needed to a maximum of 100 mg every 6 hours.

Apart from the patient with myositis, prednisone has little or no role in the treatment of scleroderma; high doses (> 15 mg daily) have been associated with scleroderma renal crisis.

Cyclophosphamide improves dyspnea and pulmonary function tests modestly in patients with severe interstitial lung disease; this highly toxic drug should only be administered by physicians familiar with its use. Bosentan, an endothelin receptor antagonist, improves exercise capacity and cardiopulmonary hemodynamics in patients with pulmonary hypertension and helps prevent digital ulceration.

Sildenafil or prostaglandins (delivered by continuous intravenous infusion or intermittent inhalation) may also be useful in treating pulmonary hypertension.

At an experimental level, immunoablative therapy with or without stem cell rescue has achieved promising results for some patients with severe, rapidly progressive diffuse scleroderma

The 9-year survival rate in scleroderma averages approximately 40%. The prognosis tends to be worse in those with diffuse scleroderma, in blacks, in males, and in older patients. Lung disease is now the number one cause of mortality

. Death from advanced chronic kidney disease or heart failure is also common. Those persons in whom severe internal organ involvement does not develop in the first 3 years have a substantially better prognosis, with 72% surviving at least 9 years. Breast and lung cancer may be more common in patients with scleroderma.