Systemic Sclerosis (SSc)

Systemic sclerosis (SSc) is a chronic autoimmune disorder of connective tissue that causes fibrosis and vascular damage. The various presentations and systemic involvement can create a challenging diagnosis for physicians, and treatment often requires a multidisciplinary team approach.¹ SSc is linked to several systemic symptoms and internal organ involvement, and the mortality rate is high. The skin, gastrointestinal system, lungs, kidneys, skeletal muscles, and pericardium are most frequently affected in SSc.²

The early identification of SSc is crucial because early therapy can greatly improve patient outcomes. However, because many patients present with vague symptoms like Raynaud phenomenon, gastroesophageal reflux, puffy fingers, and fatigue, the diagnosis can be difficult to make. Additionally, individuals with other autoimmune diseases may exhibit SSc-like symptoms. Testing for SSc-related autoantibodies facilitates the diagnosis and helps clinicians to estimate the degree of organ involvement and severity of disease.³

Diagnostic Clinical Manifestations

A diagnosis of SSc should be considered for patients with Raynaud syndrome, typical musculoskeletal or cutaneous signs, unexplained dysphagia, malabsorption, pulmonary fibrosis, pulmonary hypertension, cardiomyopathy, or conduction disorders.⁴

Systemic sclerosis can easily be diagnosed in patients with multiple characteristic symptoms, such as tight skin, dysphagia, and Raynaud syndrome (with aberrant nailfold capillaroscopy findings). However, in some cases, a clinical diagnosis cannot be made. Confirmatory laboratory tests can improve the likelihood of a diagnosis; however, negative test results do not rule out SSc.⁴ 

Read more about SSc clinical features

Diagnostic Antibody Tests

Antinuclear antibodies (ANA) are detected in 90% or more of patients, frequently in an nucleolar pattern. One-third of patients test positive for rheumatoid factor.⁴ 

Anti-centromere antibodies are usually noted in patients with limited disease; however, they are not specific. Anti-Scl-70 (topoisomerase I) antibodies are more prevalent in patients with generalized (diffuse) SSc than in those with limited disease. RNA polymerase III antibodies are associated with generalized SSc, scleroderma renal crisis, and cancer. Antibodies against fibrillarin (anti-U3RNP) are also associated with diffuse disease.⁴ 

Testing first for ANA, anti-Scl-70 antibodies, and anti-centromere antibodies is the most cost-effective way to assess for antibodies; if the results are negative, testing for other antibodies should be considered, depending on the clinical signs.⁴ 

Read more about SSc testing

ACR-EULAR Classification Criteria

The classification criteria formulated in 2013 by the European League Against Rheumatism and American College of Rheumatology (ACR/EULAR) established that SSc could be diagnosed if thickening of the skin of the fingers extends proximal to the metacarpophalangeal joints.⁵ 

Absent this finding, the presence of the following 7 features should be noted and scored: thickening of the skin of the fingers, lesions on the fingertips, telangiectasia, abnormal nailfold capillaries (ectatic blood vessels as seen on capillaroscopy examination using an ophthalmoscope), interstitial lung disease or pulmonary arterial hypertension, Raynaud phenomenon, and SSc-related autoantibodies (anti–RNA polymerase III, anticentromere, anti–Scl-70).⁵ 

Patients with a score higher than 9 meet the diagnosis of SSc.^4,5 The ACR-EULAR criteria are 91% sensitive and 92% specific for SSc.^3,5 

ACR-EULAR Criteria for the Classification of Systemic Sclerosis³

	Classify a patient as having systemic sclerosis if the sum of points for the criteria below is ≥9.
	Criterion	Points
	Skin thickened on the fingers of both hands, extending proximal to the metacarpophalangeal joints	9
1	Skin on fingers thickened (count only the highest score) Puffy fingers Sclerodactyly	2 4
2	Lesions on fingertips (count only the highest score) Ulcers on tip of digits Pitting scars on fingertips	2 3
3	Telangiectasia	2
4	Abnormal nailfold capillaries	2
5	Pulmonary arterial hypertension and/or interstitial lung disease (maximum score is 2) Pulmonary arterial hypertension Interstitial lung disease	2 2
6	Raynaud phenomenon	3
7	Presence of ≥1 of the following: Centromere antibody Scl-70 antibody RNA polymerase III antibody	3

Read more about SSc guidelines

Other Tests to Support a Diagnosis of SSc

Clinical investigation, laboratory testing, and imaging studies should play a combined role in the diagnosis of SSc.⁶

Following a diagnosis, specific tests should be performed to check for internal organ involvement. These include chest radiography or computed tomography to check for heart or lung involvement, pulmonary function testing, and echocardiography.⁷ Doppler echocardiography can assess cardiac abnormalities.⁸

Skin histology is not included in the SSc categorization criteria. Skin biopsy, however, may occasionally be useful to support a diagnosis of SSc or distinguish SSc from illnesses with similar clinical symptoms. Additionally, a few studies have used skin biopsy to compare the histological aspects of various subtypes of SSc.⁹ 

Read more about SSc differential diagnosis

References

1. 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
2. Adigun R, Goyal A, Hariz A. Systemic sclerosis. StatPearls [Internet]. Updated May 8, 2023. Accessed April 30, 2023.
3. Systemic sclerosis: laboratory markers for diagnosis and prognosis. Quest Diagnostics. Reviewed July 2021. Accessed April 30, 2023. 
4. Nevares AM. Systemic sclerosis (scleroderma). MSD Manual Professional Version. Reviewed/revised October 2022. Accessed April 30, 2023. 
5. van den Hoogen F, Khanna D, Fransen J, et al. Classification criteria for systemic sclerosis: an ACR/EULAR collaborative initiative. Arthritis Rheum. 2013;65(11):2737-2747. doi:10.1002/art.38098
6. Mierau R, Roers A, Genth E. [Laboratory diagnostics for systemic sclerosis]. [Article in German]. Z Rheumatol. 2007;66(3):206, 208-211. doi:10.1007/s00393-007-0156-6
7. Gordon JK, Lakin K. Scleroderma and systemic sclerosis (SSc): an overview. Hospital for Special Surgery. Updated March 21, 2022. Accessed April 30, 2023.
8. Schwartz RA, Systemic sclerosis workup. Medscape. Updated April 16, 2021. Accessed April 30, 2023.
9. 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 Debjyoti Talukdar, MD, on 5/3/2023.

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Harshi Dhingra, MD

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.