Scleroderma and Related Diseases Part 2

Laboratory Findings

More than 85% of patients with scleroderma have positive test results for antinuclear antibodies26 [see Table 2]. Antibodies to certain nuclear antigens are specific for scleroderma,27 and each type of antibody is associated with a particular clinical pattern of disease. Antibodies to Scl-70 and to RNA polymerases (usually RNA polymerase III) are seen in patients with systemic sclero-derma. In a meta-analysis, anti-Scl-70 antibodies had a positive predictive value of 70% for diffuse cutaneous scleroderma.28 An-ticentromere antibodies are associated with limited scleroderma (the CREST syndrome); the meta-analysis indicated a positive predictive value of 88% for limited cutaneous scleroderma.28 Antibodies to nuclear ribonucleoprotein (nRNP) are associated with diffuse and limited scleroderma. Antibodies to PM-1 and Ku are infrequent. The presence of these antibodies is usually associated with overlapping clinical features of polymyositis and scleroder-ma. About 50% of patients with localized scleroderma have antibodies to histones [see Table 2].

Management

Management of scleroderma is often a severe challenge,29 but it includes several potentially lifesaving interventions. Close attention to detecting renal and pulmonary involvement will typically improve eventual outcomes.

Renal Crisis

Renal crisis is a serious scleroderma-related manifestation that is manageable with appropriate therapy. Onset typically is within the first 2 years of the disease course and is more common in diffuse scleroderma than in the limited form of the dis-ease30; renal crisis occurs in about 15% of patients with diffuse scleroderma. A clinician should instruct patients with early diffuse scleroderma about daily blood pressure monitoring and initiate antihypertensive therapy if the patient’s blood pressure exceeds 130/80 mm Hg. Renal crisis is recognized by diminished renal function with new-onset hypertension (even of modest degree), microscopic hematuria, and proteinuria. Treatment of this medical emergency with ACE inhibitors and other potent antihypertensive drugs appears to arrest the deterioration in renal function. Even in patients who initially require dialysis, ACE inhibitors may restore renal function enough to make dialysis unnecessary.31 However, this therapy has been shown to be more beneficial when initiated before serum crea-tinine levels have exceeded 3 mg/dl. In some patients, renal failure progresses despite good control of blood pressure, necessitating dialysis and possibly renal transplantation. Despite reduced frequency with ACE inhibitor therapy and availability of dialysis, renal crisis is associated with poor survival rates.

Pulmonary Involvement

A clinician should be able to detect pulmonary involvement through yearly or twice-yearly pulmonary arterial pressure estimates (from echocardiograms) and measurements of forced vital capacity, carbon monoxide diffusing capacity, and exercise arterial blood gas levels. Patients with pulmonary function abnormalities may then be evaluated with bronchoalveolar lavage, where available, and high-resolution CT to detect the extent of lower respiratory inflammation. Progression is more likely to occur in patients with more extensive lung disease and patients who are positive for anti-Scl-70 antibodies. In diffuse scleroderma, meticulous assessment is warranted, particularly in the first 5 years after onset.33 In patients with early fibrosing alveolitis, progression of pulmonary fibrosis may be halted by long-term therapy with cyclophosphamide and low-dose pred-nisone (< 10 mg/day), but this measure is not yet supported by a randomized, controlled trial.19,33 Cyclophosphamide therapy is a powerful immunosuppressive medication; its use is sometimes associated with adverse events such as bacterial infections, herpes zoster, varicella-zoster virus infection, interstitial cystitis, and malignancies such as bladder transitional cell carcinoma. Often, intravenous cyclophosphamide is effective and somewhat less toxic than oral regimens.33

Pulmonary hypertension may be a particularly serious manifestation of scleroderma. In patients with suspected pulmonary arterial hypertension, on the basis of physiologic findings and serial echocardiographic examinations, a right heart catheter measurement of pulmonary arterial pressure should be obtained. Individuals with pulmonary arterial hypertension should receive influenza and pneumococcal immunizations and be counseled regarding cigarette smoking and other important exposures. When hypoxemia is present, supplemental oxygen is appropriate.

If serious pulmonary hypertension occurs, the patient should be referred to a specialist for this condition. Referral is important because current therapy is rapidly evolving, the medications used are not part of the usual formulary, and the specialist’s experience will lead to reduced risk of complication and toxicity. Internet resources may prove useful in identifying local specialists and support programs available to scleroder-ma patients [see Sidebar Internet Resources for Information on Scleroderma].

The therapeutic measures employed for pulmonary arterial hypertension include the use of calcium channel blockers, anticoagulation, prostaglandin medications, phosphodies-terase V inhibitors such as sildenafil, and endothelin receptor antagonists such as bosentan. In a small fraction of patients, high-dose calcium channel blockers will reduce pulmonary arterial pressure and vascular resistance without causing serious adverse effects such as hypotension34; in this subset of patients, it is necessary to administer a diuretic to reduce risk of right-sided heart failure. Warfarin therapy (achiev-ingan international normalized ratio of 2.0 to 2.5) increases survival.34

Various prostaglandins are helpful for therapy of pulmonary artery hypertension. The currently available prostaglandins include continuous intravenous epoprostanol (2 ng/kg/min) and continuous subcutaneous treprostinil (1.25 ng/kg/min); other oral and inhaled prostaglandins are under study. Epoprostanol has been shown to prolong life and decrease symptoms and improve hemodynamics35-37; however, it is exacting in terms of discomfort and disability. Subcutaneous treprostinil therapy is more convenient and improves symptoms and exercise capacity but is sometimes associated with infusion-site pain.38 Oral sil-denafil appears to improve gas exchange39 and may act synergis-tically when administered with an inhaled prostaglandin (e.g., iloprost).40 The most dramatic therapeutic development has been bosentan, an orally administered endothelin-1 antagonist (125 mg twice daily). Bosentan therapy leads to improved exercise capacity, decreased symptoms, and improved hemody-namic effects, but hepatotoxicity is a concern.41 However, the most beneficial therapies for severe pulmonary arterial hypertension are costly (annual cost of bosentan, $36,000; epoprostanol, $72,000; and treprostinil, $93,000).

^Descriptions of Web sites are derived from www.niams.nih.gov.

Cutaneous Involvement

Most patients with the Raynaud phenomenon may be managed with such measures as avoidance of cold exposure. Instructions to wear warm clothing, gloves, and a hat when exposed to a cold environment may be sufficient. Cigarette smokers have a fourfold risk of digital vascular complications in surgical debridement, amputation, or intravenous vasodilator therapy42; smoking cessation is thus a key instruction. In addition, patients should avoid vasoconstrictive agents (e.g., decon-gestants, caffeine, amphetamines, beta blockers, and ergot alkaloids). For persons with attacks of the Raynaud phenomenon so frequent or so severe as to interfere with daily activities or to put them at risk for skin necrosis, pharmacologic therapy may be employed. Low-dose aspirin (81 mg daily) is recommend-ed.30 The calcium channel blocking agents promote vasodilata-tion and generally reduce the frequency and severity of Ray-naud phenomenon.43 Although nifedipine in daily doses of 30 to 60 mg has been effective for most patients, approximately one third do not respond, and some patients experience adverse effects. In double-blind, placebo-controlled trials, other calcium channel blockers have also shown efficacy for the Ray-naud phenomenon; these agents include amlodipine, 5 to 10 mg daily, and felodipine, 5 to 10 mg daily. Ischemic digital ul-cerations may be difficult to treat and may progress to gangrene of the fingertips. Sympathectomy should be reserved for severe ischemic crises.

GI Tract Involvement

Because gastroesophageal reflux is nearly universal in scle-roderma, clinicians typically will instruct scleroderma patients to elevate the head of the bed and will administer proton pump inhibitors. Esophageal motility may be enhanced by use of metoclopramide. Esophageal dilatation may be required if strictures are present. Patients with diminished gastric emptying may be instructed regarding the frequent taking of small meals and may be given prokinetic medications such as metoclopramide. Small bowel motility may present as pain, distention, and vomiting; most episodes can be managed by increasing dietary fiber and avoiding medications that affect motility (e.g., opiates). Octreotide is used for severe small bowel dysmotility. For small bowel bacterial overgrowth with malabsorption, empirical antibiotic therapy with ciprofloxacin, metronidazole, doxycycline, or erythromycin is recommended.

Potential Disease-Modifying Therapies

Potential disease-modifying therapies for scleroderma have also been studied. Penicillamine is no longer recommended because of associated toxicity and minimal efficacy,44 and metho-trexate therapy is of uncertain benefit.45,46 Stem cell transplants are associated with a higher procedure-related mortality but typically lead to decreased skin manifestations and stabilization of lung function.47,48 A truly effective disease-modifying therapy is not yet available.

Clinical course

In the CREST syndrome, skin involvement is relatively limited, usually affecting only the hands and face; the prognosis for patients with this syndrome is generally favorable unless viscera are involved. However, even the limited CREST variant tends to be unremitting and slowly progressive. Many patients experience an indolent course with little change over several years, although the progression may be more rapid. Diffuse scleroderma is highly variable in its course and manifestations; therefore, its rate of progression is difficult to predict. With the exception of some of the sclerodermatous changes in mixed connective tissue disease, diffuse scleroderma rarely remits completely. Involvement of the viscera, such as the heart, lungs, or, particularly, the kidneys, indicates a poor prognosis. Two other features of scleroderma also indicate a poor outcome: (1) active inflammation, as manifested by an elevated erythrocyte sedimentation rate, and (2) evidence of cardiopul-monary disease, renal disease, or both within 1 year after diag-nosis.49 The life-threatening complications of scleroderma—se-vere skin involvement, pulmonary fibrosis, and renal crisis— usually occur within the first 2 to 5 years after the onset of disease. After this interval, the disease tends to run an indolent course. The 5-year survival for patients with diffuse scleroder-ma is approximately 50%, but pediatric patients with the disease have a much better prognosis.50

Eosinophilic Fasciitis

Eosinophilic fasciitis can superficially resemble scleroderma. It is characterized by pain, swelling, and tenderness of the extremities, after which induration of the skin and subcutaneous tissues occurs. Joint motion may be limited, but the Raynaud phenomenon, sclerodactyly, and other manifestations of scle-roderma are not seen. Laboratory test abnormalities include peripheral blood eosinophilia, which may be marked; elevation of the erythrocyte sedimentation rate; and hyperglobulin-emia. Antinuclear antibody and rheumatoid factor test results are negative. Biopsy specimens of involved areas have shown inflammation and thickening of the fascia deep to the subcutaneous tissues. The skin appears normal, but the underlying deep fascia is infiltrated with lymphocytes, plasma cells, histio-cytes, and sometimes eosinophils. Eosinophilic fasciitis seems to be either self-limited or responsive to low doses of glucocor-ticoids. Its etiology remains unknown, but several cases have been reported after strenuous muscle exertion.

Eosinophilia-Myalgia Syndrome

In 1989, a previously unrecognized syndrome associated with ingestion of contaminated L-tryptophan appeared.51 The eosinophilia-myalgia syndrome is characterized by peripheral eosinophilia, severe and incapacitating myalgias, and fatigue of several weeks’ duration. Dyspnea and cough may also be present. Skin involvement consists of variable rashes, edema, and scleroderma-like changes, usually without the visceral manifestations of scleroderma. Interstitial pulmonary infiltrates, hypoxia, pulmonary hypertension, and hypersensitivity pneumonitis may occur. Polyneuropathy has been described in a pattern of mononeuritis multiplex. Neurocognitive disorders, such as memory disturbances and difficulty in concentration, have been reported. Most patients continue to manifest symptoms from 2 to 4 years after onset but have no new signs of inflammation.