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Scleroderma Workup

  • Author: Sergio A Jimenez, MD; Chief Editor: Herbert S Diamond, MD  more...
 
Updated: Oct 26, 2015
 

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
  • Serum CXCL4 level
  • 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.[99] 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.[100] 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 the 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.[101, 102]

Assessment of cardiovascular involvement

Elevated CXCL4 serum levels correlate with the severity of pulmonary fibrosis and progression of pulmonary hypertension.[103] Elevated serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) may correlate with early pulmonary hypertension.[104, 105, 106]

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.[107]

Electrocardiograms (ECGs) should be performed routinely to identify arrhythmias and conduction defects. ECGs 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.

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.

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.[108, 109]

Other studies

The workup may also include the following:

  • Extremity radiography should be performed to reveal calcinosis, resorption of the distal tufts of the digits, and to exclude osteomyelitis secondary to infected digital ulcers [110, 111]
  • 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 [112, 113, 114, 115]
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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 [103]
  • Elevated serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) may correlate with early pulmonary hypertension [104, 105, 106]
  • 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
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Autoantibodies

Owing to the almost universal involvement of the immune system, most patients have specific humoral and cell-mediated immunity abnormalities.[116, 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-ThRNP 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.

Fibrillarin antibodies and antibodies to ribonucleoprotein (RNP) may be present. Anti-RNP 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.

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Computed Tomography

High-resolution computerized tomography (HRCT) scans are required to evaluate pulmonary involvement.[116, 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.

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.

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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.

Carbon monoxide diffusion capacity (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 and total lung capacity and a low DLCO. These changes reflect fibrotic infiltration in the lung (see images below). An isolated or disproportionate reduction of DLCO with a ratio of forced vital capacity (FVC) or total lung capacity (TLC) to DLCO of greater than 1.6 indicates pulmonary vascular obliteration associated with pulmonary hypertension.

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Transthoracic Echocardiography

Transthoracic echocardiography is a noninvasive study for assessing pulmonary artery pressure.[22, 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.

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Electrocardiography and Holter Monitoring

Electrocardiograms should be performed routinely 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.

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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 alterations can be evaluated:

  • Reflux due to decreased lower esophageal sphincter pressure
  • Severe esophagitis
  • Candida esophagitis
  • Barrett metaplasia
  • Esophageal cancer
  • Gastric vascular antral ectasia (GAVE; dilated submucosal capillaries), with an endoscopic appearance that has been described as “watermelon stomach”
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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.[112, 113, 114, 115] The typical findings demonstrate fewer capillaries than normal (ie, capillary loop drop; see image below) and numerous dilated, and irregular and tortuous capillary loops. Recent evidence indicates a predictive value of nailfold capillaroscopy for future severe organ involvement.

Fingernail capillary bed demonstrating capillary d Fingernail capillary bed demonstrating capillary dropout with large dilated vessels.
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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 biopsy Skin 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.
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.

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 image below).

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

The renal 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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Contributor Information and Disclosures
Author

Sergio A Jimenez, MD MACR, FACP, FRCP(UK, Hon), Professor and Director, The Scleroderma Center; Co-Director, Jefferson Institute of Molecular Medicine; Director, Division of Connective Tissue Diseases, Jefferson Medical College of Thomas Jefferson University

Sergio A Jimenez, MD is a member of the following medical societies: Royal College of Physicians, American Society for Biochemistry and Molecular Biology, American College of Physicians, American College of Rheumatology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Coauthor(s)

Fabian A Mendoza, MD, FACR Assistant Professor of Medicine, Division of Rheumatology, Jefferson Medical College and Jefferson Institute of Molecular Medicine; Associate Director of The Scleroderma Center, Director of Scleroderma Program, Thomas Jefferson University

Fabian A Mendoza, MD, FACR is a member of the following medical societies: American College of Rheumatology

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Elliot Goldberg, MD Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Temple University School of Medicine

Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology

Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD Visiting Professor of Medicine, Division of Rheumatology, State University of New York Downstate Medical Center; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, Phi Beta Kappa

Disclosure: Nothing to disclose.

Additional Contributors

John Varga, MD Professor, Department of Internal Medicine, Division of Rheumatology, Northwestern University

John Varga, MD is a member of the following medical societies: American College of Physicians, American College of Rheumatology, Central Society for Clinical and Translational Research, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Acknowledgements

Patrick M Cronin, DO, FACR Clinical Associate Professor of Medicine, Department of Medicine, Division of Rheumatology, University of Pennsylvania Health System, Pennsylvania Hospital

Patrick M Cronin, DO, FACR is a member of the following medical societies: American College of Rheumatology, American Osteopathic Association, and Pennsylvania Medical Society

Disclosure: Nothing to disclose.

Andrew S Koenig, DO Consulting Staff, Division of Rheumatology, Rancoccas Hospital

Andrew S Koenig, DO is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American College of Rheumatology, and American Osteopathic Association

Disclosure: Nothing to disclose.

Marie Spevak O'Brien, DO Assistant Clinical Professor of Medicine, Arthritis and Rheumatology, Lehigh Valley Physician Group

Marie Spevak O'Brien, DO is a member of the following medical societies: American College of Physicians, American College of Rheumatology, American Medical Association, American Osteopathic Association, International Society for Clinical Densitometry, and Pennsylvania Medical Society

Disclosure: Nothing to disclose.

Acknowledgments

The assistance of Kenneth Brown in the preparation of this manuscript is gratefully acknowledged.

Sergio A Jimenez, MD, was recipient of NIH/NIAMS grant #RO-1 AR19616.

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Tightening of the skin in the face, with a characteristic beaklike facies and paucity of wrinkles.
Sclerodactyly with digital ulceration, loss of skin creases, joint contractures, and sparse hair.
Anterior chest demonstrating salt-and-pepper hypopigmentation and diffuse hyperpigmentation in a white woman.
A radiograph of the distal digits demonstrating calcinosis and distal phalanx reabsorption (acral osteolysis).
Fingernail capillary bed demonstrating capillary dropout with large dilated vessels.
Lung biopsy demonstrating severe interstitial fibrosis and medial fibrosis and smooth muscle hyperplasia of a pulmonary arteriole compatible with pulmonary hypertension.
Lung biopsy demonstrating expansion of the interstitium of the lung by fibrous tissue along with chronic inflammatory cells.
Barium swallow demonstrating reflux into the distal esophagus, as well as an accordion appearance in the duodenum.
Skin 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.
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.
Overall scheme illustrating a current understanding of SSc pathogenesis. Hypothetical sequence of events involved in tissue fibrosis and fibroproliferative vasculopathy in SSc. An unknown causative agent induces activation of immune and inflammatory cells in genetically predisposed hosts resulting in chronic inflammation. Activated inflammatory and immune cells secrete cytokines, chemokines, and growth factors which cause fibroblast activation, differentiation of endothelial and epithelial cells into myofibroblasts, and recruitment of fibrocytes from the bone marrow and the peripheral blood circulation. The activated myofibroblasts produce exaggerated amounts of ECM resulting in tissue fibrosis.
Table.
Table 1: ACR/EULAR Revised Systemic Sclerosis Classification Criteria
Item Sub-item(s) Score*
Skin thickening of the fingers of both hands extending proximally to the metacarpophalangeal joints (presence of this criterion is sufficient criterion for SSc classification) None 9
Skin thickening of the fingers (count the higher score only) Puffy fingers 2
Sclerodactyly (distal to the metacarpophalangeal joints but proximal to the proximal interphalangeal joints) 4
Fingertip lesions (count the higher score only) Digital tip ulcers 2
Fingertip pitting scars 3
Telangiectasia None 2
Abnormal nailfold capillaries None 2
Pulmonary arterial hypertension and/or interstitial lung disease (maximum score is 2) Pulmonary arterial hypertension 2
Interstitial lung disease 2
Raynaud phenomenon None 3
Systemic sclerosis–related autoantibodies (maximum score is 3) Anticentromere 3
Anti–topoisomerase I 3
Anti–RNA polymerase III 3
*The total score is determined by adding the maximum score in each category. Patients with a total score equal to or greater than 9 are classified as having definite systemic sclerosis (modified from van den Hoogen F, Khanna D, Fransen J, et al. 2013 classification criteria for systemic sclerosis: an American College of Rheumatology/European League against Rheumatism collaborative initiative. Arthritis Rheum. Nov 2013;65(11):2737-47.[5] )
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