Harshi Dhingra is a licensed medical doctor with specialization in Pathology. She is currently employed as faculty in a medical school with a tertiary care hospital and research center in India. Dr. Dhingra has over a decade of experience in diagnostic, clinical, research, and teaching work, and has written several publications and citations in indexed peer reviewed journals. She holds medical degrees for MBBS and an MD in Pathology.
Systemic sclerosis (SSc) is a heterogeneous, chronic autoimmune disorder that can affect multiple organ systems. The characteristic features of SSc include inflammation, vasculopathy, and progressive fibrosis of the skin and internal organs. An early diagnosis is required to delay, reduce, or prevent irreversible end-organ damage.1 Various tests are helpful in the diagnostic process to meet criteria and eliminate differential diagnoses.
Laboratory Testing for SSc
Basic Laboratory Testing
- Complete blood cell counts are required to check for various causes of anemia in SSc.2 The erythrocyte sedimentation rate is elevated in SSc.3
- Renal function is monitored closely with a 24-hour urinary protein test or the urinary protein/creatinine ratio.2 Urea and creatinine levels are elevated in patients with renal involvement.3
- Muscle enzymes, such as creatine kinase and aldolase, can be elevated, particularly in cases of inflammatory myopathy.2
- C-reactive protein is a nonspecific inflammatory marker that is increased in roughly 25% of patients with SSc, particularly in early disease. Increased levels correlate with disease activity and severity, reduced lung function, and shorter survival.3
Read more about SSc diagnosis
Autoantibodies are produced as a result of immune system activation in SSc. The autoantibodies most commonly seen in patients with SSc are antinuclear antibodies (ANA). Besides serving as a diagnostic guide, numerous disease-specific autoantibodies can predict disease phenotype and give prognostic information.4
The initial test used to identify autoantibodies in a patient with nonspecific symptoms, such as Raynaud phenomenon, is the ANA immunofluorescence assay (IFA). Although ANA are detected in 85% to 95% of people with SSc, they are also found in individuals with many other autoimmune diseases. For this reason, patients should undergo testing for more specific antibodies (anti-centromere B, anti-Scl-70 [topoisomerase I], and anti-RNA polymerase III antibodies) if the result of an ANA IFA test is positive. A negative ANA IFA test result makes SSc less probable but does not exclude it.1
Anti-centromere antibodies that target 4 centromere antigens (CENP-B, -A, -C, and -D) are present in limited cutaneous SSc and occasionally in diffuse cutaneous SSc. These antibodies are associated with an increased risk of pulmonary arterial hypertension, a lower risk of interstitial lung disease (ILD), and overall better survival in comparison with other autoantibodies.2
Read more about SSc life expectancy
Anti-Scl-70 (Anti-topoisomerase I) Antibodies
Autoantibodies against topoisomerase I (topo I, ATA, Scl-70) are strongly associated with diffuse cutaneous SSc but can also be seen in limited cutaneous SSc. These antibodies are associated with pulmonary complications, digital ulcers, and progressive disability of the hands. They are highly specific in SSc and are included in the 2013 ACR-EULAR classification criteria.1,4
Anti-RNA Polymerase III Antibodies
These antibodies target the eukaryotic RNA polymerase III. They are relatively specific for the diffuse cutaneous form of SSc and are linked to diffuse skin involvement that progresses quickly and aggressively, poor cutaneous outcomes, and scleroderma renal crisis.2
Less Frequently Observed Autoantibodies
The following autoantibodies are occasionally found in patients with SSc:
- Antibodies against fibrillarin (anti-U3RNP)4
- Anti-Th/To antibodies2
- Anti-PM/Scl antibodies2
- Anti-Ku antibodies2
Read more about SSc clinical features
Radiographic Testing and Imaging Studies for SSc
X-ray films of the bones show generalized osteopenia affecting mainly the hands. Intra-articular calcifications are also usually noted.3
High-resolution computed tomography of the chest is important because it shows the characteristic features of SSc-associated ILD. The nonspecific interstitial pneumonia pattern in ILD appears as ground-glass opacities in a peripheral distribution with subpleural and basilar predominance. Ground-glass opacities are associated with the early stages of SSc.4
Barium radiography, scintigraphy, or antroduodenal manometry confirms the presence of gastroparesis, seen in 50% of patients with SSc.4
Doppler echocardiography assesses cardiac abnormalities. One of the most common cardiac findings is diastolic dysfunction.3
Doppler flowmetry with laser in the distal portion of the upper extremity is recommended as the early changes in SSc involve the microcirculation.3
High-resolution ultrasonography of the skin in patients with SSc is used for a quantitative determination of the thickness of the dermis.3
Magnetic resonance imaging (MRI), computed tomography (CT), single-photon emission computed tomography (SPECT), and positron emission tomography (PET) are used to evaluate neurological damage in SSc. Nerve conduction testing is the main method used to confirm peripheral nerve involvement. Electromyography (EMG) can demonstrate the nature of peripheral nerve involvement, differentiating between polyneuropathy and mononeuropathy and between neurogenic and myogenic lesions.4
Ultrasonography and MRI are important for detecting tendonitis, synovitis, and tenosynovitis in patients with SSc. Ultrasonography identifies inflammatory abnormalities in joints and structural changes in bone.4
Pulmonary function tests that include lung volume measurement, spirometry, and diffusion capacity measurement are also useful as they identify a restrictive pattern in early stages of the disease.2
Read more about SSc signs and symptoms
Biopsy and Histopathologic Examination for SSc
Histologic evaluation of the skin is not required for a diagnosis of SSc.5 The history, physical examination findings, test results, and 2013 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria are used for this purpose. Skin histology is not included in the SSc categorization criteria.6
However, skin biopsy may occasionally be useful to support a diagnosis of SSc or distinguish it from illnesses with similar clinical symptoms. Additionally, a few studies have used skin biopsy to compare the histological aspects of various subtypes of SSc.6
Histological examination of the lungs, kidneys, and heart is not used routinely because access to these tissues is limited. The results of high-resolution CT of the chest and pulmonary function testing are used in decision making.5
Read more about SSc histology
- Systemic sclerosis: laboratory markers for diagnosis and prognosis. Quest Diagnostics. Reviewed July 2021. Accessed April 27, 2023.
- Adigun R, Goyal A, Hariz A. Systemic sclerosis. StatPearls [Internet]. Updated May 8, 2022. Accessed April 27, 2023.
- Schwartz RA, Systemic sclerosis workup. Medscape. Updated April 16, 2021. Accessed April 27, 2023.
- Sobolewski P, Maślińska M, Wieczorek M, et al. Systemic sclerosis – multidisciplinary disease: clinical features and treatment. Reumatologia. 2019;57(4):221-233. doi:10.5114/reum.2019.87619
- Avouac J. SP0126 histopathology of systemic sclerosis: the skin and beyond. Ann Rheum Dis. 2015;74:31. doi:10.1136/annrheumdis-2015-eular.6642
- Showalter K, Gordon JK. Skin histology in systemic sclerosis: a relevant clinical biomarker. Curr Rheumatol Rep. 2020;23(1):3. doi:10.1007/s11926-020-00970-z
Reviewed by Kyle Habet, MD, on 4/30/2023.