Elsevier

Autoimmunity Reviews

Volume 7, Issue 8, September 2008, Pages 588-593
Autoimmunity Reviews

Predictive value of antinuclear autoantibodies: The lessons of the systemic sclerosis autoantibodies

https://doi.org/10.1016/j.autrev.2008.06.010Get rights and content

Abstract

Physicians who provide care to patients with systemic sclerosis (SSc, scleroderma) ask themselves several questions: Is SSc the correct diagnosis? Can the disease course be predicted? Is there a greater risk for involvement of certain organs? Can the vital prognosis be predicted?

In this brief review, we answer these questions by excerpting data from the literature focused on the 4 major SSc specific autoantibodies (aAbs) to nuclear autoantigens (ANAs): anti-centromere (anti-CENP-B), anti-Th/To, anti-topoisomerase I (anti-topo I) and anti-RNA polymerase III (anti-RNAPIII).

The data show that these aAbs are highly valuable as markers for the diagnosis of SSc, as biomarkers for phenotypic subsets and as prognostic markers.

We also identify areas for future clinical research.

Section snippets

The major autoantibodies specific for systemic sclerosis

The major autoantibodies (aAbs) to nuclear autoantigens (ANAs) associated with systemic sclerosis (SSc, scleroderma) are shown in Table 1. Four major ANAs have been associated thus far with “pure” SSc, i.e. SSc unassociated with overlap connective tissue disease (CTD) features, and are useful as specific diagnostic markers: anti-centromere, directed against centromere protein B (anti-CENP-B), anti-Th/To, anti-topoisomerase I (anti-topo I) and anti-RNA polymerase III (anti-RNAPIII) [1], [2].

Identification of the major autoantibodies specific for systemic sclerosis

Anti-CENP-B (anti-centromere) aAbs are routinely detected by indirect immunofluorescence tests for ANAs. In interphase cultured cells, anti-CENP-B are associated with a distinct multiple speckled nuclear fluorescence pattern whereas in mitosis, the distribution of the speckled pattern varies in keeping with the migration of chromosomes (Fig. 1). CENP-B is the major autoantigen recognized by > 95% of anti-centromere positive SSc sera [9]. Uncommonly, anti-centromere aAbs may be present in

Geoethnic variations in the frequency of the major autoantibodies specific for systemic sclerosis

The four major SSc specific aAbs are present in SSc populations worldwide, with mean frequencies for ACA, anti-Th/To, anti-topo I and anti-RNAPIII of 26.1%, 3%, 28.6% and 10.3%, respectively (Table 2). However, major geoethnic and immunogenetic variations are present. For example, the worldwide frequency of anti-centromere aAbs ranges from 11% to 42% whereas the frequency of anti-topo I ranges from 9.4% to 42% (Table 2). Therefore, although SSc aAbs are universal, frequency data obtained

The diagnostic value of the major systemic sclerosis autoantibodies

The American College of Rheumatology (ACR) ad hoc Committee on immunologic testing guidelines has provided evidence based data, on the diagnostic value of anti-centromere and anti-topo I [14]. Strict criteria were used for selection of studies and positive likelihood ratios (+LR) were determined. LR combine sensitivity and specificity data in a single number and, contrarily to predictive values, are independent of prevalence, thus providing a robust indicator of the diagnostic value of a test.

Systemic sclerosis autoantibodies as biomarkers for cutaneous phenotypes

The clinical spectrum of SSc encompasses distinct clinical subsets, characterized by different manifestations with respect to cutaneous and visceral involvement, rapidity of disease progression and survival. Two major subsets, the limited (lcSSc) and the diffuse (dcSSc) cutaneous subsets, are recognized clinically [17]. In lcSSc, Raynaud's phenomenon (RP) is characteristically the first manifestation, preceding by several years or even decades the onset of other signs and symptoms. Other lcSSc

The need for improved definitions for systemic sclerosis subsets

The 2-subset classification, although useful clinically, is imperfect and is best viewed as work in progress [20]. First, the clinical boundaries of the 2 subsets are not well defined and, in individual patients, the described disease course may not fit the rule. For example, although anti-topo I are often associated with dcSSc, about 25% of patients have lcSSc which, on follow-up, does not progress to dcSSc (Table 4) [21], [22]. Second, the use of additional cutaneous SSc subsets and the

Systemic sclerosis autoantibodies as biomarkers for vascular and visceral involvement

Table 4 shows that each SSc aAb is associated with a particular phenotype with respect to vascular and visceral involvement. Thus, anti-CENP-B are associated with slowly progressive, initially clinically silent, iPAH, which is a major cause of morbidity and late mortality in lcSSc [15]. In contrast with anti-CENP-B, anti-topo I are strongly associated with pulmonary fibrosis (Table 4) [18], [26]. Altogether, these two causes of pulmonary involvement have become the leading causes of death in

Take-home messages

  • Each major SSc aAb is a biomarker for a particular phenotype of cutaneous, vascular and visceral involvement.

  • Anti-CENP-B are associated with isolated pulmonary arterial hypertension (iPAH), whereas anti-Th/To are associated with iPAH and pulmonary fibrosis (PF), anti-topoisomerase I with PF and anti-RNA polymerase III with renal crisis.

  • Clinicians can use these biomarkers to tailor the clinical management and follow up to each patient, based on the aAb present and the complications at risk.

Acknowledgements

Supported by the Canadian Institutes of Health Research (grant MOP-68966) and a Sclérodermie Québec research grant. JLS holds the Scleroderma Research Chair at the University of Montreal. MK was supported by a Sclérodermie Québec Fellowship.

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