eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Juvenile Systemic Sclerosis: Differential Diagnoses & Workup

Author: Luke M Webb, MD, Fellow, Department of Allergy and Immunology, Walter Reed Army Medical Center
Coauthor(s): David J Schwartz, MD, Fellow, Department of Allergy and Immunology, Walter Reed Army Medical Center; Cecilia P Mikita, MD, MPH, Associate Program Director, Allergy-Immunology Fellowship, Assistant Professor of Pediatrics and Medicine, Uniformed Services University of the Health Sciences; Hospital Intern Director, Staff Allergist/Immunologist, Walter Reed Army Medical Center
Contributor Information and Disclosures

Updated: Jul 20, 2009

Differential Diagnoses

Other Problems to Be Considered

Many of the pediatric systemic rheumatic diseases, including dermatomyositis, systemic lupus erythematosus (SLE), systemic vasculitis, and juvenile rheumatoid arthritis (JRA), have numerous clinical features in common. These clinical similarities, in addition to the common laboratory findings that may be found among these diseases, can lead to diagnostic difficulties. Occasionally, even experienced rheumatologists may have some difficulty in making a definitive diagnosis.

Overlap syndromes are well described and mentioned in this topic because systemic sclerosis, dermatomyositis, SLE, systemic vasculitis, and systemic JRA (ie, Still disease) have been previously noted in various combinations within pediatric patients or in the evolution of any single rheumatic disease of childhood.

Establishing a specific diagnosis is important for prognosis and treatment. In some patients, a specific diagnosis may take months to years to establish. With recent attempts at better defining diagnostic criteria for juvenile systemic sclerosis (JSSc), the elapsed time between onset of symptoms and diagnosis will hopefully decrease. Some of the most challenging pediatric rheumatologic diseases to differentiate include those that overlap between scleroderma and dermatomyositis. Systemic vasculitis may mimic almost any of the other systemic rheumatic diseases.

Workup

Laboratory Studies

In juvenile systemic sclerosis (JSSc), as in many of the systemic rheumatic diseases, inflammation early in systemic disease may be associated with anemia, thrombocytosis and possibly eosinophilia. Therefore, obtaining routine CBC counts and erythrocyte sediment rates (ESRs) is prudent. Other early studies may include a urinalysis, chemistry survey, and ANA tests. These tests help to establish baseline values before the introduction of potentially toxic medications (see Medication).

• Early in the course of the disease, few, if any, laboratory finding abnormalities may be present. Later, mild anemia with slight thrombocytosis may be evident. Regular monitoring of these values may be warranted when a diagnosis of systemic sclerosis is suspected.
• The ESR is often normal or only mildly elevated in patients with juvenile systemic sclerosis. The largest published case series showed elevation of ESR in 34% of patients. 
• Peripheral eosinophilia should alert the clinician to one of the variants of scleroderma.
• Hematuria, proteinuria, and cellular casts are an ominous sign in patients with juvenile systemic sclerosis and may represent impending renal insufficiency.
• Survey chemistry findings are useful in monitoring disease activity and drug-associated toxicities.
• Rheumatoid factor (RF) is present in 17% of patients with juvenile systemic sclerosis, slightly less than the 25% of those with adult-onset disease.
• Immunologic tests are often helpful in patients with juvenile systemic sclerosis. Patients often have a positive ANA finding on nucleolar staining. The precise frequency is debated, but most experts estimate that between 81-97% of patients with juvenile systemic sclerosis have positive ANA findings. Antinucleolar staining (one cause of a speckled ANA pattern) is observed almost exclusively in adult and pediatric systemic sclerosis. Some of the other autoantibodies suggestive of systemic sclerosis or scleroderma that have been described include those listed below. However, note that as many as one third of patients who are diagnosed with juvenile systemic sclerosis and have positive ANA findings do not have any of the more specific autoantibodies, including the following: 
  • Anti-SCL 70 - Specific for topoisomerase I, found in 28-34% of cases
  • Anti–RNA polymerase
  • Anti-centromere - Only found in 7-8% of juvenile systemic sclerosis cases compared with 21-23% of adults systemic sclerosis cases
  • Antifibrillarin
  • Anti-PM-Scl
  • Anti-RNA polymerase I or II
• Contrary to findings in adult disease, the presence of anti-topoisomerase I and anti-RNA polymerase III antibodies are not associated with poorer survival in juvenile systemic sclerosis.
• In one third of cases, quantitative immunoglobulin levels may demonstrate a mild to modest immunoglobulin G (IgG) hypergammaglobulinemia. This nonspecific polyclonal gammopathy is detectable in many chronic inflammatory and systemic rheumatic diseases. Complement levels are normal in most cases. Test results for circulating immunocomplexes are usually negative.

Imaging Studies

• Although once commonly obtained in patients with juvenile systemic sclerosis, barium swallow with small bowel follow-through has been replaced by esophageal manometry.
• High-resolution thin-cut CT (HRCT) of the lungs has been helpful in making the diagnosis and in following the progress of diffuse interstitial pneumonitis and pulmonary fibrosis in patients with juvenile systemic sclerosis.

Other Tests

• Nailfold capillaroscopy may reveal changes prior to the onset of systemic symptoms. The changes noted on nailfold capillaroscopy in patients with Raynaud phenomenon include abnormal capillary dilation (resulting from vasculopathy) or loss of nailfold capillaries.
• Although HRCT remains the imaging study of choice when monitoring patients with juvenile systemic sclerosis for early evidence of interstitial pneumonitis and pulmonary fibrosis, the diffusing capacity of the lung for carbon monoxide (DLCO) test is the most sensitive for detecting early evidence of pulmonary fibrosis.  
• Although skin biopsies have been useful in assessing patients with systemic sclerosis for years, the results are not specific and must always be correlated with clinical features. Tests for collagen synthesis have not been consistently helpful, and their performance and interpretation requires the expertise of a research laboratory.
• Esophageal manometry is currently the study of choice for diagnosis of esophageal involvement in patient with juvenile systemic sclerosis.

Histologic Findings

• Early in the course of systemic sclerosis, an inflammatory reaction with subintimal vascular proliferation and an infiltration of round cells often goes unrecognized. After a varying length of time, fibrosis follows this reaction. Fibrosis characterizes the final common pathway in systemic sclerosis.
• In the skin, thinning of the epidermis occurs, with loss of rete pegs as collagens and accumulation of other matrix proteins in the dermis. Early studies made use of this feature to quantitate dermal thickness in skin biopsies and relate the degree of fibrosis with disease severity.
• Arteriolar and capillary endothelial proliferation precedes fibrosis in the visceral organs. Prognosis is related to the intensity and rapidity of fibrosis in the lungs, heart, GI tract, and kidney. Finally, atrophy ensues, and vital function is compromised.
• Humoral and cellular immunity both contribute to the pathology of systemic sclerosis, but the intimate details remain to be elucidated. The complex relationships among immune, vascular, and fibrotic perturbations may help explain the difficulties encountered in the treatment of patients with systemic sclerosis.

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