Systemic Sclerosis (Scleroderma)

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

Symptoms usually appear in the third to fifth decades, and women are affected 2- to 3-times as frequently as men.

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

In limited systemic sclerosis, which often has one or more features of the CREST syndrome (calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia), the hardening of the skin (scleroderma) is limited to the face, neck, and skin distal to the elbows and knees.

In contrast, diffuse systemic sclerosis, the skin changes also involve the trunk and proximal extremities. Tendon friction rubs over the forearms and shins occur uniquely (but not universally) in diffuse systemic sclerosis.

In general, patients with limited systemic sclerosis have better outcomes than those with diffuse disease, largely because life-threatening lung or kidney disease is rare.

Cardiac disease is also more characteristic of diffuse systemic sclerosis.

Patients with limited disease, however, are more susceptible to digital ischemia, leading to finger loss, and to life-threatening pulmonary hypertension.

Small and large bowel hypomotility, which may occur in either form of systemic sclerosis, can cause constipation alternating with diarrhea, malabsorption due to bacterial overgrowth, pseudoobstruction, and severe bowel distention with rupture.

Diagnostic Essentials

• Limited disease (CREST syndrome): skin thickening confined to face, neck, and distal extremities.
• Diffuse disease (20%): widespread thickening of skin, including truncal involvement, with areas of increased pigmentation and depigmentation.
• Raynaud phenomenon and antinuclear antibodies are present in virtually all patients.
• Systemic features: gastroesophageal reflux, GI hypomotility, pulmonary fibrosis, pulmonary hypertension, renal involvement.

Clinical Findings

Symptoms and Signs

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

Polyarthralgia, weight loss, and malaise are common early features of diffuse systemic sclerosis but are infrequent in limited disease.

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 of the fingertips and subcutaneous 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 GI 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 pericardial effusions, heart block, myocardial fibrosis, and right heart failure secondary to pulmonary hypertension.

Systemic sclerosis–associated renal crisis, resulting from intimal proliferation of smaller renal arteries and usually associated with hypertension, is a life-threatening emergency. Many cases can be treated effectively with ACE inhibitors.

Laboratory Findings

Mild anemia is often present.

In 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.

Mild proteinuria with few cells or casts can occur.

Antinuclear antibody tests are nearly always positive, frequently in high titers (Table 1–7ck).

The scleroderma antibody (anti-SCL-70), directed against topoisomerase III, is found in 33% of patients with diffuse systemic sclerosis and in 20% of those with limited disease. 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 limited systemic sclerosis and in 3% of individuals with diffuse disease (Table 1–7ck). Anticentromere antibodies are highly specific for limited systemic sclerosis, but they also occur occasionally in overlap syndromes.

Anti-RNA polymerase III antibodies develop in 10–20% of systemic sclerosis patients overall and are associated with rapidly progressive skin disease, renal crisis, and a higher risk of concomitant solid cancers, especially breast cancer.

Differential Diagnosis

Early in its course, systemic sclerosis can cause diagnostic confusion with other causes of Raynaud phenomenon, particularly SLE, mixed connective tissue disease, and the inflammatory myopathies.

Eosinophilic fasciitis is a rare disorder presenting with skin hardening that resembles diffuse systemic sclerosis. The inflammatory abnormalities, however, are limited to the fascia rather than the dermis and epidermis. Moreover, patients with eosinophilic fasciitis are distinguished from those with systemic sclerosis by the presence of peripheral blood eosinophilia, the absence of Raynaud phenomenon, a good response to prednisone, and an association (in some cases) with paraproteinemias.

Diffuse skin thickening and visceral involvement are features of scleromyxedema; the presence of a paraprotein, the absence of Raynaud phenomenon, and distinct skin histology point to scleromyxedema.

Diabetic cheiropathy typically develops in longstanding, poorly controlled diabetes mellitus and can mimic sclerodactyly.

Morphea and linear scleroderma cause sclerodermatous changes limited to circumscribed areas of the skin and usually have excellent outcomes.

Treatment

Treatment of systemic sclerosis focuses on the organ systems involved. Although there is no effective therapy for the underlying disease process, interventions for management of specific organ manifestations have improved substantially.

Treatment for Raynaud phenomenon is discussed here.

The hypertensive crises in scleroderma renal crisis must be treated early and aggressively (in the hospital) with ACE inhibitors, eg, captopril, initiated at 25 mg po q6h and titrated up as tolerated to a maximum of 100 mg q6h.

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

Esophageal reflux can be reduced and the risk of scarring diminished by avoiding late-night meals and using PPIs (eg, omeprazole, 20–40 mg/day orally), which achieve near-complete inhibition of gastric acid production and are 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.

Oral prokinetic agents such as metoclopramide (10 mg qid) or cisapride (10–20 mg qid) can improve dysphagia caused by esophageal hypomotility. Erythromycin (250 mg tid) can be used if prokinetic agents fail. Since erythromycin impairs the metabolism of cisapride, combined use of these two agents is contraindicated.

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

Malabsorption due to bacterial overgrowth responds to antibiotics, eg, rifaximin, 550 mg po tid, often prescribed cyclically.

Apart from the patient with myositis, prednisone has little or no role in the treatment of systemic sclerosis; doses > 15 mg/day have been associated with scleroderma renal crisis.

In patients with early diffuse systemic sclerosis (scleroderma), methotrexate can be used in the treatment of skin disease, arthritis, and myositis. The usual initial dose is 7.5 mg of methotrexate po once weekly. If the patient has tolerated methotrexate but has not responded in 1 month, the dose can be increased to 15 mg orally once per week. The maximal dose is usually 20 mg/week.

For patients who require treatment for interstitial lung disease, mycophenolate mofetil (1000–1500 mg po bid) can improve dyspnea and pulmonary function tests modestly.

Cyclophosphamide has similar efficacy but greater toxicity; this drug should only be administered by physicians familiar with its use.

The IL-6 inhibitor tocilizumab, 162 mg subcutaneously once weekly, slows the rate of decline in pulmonary function and may be used as an alternative for patients who cannot tolerate mycophenolate mofetil.

Azathioprine is an additional option for treatment of systemic sclerosis–associated lung disease.

In patients who do not respond to or cannot take the agents above, nintedanib (an inhibitor of multiple tyrosine kinases) can slow the progression of systemic sclerosis–associated lung disease and is FDA-approved for this indication.

Treatment of pulmonary hypertension in systemic sclerosis is largely extrapolated from general trials of pulmonary hypertension. Therapies include phosphodiesterase type 5 inhibitors (sildenafil, tadalafil, vardenafil), a guanylate cyclase stimulant (riociguat), endothelin-1 receptor antagonists (bosentan, ambrisentan, macitentan), and an endothelin-A receptor antagonist (ambrisentan).

Refractory pulmonary hypertension may require prostacyclin pathway agonists (epoprostenol, treprostinil, iloprost, selexipag).

For patients with severe, diffuse systemic sclerosis, myeloablation followed by autologous stem cell transplantation is superior to immunosuppression with cyclophosphamide but has greater toxicity.

The 9-year survival rate in systemic sclerosis averages approximately 40%.

The prognosis tends to be worse in those with diffuse disease, in Black patients, men, and older patients.

Lung disease—in the form of pulmonary fibrosis or pulmonary arterial hypertension—is the leading cause of mortality.

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.

Studies conducted in a small number of patients with simultaneous onset of cancer and systemic sclerosis have demonstrated that the disease developed due to an immune response directed at the cancer.

When to Refer

• Appropriate management of systemic sclerosis requires frequent consultations with a rheumatologist.
• Severity of organ involvement dictates referral to cardiologists, pulmonologists, gastroenterologists, or nephrologists.