Frequency of disease-associated and other nuclear autoantibodies in patients of the German Network for Systemic Scleroderma: correlation with characteristic clinical features

Laboratory at Rheumaklinik Aachen, Hauptstrasse 21, Aachen, D-52066, Germany.
Arthritis research & therapy (Impact Factor: 3.75). 10/2011; 13(5):R172. DOI: 10.1186/ar3495
Source: PubMed


In the present study, we analysed in detail nuclear autoantibodies and their associations in systemic sclerosis (SSc) patients included in the German Network for Systemic Scleroderma Registry.
Sera of 863 patients were analysed according to a standardised protocol including immunofluorescence, immunoprecipitation, line immunoassay and immunodiffusion.
Antinuclear antibodies (ANA) were detected in 94.2% of patients. In 81.6%, at least one of the autoantibodies highly associated with SSc or with overlap syndromes with scleroderma features was detected, that is, anti-centromere (35.9%) or anti-topoisomerase I (30.1%), followed in markedly lower frequency by antibodies to PM-Scl (4.9%), U1-ribonucleoprotein (U1-RNP) (4.8%), RNA polymerases (RNAPs) (3.8%), fibrillarin (1.4%), Ku (1.2%), aminoacyl-transfer RNA synthetases (0.5%), To (0.2%) and U11-RNP (0.1%). We found that the simultaneous presence of SSc-associated autoantibodies was rare (1.6%). Furthermore, additional autoantibodies were detected in 55.4% of the patients with SSc, of which anti-Ro/anti-La, anti-mitochondrial and anti-p25/p23 antibodies were most frequent. The coexistence of SSc-associated and other autoantibodies was common (43% of patients). SSc-associated autoantibodies disclosed characteristic associations with clinical features of patients, some of which were previously not acknowledged.
This study shows that five autoantigens (that is, centromere, topoisomerase I, PM-Scl, U1-RNP and RNAP) detected more than 95% of the known SSc-associated antibody responses in ANA-positive SSc patients and characterise around 79% of all SSc patients in a central European cohort. These data confirm and extend previous data underlining the central role of the determination of ANAs in defining the diagnosis, subset allocation and prognosis of SSc patients.

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    • "Anti-Th/To antibodies are one of the specificities that show homogenous nucleolar staining in indirect immunofluorescence (IIF) antinuclear antibody (ANA) tests [6,10,11]. In SSc, anti-Th/To has been associated with limited cutaneous SSc (lcSSc) subset and the reported prevalence of anti-Th/To antibodies varies between 1 and 13% [6,12,13]. In addition to SSc, a few reports have described anti-Th/To antibodies in rheumatoid arthritis (RA) and interstitial lung disease (ILD) [14,15]. "
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    ABSTRACT: Introduction Autoantibodies to the Th/To antigen have been described in systemic sclerosis (SSc) and several proteins of the macromolecular Th/To complex have been reported to react with anti-Th/To antibodies. However, anti-Th/To has not been clinically utilized due to unavailability of commercial tests. The objective of the present study is to evaluate the newly developed ELISA and chemiluminescent immunoassay (CLIA) to measure autoantibodies to Rpp25 (a component of the Th/To complex) using immunoprecipitation (IP) as the reference method. Methods The first cohort consisted of 123 SSc patients including 7 anti-Th/To positive samples confirmed by IP. Additional seven anti-Th/To positive samples from non-SSc patients were also tested. For evaluation of the QUANTA Flash Rpp25 CLIA (research use only), 8 anti-Th/To IP positives, a cohort of 70 unselected SSc patients and sera from various disease controls (n = 357) and random healthy individuals (n = 10) were studied. Results Anti-Rpp25 antibodies determined by ELISA were found in 11/14 anti-Th/To IP positive but only in 1/156 (0.6%) negative samples resulting in a positive percent agreement of 78.6% (95% confidence interval [CI] 49.2, 95.3%) and a negative percent agreement of 99.4% (95% CI 96.4, 100.0%). To verify the results using a second method, 53 samples were tested by ELISA and CLIA for anti-Rpp25 reactivity and the results were highly correlated (rho = 0.71, 95% CI 0.56, 0.81; P < 0.0001). To define the cutoff of the CLIA, anti-Th/To IP positive and negative sera were tested using the anti-Rpp25 CLIA. At the cutoff selected by receiver operating characteristic (ROC) analysis 8/8 (100.0%) of the anti-Th/To positive sera but only 2/367 (0.5%) of the controls were positive for anti-Rpp25 antibodies. The positive and negative percent agreements were 100.0% (95% CI 63.1, 100.0%) and 99.5% (95% CI 98.0, 99.9%), respectively. In the disease cohorts 2/70 (2.9%) of the SSc patients were positive for anti-Rpp25 antibodies compared to 2/367 (0.5%) of the controls (P = 0.032). ROC analysis showed discrimination between SSc patients and controls with an area under the curve value of 0.732 (95% CI 0.655, 0.809). Conclusion Rpp25 is a major target of autoantibodies to the Th/To autoantigen complex. Further studies are needed to evaluate the clinical utility of the new assays.
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    ABSTRACT: An essential prerequisite for progress in understanding the pathophysiology and the clinical treatment of rare diseases is the national cooperation of specialized centers. The German network for systemic sclerosis (DNSS) is such an interdisciplinary union of hospitals and research centers with a special interest in systemic sclerosis (SSc). A core activity is the patient register of the DNSS which includes over 3,100 patients. It is one of largest national registers of SSc patients worldwide and comprises prospective data on diagnostics as well as primarily therapy of the patients. The register has now proven to be an extremely successful basis for clinical research and basic studies within the framework of international cooperation. The most important results of the cooperation and the register will be presented in this article.
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    ABSTRACT: Connective tissue diseases can present with a wide spectrum of neurological symptoms. The present review summarizes the neurological involvement in connective tissue diseases and highlights recent findings on the diagnosis of neurological manifestations and potential underlying mechanisms. The wide range in the prevalence of neurological manifestations in systemic lupus erythematosus (SLE) and Sjögren's syndrome reveals the necessity of clear decision algorithms for the association of neurological symptoms with a systemic autoimmune disease. For this purpose new recommendations for the diagnosis and treatment of neuropsychiatric SLE have been published. Recent studies identified potential paraclinical markers for the diagnosis of nervous system involvement in connective tissue diseases. Antiaquaporin-4 antibodies occur highly specifically in those patients with connective tissue diseases that present with symptoms typical for neuromyelitis optica. To date there is no specific marker available to prove neurological manifestation of connective tissue diseases. However, some progress has been achieved in characterizing typical clinical features and potential disease associated autoantibodies, which may lead to a better management of these patients.
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