Scleroderma Antibodies and Clinical Relevance

Historically, systemic scleroderma was diagnosed as either diffuse or limited.  The presence of anti-SCL-70 (anti-topoisomerase) antibodies is highly specific to the diagnosis of diffuse scleroderma, while the presence of anti-centromere antibodies is highly specific to the diagnosis of limited scleroderma. Over the past 35 years, however, several additional antibodies have been isolated that are related to the scleroderma family of diseases.  Some of these more recently isolated antibodies are specific to scleroderma, for example, anti-RNA polymerase III and anti-Th/To.  Others are found in other autoimmune disorders and include symptoms of scleroderma as well as other disorders (e.g., anti-PM-Scl).

Several studies have shown that there is clear clinical relevance based on the specific antibody type.  Different antibodies have very different risk profiles.  For example, with RNA Polymerase III antibodies, there is a significantly increased risk of kidney involvement early in the disease process.  With centromere antibodies, pulmonary artery hypertension is a significant risk, but usually later in the disease process.

As indicated in Table 2 below, the three most common antibodies found in patients with systemic scleroderma are Scl-70, centromere, and RNA Polymerase III.  While relatively complete scleroderma antibody panels are available from some commercial reference labs (e.g., RDL Reference Laboratory and ARUP Laboratories), individual antibody testing can be done at most other labs.  Since most patients with systemic scleroderma will have one of these three common antibodies, many clinicians will start with testing for these antibodies before doing additional testing for rarer antibodies.

One cautionary note about Scl-70 testing: there is some data that suggests a significant false positive error rate when testing for Scl-70 antibodies using newer solid-phase multiplex testing methods (Meier et al. 2011), primarily when results are in the low positive range.  Because of this potential issue, RDL Reference Lab confirms all positive Scl-70 results initially done by the ELISA method using a more accurate method called immunodiffusion.  Another reference lab, ARUP Laboratories, notes that if more than one scleroderma-specific antibody tests positive in their full scleroderma antibody panel, the Scl-70 is probably a false positive and should be ignored.  Research shows that fewer than 2% of systemic scleroderma have more than positive scleroderma specific antibody when testing problems are eliminated.

Table 2 lists all generally accepted scleroderma-related antibodies along with some general information on risks and other clinical associations.

Table 2: Scleroderma-Related Antibodies

Estimated Prevalence
Testing Available Clinical Associations
Anti-centromere (ACA) 20 to 30% Limited Yes CREST, PAH Skin changes often delayed for many years
15 to 20% Diffuse Yes ILD Rapid skin thickening, early internal organ involvement
Anti-RNA polymerase III ~ 20% Diffuse Yes PAH, cardiac, kidney Increased mortality
Anti-Th/To 2 to 5% Limited Yes PAH, ILD Worse prognosis than ACA
Anti-PM-Scl 2 to 3% Overlap Yes Myositis (muscle) Good prognosis, often responsive to steroids
~ 4% Diffuse Yes Myositis, PAH, kidney, cardiac Seen in younger patients with greater internal organ involvement
Anti-U1-RNP ~ 8% Overlap Yes Myositis, ILD, joint MCTD. More benign, responsive to steroids
Anti-Ku Rare Overlap Yes Myositis Limited cutaneous involvement
Anti-U11/U12-RNP ~ 3% Diffuse/
No ILD, joint Severe lung fibrosis
Anti-RuvBL1/2 ~ 2% Overlap No Myositis Diffuse cutaneous involvement

* classification as diffuse or limited refers to the skin fibrosis pattern seen with the antibody.

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