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    Drugs & Diseases>Rheumatology

    Scleroderma Workup

    Updated: Mar 01, 2023
    • Author: Abhishek Nandan, MD; Chief Editor: Herbert S Diamond, MD  more...
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    Workup

    Approach Considerations

    The diagnosis of systemic sclerosis is based on the clinical manifestations. Nevertheless, a number of tests and procedures may be used in the initial diagnosis (eg, to exclude alternative diagnoses), the assessment of organ involvement, and monitoring of disease progression.

    Laboratory testing may include the following:

    • Complete blood cell count (CBC)
    • Serum muscle enzyme levels
    • Erythrocyte sedimentation rate
    • C-reactive protein
    • Creatinine
    • N-terminal pro-brain natriuretic peptide
    • Autoantibody assays

    Assessment of gastrointestinal involvement

    Conventional radiography is the principal imaging study for assessment of gastrointestinal involvement in systemic sclerosis. Plain abdominal radiographs may reveal pseudointestinal obstruction, or rarely pneumatosis cystoides intestinalis. For more information, see Gastrointestinal Scleroderma Imaging.

    Esophagogastroduodenoscopy with appropriate biopsies, esophageal manometry assessment, and pH monitoring studies should be performed to survey and evaluate the upper gastrointestinal system, including documentation of esophageal dysmotility and an incompetent lower esophageal sphincter. [100] A gastric emptying study should be performed to document delayed gastric emptying. Colonoscopy can identify wide-mouth colonic diverticula, which are uniquely characteristic for systemic sclerosis.

    Assessment of pulmonary involvement

    Chest radiography is an insensitive imaging procedure that typically shows only late findings of pulmonary fibrosis, such as increased interstitial markings. [101] High-resolution computerized tomography (HRCT) is highly sensitive for revealing pulmonary involvement. HRCT scanning should be performed every 6 months if active alveolitis or interstitial pulmonary fibrosis is present and every year if these abnormalities are not present. For more information, see Thoracic Scleroderma Imaging.

    Pulmonary function testing is important in all patients with systemic sclerosis, although lung volumes may correlate poorly with the extent of interstitial lung disease. Results of pulmonary function testing are ultimately abnormal in 80% of patients. Pulmonary function tests should be performed every 6 to 12 months to detect early abnormalities indicative of development and/or progression of pulmonary hypertension or pulmonary fibrosis.

    Bronchoscopy with bronchoalveolar lavage is used to differentiate active infections from progressive interstitial lung disease. [102, 103]

    Assessment of cardiovascular involvement

    Elevated CXCL4 serum levels correlate with the severity of pulmonary fibrosis and progression of pulmonary hypertension. [104] Elevated serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) may correlate with early pulmonary hypertension. [105, 106, 107]

    Hughes et al propose using cardiac troponins as a screening tool to detect asymptomatic cardiac involvement, with measurement of cardiac troponin T followed by confirmatory cardiac troponin I. Cardiac involvement is unlikely if levels of both troponins are normal and is probable if levels of both are high. Low-titer troponin T levels may reflect skeletal muscle involvement, but cardiac assessment is nevertheless warranted. [108]

    Electrocardiograms (ECGs) should be performed annually to identify arrhythmias and conduction defects. Consider performing baseline ECGs in all new patients with sclerderma. ECGs can identify early changes of right ventricular strain caused by pulmonary hypertension, and in advanced states, right atrial hypertrophy. 24-hour ambulatory Holter monitoring may be performed to evaluate arrhythmias and serious conduction defects.

    Transthoracic echocardiography is a noninvasive study for assessing pulmonary artery pressure. Conduct this test to evaluate the patient's pulmonary artery pressure at initial evaluation and during serial follow ups and to assess septal fibrosis or pericardial effusions. Especially in patients with diffuse disease and in those with decreases in diffusing capacity for carbon monoxide (DLCO), this test should be performed annually to screen for pulmonary artery hypertension.

    Right-heart catheterization is the standard criterion and only definitive test for diagnosing pulmonary hypertension. It is usually performed after an elevated pulmonary artery pressure is found on echocardiographic screening. [109, 110]

    Other studies

    The workup may also include the following:

    • Extremity radiography may be performed as indicated to reveal calcinosis, resorption of the distal tufts of the digits, and to exclude osteomyelitis secondary to infected digital ulcers (see the image below). [111, 112]

      A radiograph of the distal digits demonstrating caA radiograph of the distal digits demonstrating calcinosis and distal phalanx reabsorption (acral osteolysis).
      View Media Gallery

    • Mandibular radiographs may reveal resorption of the ramus and the angle of the mandible

    • Nail-fold capillary microscopy is a noninvasive procedure of substantial value for the assessment of microvascular alterations in systemic sclerosis [113, 114, 115, 116]

    Next: Laboratory Studies

    Laboratory Studies

    Findings on laboratory studies may include the following:

    • A rapid increase in serum creatinine levels is typical of scleroderma renal crisis.

    • A microangiopathic hematologic picture and thrombocytopenia may precede renal crisis.

    • Serum levels of muscle enzymes (creatine kinase, aldolase) are elevated in patients with inflammatory myopathy.

    • CXCL4 is a very potent anti-antiangiogesis cytokine produced by plasmocytoid dendritic cells. Elevated CXCL4 serum levels have been found in a large proportion of systemic sclerosis patients and higher levels correlated with the severity of pulmonary fibrosis and progression of pulmonary hypertension. [104]

    • Elevated serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) may correlate with early pulmonary hypertension. [105, 106, 107]

    • The erythrocyte sedimentation rate (ESR) is almost always normal; however, an elevated ESR is associated with a poor outcome.

    • Anemia (microcytic) resulting from chronic blood loss is frequent and is often associated with iron deficiency; this finding should prompt consideration of gastric antral vascular ectasias (GAVE), which can be confirmed via an upper endoscopy.

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    Next: Laboratory Studies

    Autoantibodies

    Owing to the almost universal involvement of the immune system, most patients have specific humoral and cell-mediated immunity abnormalities. [117, 118, 119, 120] The value of serology testing is for initial diagnosis and assessment of associated conditions; it is of little use for monitoring disease activity.

    Antinuclear antibodies are present in about 90%-95% of affected patients, usually with a speckled or centromere pattern. A nucleolar pattern, although less common, is more specific for systemic sclerosis.

    Topoisomerase I antibodies (also known as Scl-70) are present in approximately 30% of patients with diffuse disease (absent in limited disease). Patients harboring Scl-70 antibodies are at higher risk of developing pulmonary parenchymal involvement, in contrast to patients harboring anti-centromere antibodies.

    Anticentromere antibodies are present in about 45%-50% of patients with limited disease. They are rare in patients with diffuse disease.

    Anti-RNA polymerase I and III antibodies are present in 15%-20% of patients with diffuse disease and correlate with rapid cutaneous involvement and high frequency of renal crisis. Anti-Th/To  is present mostly in limited disease and is associated with more extensive visceral disease. Anti-PM-Scl is present in patients with overlap connective tissue disease or with mixed connective tissue disease (MCTD) and is associated with myositis and renal involvement.

    Antibodies to ribonucleoprotein (U1-RNP) may be present. Anti-U1RNP is present mostly in patients with diffuse disease with overlap syndromes and in patients with MCTD. These antibodies are more common in patients with skeletal muscle involvement and pulmonary disease.

    Fibrillarin antibodies (anti-U3RNP) is another specific antibody for scleroderma. It generally suggests diffuse systemic sclerosis and is also associated with cardiac fibrosis as a manifestation. Patients with anti-U3RNP are also at increased risk for progressive pulmonary manifestations.

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    Next: Laboratory Studies

    Computed Tomography

    High-resolution computerized tomography (HRCT) scans are required to evaluate pulmonary involvement. [117, 121] HRCT is highly sensitive for revealing pulmonary involvement. Patients with normal initial HRCT findings have a good long-term prognosis.

    On HRCT, the first abnormality observed during the development of lung fibrosis is a ground-glass appearance, which occurs in areas of active alveolitis or septal fibrosis. As interstitial fibrosis becomes established, the ground-glass appearance is subsequently replaced by honeycombing and traction bronchiectasis or bronchiolectasis. This pattern of lung involvement is often termed nonspecific interstitial pneumonia (NSIP), but cases of usual interstitial pneumonia (UIP) pattern have also been known to occur. 

    HRCT scanning should be performed every 6 months if active alveolitis or interstitial pulmonary fibrosis is present.

    For more information, see Thoracic Scleroderma Imaging.

    Previous
    Next: Laboratory Studies

    Pulmonary Function Studies

    Pulmonary function testing is important in all patients with systemic sclerosis, [122, 123, 124, 125] although lung volumes may correlate poorly with the extent of interstitial lung disease. Pulmonary function tests should be performed every 6 to 12 months to detect early abnormalities indicative of development and/or progression of pulmonary hypertension or pulmonary fibrosis. Results of pulmonary function testing are ultimately abnormal in 80% of the patients.

    Diffusing capacity for carbon monoxide (DLCO) is very sensitive and helps establish lung involvement at an earlier stage. Pulmonary function tests may demonstrate a restrictive pattern with decreased forced vital capacity (FVC) and total lung capacity (TLC) and a low DLCO. These changes reflect fibrotic infiltration in the lung. An isolated or disproportionate reduction of DLCO with an FVC/DLCO or TLC/DLCO ratio of greater than 1.6 indicates pulmonary vascular obliteration associated with pulmonary hypertension.

     

     

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    Next: Laboratory Studies

    Transthoracic Echocardiography

    Transthoracic echocardiography is a noninvasive study for assessing pulmonary artery pressure. [24, 126] Conduct this test to evaluate the patient's pulmonary artery pressure at initial evaluation and during serial follow ups and to assess septal fibrosis or pericardial effusions. Roughly 30% of patients have asymptomatic pericardial effusions.

    A systolic pulmonary artery pressure of greater than 35 mm Hg is considered to represent pulmonary arterial hypertension. However, right-sided heart catheterization is required to obtain an accurate evaluation of pulmonary artery pressure.

    Previous
    Next: Laboratory Studies

    Electrocardiography and Holter Monitoring

    Electrocardiograms should be performed annually to identify arrhythmias and conduction defects. [127, 128] Electrocardiography can identify early changes of right ventricular strain caused by pulmonary hypertension, and in advanced states, right atrial hypertrophy. Perform 24-hour ambulatory Holter monitoring to evaluate arrhythmias and serious conduction defects.

    Previous
    Next: Laboratory Studies

    Gastrointestinal Endoscopy

    Esophagogastroduodenoscopy with appropriate biopsies, esophageal manometry assessment, and pH monitoring studies should be performed to survey and evaluate the upper gastrointestinal system. [129, 130] The following disorders can be evaluated:

    • Reflux due to decreased lower esophageal sphincter pressure
    • Severe esophagitis
    • Candida esophagitis
    • Esophageal strictures
    • Barrett metaplasia
    • Esophageal cancer
    • Gastric vascular antral ectasia (GAVE; dilated submucosal capillaries), with an endoscopic appearance that has been described as “watermelon stomach”
    Previous
    Next: Laboratory Studies

    Nail-fold Capillary Microscopy

    Nail-fold capillary microscopy is a non-invasive procedure of substantial value for the assessment of microvascular alterations in systemic sclerosis. [113, 114, 115, 116] Typical findings in systemic sclerosis are fewer capillaries than normal (ie, capillary loop drop; see image below) and numerous dilated, irregular, tortuous capillary loops. Severe findings on nail-fold capillaroscopy appear to predict future severe organ involvement. [116]

    Scleroderma: Fingernail capillary bed demonstratinScleroderma: Fingernail capillary bed demonstrating capillary dropout with large dilated vessels.
    View Media Gallery
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    Next: Laboratory Studies

    Histologic Findings

    Skin biopsies and lung biopsies provide conclusive diagnosis of systemic sclerosis, however, these are not routinely used for diagnostic purposes as the diagnosis of systemic sclerosis is based on the clinical manifestations. However, biopsy specimens are obtained to exclude systemic sclerosis mimics, as listed in Diagnostic Considerations.

    The pathologic changes in systemic sclerosis encompass a spectrum reflecting variable stages of development and progression of the three major processes occurring in the affected tissues, as follows:

    • Severe tissue fibrosis with exaggerated deposition of collagen and other connective tissue components in the extracellular matrix

    • Chronic inflammation, occurring predominantly in the early stages of disease and characterized by infiltration with mononuclear cells, mostly of the macrophage and T-cell lineages

    • Microvascular disease, characterized by intimal proliferation, concentric subendothelial deposition of collagen and mucinous material, and narrowing and thrombosis of the vessel lumen

    The histopathological findings in the skin include marked thickening of the dermis with massive accumulation of dense collagen causing epidermal atrophy, flattening of the rete pegs, and replacement of sebaceous and sweat glands, as well as hair follicles (see image below). A prominent inflammatory infiltrate is often present at the dermal-adipose tissue interphase, especially in early lesions. The small vessels of the lower dermis show fibrous thickening but evidence of vasculitis is absent.

    Skin biopsy showing extensive fibrosis. The biopsySkin biopsy showing extensive fibrosis. The biopsy has a square morphology, which reflects the rigidity of the tissue biopsy specimen due to striking pan-dermal sclerosis. In addition, the fibrosing reaction extends into the panniculus. The number of adnexal structures is reduced, another characteristic feature of scleroderma. A significant inflammatory cell infiltrate is not observed. This is in contradistinction to morphea, in which a prominent inflammatory cell infiltrate is present.
    View Media Gallery
    Skin biopsy showing severe fibrosis. The fibrosis Skin biopsy showing severe fibrosis. The fibrosis reflects a widening of collagen bundles in concert with an increase in the number of collagen fibers. Note the superimposed deposition of the newly synthesized delicate collagen bundles interposed between the preexisting collagen bundles, the latter appearing wide and manifesting a hyalinized morphology.
    View Media Gallery

    In the lungs, fibrosis of the alveolo-capillary membrane and the parenchymal interstitium accompanied by severe mononuclear cell infiltration is present frequently, resulting in marked disruption of their architecture. Prominent vascular abnormalities with intimal proliferation causing narrowing or complete obliteration of small vessels are frequent (see the images below).

    Lung biopsy demonstrating severe interstitial fibrLung biopsy demonstrating severe interstitial fibrosis and medial fibrosis and smooth muscle hyperplasia of a pulmonary arteriole compatible with pulmonary hypertension.
    View Media Gallery
    Lung biopsy demonstrating expansion of the interstLung biopsy demonstrating expansion of the interstitium of the lung by fibrous tissue along with chronic inflammatory cells.
    View Media Gallery

    Kidney lesions display severe narrowing and obliteration of the medium-size arterioles due to sub-intimal accumulation of loose connective tissue and intimal and perivascular fibrosis. The glomeruli frequently appear ischemic and there is no evidence of glomerulitis. Severe interstitial, perivascular, and periglomerular fibrosis may be present in cases of long duration.

    Other affected organs display variable degrees of fibrosis, mononuclear cell infiltration, and microvascular obliteration and fibrosis.

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