Clinical Information

Systemic sclerosis (SSc) is a multisystem autoimmune connective tissue disease (CTD) characterized by vascular dysfunction, fibrotic changes in the skin, organ involvement, and autoimmune response manifested by the production of diverse antibodies.(1,2) The clinical manifestations in SSc may overlap with other systemic autoimmune rheumatic diseases (SARD), complicating early diagnosis and appropriate management.(1,3,4) Clinically, early diagnosis and risk stratification of patients with SSc for specific clinical manifestations is important for appropriate management.(1,3,4) A characteristic clinical feature of SSc is Raynaud phenomenon’s vasculopathy characterized by SSc capillaroscopic changes on nailfold capillaroscopy.(3,4) Fibrosis and vasculopathy can extend to internal organs, causing severe complications such as interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), and scleroderma renal crisis (SRC).(2,4-6) Although SSc has traditionally been categorized into two main subsets (limited cutaneous [lcSSc] and diffuse cutaneous [dcSSc]), the clinical manifestations and severity of disease are highly variable.(3-7) Of the two forms, the dcSSc has the worse prognosis and survival rates compared to the lcSSc subset.(6,7)

Immunologically, SSc may be characterized by the presence of mutually exclusive disease-specific or SSc-associated autoantibodies, which could be helpful in the diagnosis, risk stratification, or management of patients.(1-8).Of the described autoantibodies in SSc, the 2013 American College of Rheumatology/European League against Rheumatism classification criteria for SSc recommend testing for centromere (ACA), topoisomerase I (topo I or Scl-70), and RNA polymerase III (RNAP) autoantibodies.(4) Antibodies to Scl-70 and RNAP are generally associated with dcSSc while ACA is typically correlates with the lcSSc form of the disease.(1-3,5) In addition to their correlations with lcSSc or dcSSc, these antibodies may be useful in predicting certain clinical manifestations, disease severity, and have varied prevalence in different racial/ethnic populations.(2,5,7,8) Depending on the racial/ethnic cohort, after ACA and anti-Scl-70 antibodies, autoantibodies to RNAP are the most frequent antinuclear antibodies in SSc.(7,8) In a reported meta-analysis of 30 peer-reviewed studies, the overall pooled prevalence of anti-RNAP antibodies was 11% with a 95% confidence interval of 8% to 14%.(5)

Other noncriteria autoantibodies specific or associated with potential for diagnosis or phenotypic stratification in SSc have been described.(2,5,7,8) The two best described SSc-specific antibodies include those targeting Th/To and U3RNP antigens expressed as antinuclear antibody (ANA) nucleolar pattern when detected using HEp-2 substrate by indirect immunofluorescence assay (HEp-2 IFA).(2,5,8) Anti-Th/To and anti-U3RNP antibodies are associated with unique clinical features (lcSSc or dcSSc) and are useful in predicting certain clinical manifestations in patients with SSc.(2,5,8) The SSc-associated antibodies useful diagnosis and risk stratification includes anti-U1RNP, anti-PM/Scl, anti-Ku, anti-Ro52, anti-Nor90 autoantibodies. These autoantibodies may be used to identify SSc with overlap syndromes (OS) or patients at risk for certain clinical manifestations such as ILD, and myositis.(1,2,5-7) Except for anti-Ro52 and anti-U1RNP autoantibody tests that are widely available, the routine use of the noncriteria antibodies is restricted to a few specialty laboratories with limited availability of commercial tests due technical issues that limit their sensitivities and specificities in methods typically used in the clinical laboratories.(5,8,9)

Antinuclear antibody  detected using HEp-2 IFA is present in most patients with SSc.(2,5,8) The most unique SSc pattern identified by HEp-2 IFA is ACA with the nucleolar pattern suggesting the presence of anti-U3 RNP, anti-Th/To, anti-NOR 90, or anti-PM/Scl antibodies.(2,5,8). In addition, the presence of anti-Scl70, anti-RNAP, anti-Ro52, anti-U1RNP, anti-Ku, or the other recently reported antibodies (anti-U11/U12 RNP, and anti-RuvBL1/2) may be characterized by composite or unique nuclear (nucleolar, speckled, homogeneous nuclear), cytoplasmic patterns and metaphase staining (for examples see www.anapatterns.org), confirming that the ANA test using HEp-2 IFA is important for the evaluation of SSc and SSc/OS.(2,5) Due to the complexity of diagnosing SSc including its clinical overlap with other ANA-CTD and high prevalence of ANA, the use of HEp-2 IFA in addition to criteria antibody tests is optimal for the initial evaluation of at-risk patients. The use of the HEp-2 IFA is also optimal in the interpretation of specific antibodies and may be clinically relevant in the absence of defined autoantibody specificities. ACA is optimally detected with HEp-2 IFA while anti-Scl-70 and anti-RNAP antibodies are routinely detected or measured with diverse solid-phase immunoassays (SPAs) such as the line immunoblot (LIA), enzyme-linked immunosorbent assay (ELISA), multiplex bead immunoassay (MBIA), chemiluminescence immunoassay (CIA), and fluorescence enzyme immunoassay (FEIA).(2,5-9) These SPAs have been reported to be less specific than the classical methods, especially in distinguishing SSc patients from those with other SARD, with ACA, anti-Scl70 and anti-RNAP antibodies generally demonstrating moderate to excellent correlations (Cohen’s kappa: 0.53 to 0.97).(9) However, in routine laboratory evaluation, tests for anti-Scl-70 antibodies have been reported to lack diagnostic specificity.(10,11) Therefore, results for these and other autoantibodies must be interpreted in the appropriate clinical context taking into consideration the presence of a positive ANA test using HEp-2 IFA, the degree of antibody positivity, and the method of their detection.(1,2,5,10)