Systemic Sclerosis (SSc)

Systemic sclerosis (SSc) is a chronic autoimmune disease mediated systemic connective tissue disorder characterized by characteristic vascular damage and fibrosis of the skin and internal organs (1). Diagnosis of SSc is based on the clinical course and features in addition to laboratory findings including autoantibody profiles. SSc patients can be classified clinically into two groups, limited cutaneous systemic sclerosis (lcSSc) and diffuse cutaneous systemic sclerosis (dcSSc), according to the peak extent of skin involvement (3). Skin thickening in lcSSc patients is limited to the face and the distal aspect from the elbows and knees, whereas that of dcSSc patients involves the trunk and proximal extremities in addition to distal areas.

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Patients with dcSSc show more severe and rapid progression of skin thickening and internal organ involvement including interstitial lung disease (ILD), cardiovascular lesions, and renal crisis. Vascular involvement, including digital ulcers and pulmonary arterial hypertension (PAH), can be detected in both lcSSc and dcSSc (2).

SSc Classification Criteria Criteria and Serology Biomarkers

  • Most SSc patients are seropositive for antinuclear antibodies and have disease-specific autoantibodies, which can be detected prior to the development of clinical symptoms. Disease-specific autoantibody profiles support not only conclusive and phenotypic diagnoses but can also be associated with clinical manifestations and disease progression of SSc. Anticentromere antibody, anti-topoisomerase I antibody, and anti-RNA polymerase III antibody are specific and included in 2013 ACR/EULAR criteria [Van Den Hoogen, 2013).

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Anti-Nuclear Antibody (ANA)​

  • ANA are common in the sera of patients with SSc reported in between 75-95% of patients with SSc. The diagnostic sensitivity of 85% and specificity of 54% when evaluated by indirect immunofluorescence using human epithelial cells (HEp2) as a substrate (Solomon, 2002).

 

​Anti-Topoisomerase I Antibody (SCl-70)​

  • The presence of Scl-70 antibodies (also referred to as topoisomerase I, topo-I or ATA) is considered diagnostic for systemic sclerosis (SSc). Scl-70 antibodies are detected in about 20 percent of SSc patients and are associated with the diffuse form of the disease, which may include specific organ involvement and poor prognosis. Scl-70 antibodies have also been reported in a varying percentage of patients with systemic lupus erythematosus (SLE). Negative results do not necessarily rule out the presence of SSc (Solomon, 2002).

​Anti-RNA polymerase III Antibody​

  • Anti-RNA polymerase III antibody correlates with increased risk of dcSSc, renal crisis, joint contractures, and is often associated with the complication of malignancies. Moreover, presence of this antibody is associated with rapidly increasing skin thickening and a shorter interval between the first appearance of any SSc-related symptoms and peak skin thickness. The prevalence of anti-RNA polymerase III antibodies in patients with SSc is variable with a pooled prevalence of 11% and ranges from 0 to 41% in different studies. Positivity for anti-RNA polymerase III antibody is mutually exclusive of other SSc-specific antibodies such as centromere and Scl 70. In addition, SSc patients who evaluate positive for anti-RNA polymerase III antibody have increased risk for the diffuse cutaneous involvement, hypertensive kidney disease, and poor prognosis (Sobanski, 2014).

Anti-Centromere Antibody (ACA)

  • Anticentromere antibody is detected in about 70% of SSc but may also be found in patients with other collagen diseases and primary biliary cholangitis. While for SSc this antibody is associated with modest fibrosis of the skin (lcSSc) and internal organs, it is also associated with slowly progressive vascular involvement such as digital ulcers and PAH. The presence of ACA has long been strongly associated with CREST, a variant of SSc, defined by the presence of calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangectasia. With a specificity of close to 100% the finding of ACA can also distinguish CREST serologically from patients with other variants of SSc [from patients with other connective tissue disorders and from patients with primary Raynaud's phenomenon (Ho, 2003, Solomon, 2002)

Anti-U1-RNP

  • The frequency of anti-U1-RNP antibodies in SSc is about 8% (ranging from 2% to 14%). Anti-U1-RNP antibodies in high titers are most often found in association with an overlap syndrome/Mixed connective tissue disease (MCTD) with a frequency of more than 90%. Anti-U1-RNP antibodies in patients with CTD are associated with the presence of Raynaud's phenomenon (Ho, 2003).

Anti-RNP 70

  • Autoantibodies directed against ribonucleoprotein 70 (RNP,70) have been important diagnostic markers for the serological detection of MCTD. The antibodies are directed against the 70kDa protein which is part of the U1-snRNP complex. The sensitivity is 100%, and its absence can rule out MCTD. However, some patients with SLE and systemic sclerosis are also found to test positive for anti-RNP (Ho, 2003).

Systemic Sclerosis (SSc) Tests

Selected References

  1. Allanore Y., Simms R., Distler O., Trojanowska M., Pope J., Denton C.P., Varga J. Systemic sclerosis. Nat. Rev. Dis. Primers. 2015; 1:15002. 

  2. Denton C.P., Khanna D. Systemic sclerosis. Lancet. 2017; 390:1685–1699. doi: 10.1016/S0140-6736(17)30933-9. 

  3. LeRoy E.C., Black C., Fleischmajer R., Jablonska S., Krieg T., Medsger T.A., Jr., Rowell N., Wollheim F. Scleroderma (systemic sclerosis): Classification, subsets, and pathogenesis. J. Rheumatol. 1988; 15:202–205.

  4. Ho, K. T., & Reveille, J. D. (2003). The clinical relevance of autoantibodies in scleroderma. Arthritis Res Ther, 5(2), 1-14.

  5. Sobanski V, Dauchet L, Lefevre G, et al: Prevalence of anti-RNA polymerase III antibodies in systemic sclerosis: new data from a French cohort and a systematic review and meta-analysis. Arthritis Rheumatol. 2014 Feb;66(2):407-417.

  6. Solomon DH, Kavanaugh AJ, Schur PH, The American College of Rheumatology Ad Hoc Committee on Immunologic Testing Guidelines Evidence-based guidelines for the use of immunologic tests: antinuclear antibody testing. Arthritis Rheum. 2002; 47:434–444. 

  7. Van Den Hoogen F., Khanna D., Fransen J., Johnson S.R., Baron M., Tyndall A., Matucci-Cerinic M., Naden R.P., Medsger T.A., Jr., Carreira P.E., et al. 2013 classification criteria for systemic sclerosis: An American college of rheumatology/European league against rheumatism collaborative initiative. Ann. Rheum. Dis. 2013; 72:1747–1755.