Are anti-nucleosome antibodies a better diagnostic marker than anti-dsDNA antibodies for systemic lupus erythematosus? A systematic review and a study of metanalysis.
BACKGROUND
Methods to detect anti-nucleosome antibodies (ANuA) have been available for more than 10 years and the test has demonstrated its good sensitivity and high specificity in diagnosing systemic lupus erythematosus (SLE). Despite these data produced through clinical and laboratory research, the test is little used.


OBJECTIVE
To verify the diagnostic performance of methods for measuring ANuA and to compare them with those for anti-dsDNA antibodies.


METHODS
A systematic review of English and non-English articles using MEDLINE and EMBASE with the search terms "nucleosome", "chromatin", "anti-nucleosome antibodies" and "anti-chromatin antibodies". Additional studies were identified checking reference lists in the selected articles.


METHODS
We selected studies reporting on anti-nucleosome tests performed by quantitative immunoassays, on patients with SLE as the index disease (sensitivity) and a control group (specificity). A total of 610 titles were initially identified with the search strategy described. 548 publications were subsequently excluded based on abstract and title. Full-text review was undertaken as the next step on 62 publications providing data on anti-nucleosome testing; 25 articles were then excluded because they did not include either SLE patients or a control group, and 37 articles were selected for the metanalysis. Finally, a sub-metanalysis study was conducted on the 26 articles providing data on both ANuA and anti-dsDNA antibody assays in the same series of patients.


METHODS
Extraction of data from selected articles was performed by two authors independently, using predefined criteria: the number of patients with SLE as the index case, and the number of healthy or diseased controls; specification of the analytical method used to detect anti-nucleosome and anti-dsDNA antibodies; the cut-off used in the study; and the sensitivity and specificity of the assay. Demographic and clinical data on the population investigated (adults or children; lupus patients with or without nephritis; patients with active or inactive disease) were also recorded and analyzed in a separate evaluation.


RESULTS
The systematic review and metanalysis showed that the overall sensitivity of the ANuA assay is 61% (confidence interval-CI, 60-62) and the specificity 94% (CI, 94-95). The overall positive likelihood ratio is 13.81 (CI, 9.05-21.09) and the negative likelihood ratio 0.38 (CI, 0.33-0.44). The odds ratio for having SLE in ANuA-positive patients is 40.7. The comparative analysis on anti-dsDNA antibodies conducted on the 26 studies which provided data for both antibodies showed that ANuA have greater diagnostic sensitivity (59.9% vs 52.4%) and a specificity rating only slightly higher (94.9% vs 94.2%). The probability that a subject with positive ANuA have SLE is 41 times greater than a subject with negative ANuA, while for anti-dsDNA the probability is 28 times greater. These figures are even more impressive in children, in whom ANuA have an odds ratio for the diagnosis of SLE of 146, compared to 51 for anti-dsDNA antibodies. In selected studies, ANuA (p<0.0001) but not anti-dsDNA antibodies (p=0.256) were significantly associated with disease activity measured by the international score systems. However, neither antibody appears to correlate with kidney involvement.


CONCLUSIONS
Data from the metanalysis have shown that ANuA have equal specificity but higher sensitivity and prognostic value than anti-dsDNA antibodies in the diagnosis of SLE. Despite a certain heterogeneity among the various studies, the use of ANuA appears more efficacious than anti-dsDNA.
Laboratory of Clinical Pathology, San Antonio Hospital, Tolmezzo, Italy. nicola.bizzaro@ass3.sanita.fvg.it
Nicola
N
Bizzaro
Danilo
D
Villalta
Davide
D
Giavarina
Renato
R
Tozzoli
D000367:Age Factors; D000974:Antibodies, Antinuclear; D015415:Biomarkers; D018450:Disease Progression; D006801:Humans; D007159:Immunologic Tests / Q000191:economics; D007674:Kidney Diseases / Q000209:etiology; D008180:Lupus Erythematosus, Systemic / Q000150:complications / Q000175:diagnosis* / Q000276:immunology; D009707:Nucleosomes / Q000276:immunology*; D016017:Odds Ratio; D012330:RNA, Double-Stranded / Q000276:immunology*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
D000974:Antibodies, Antinuclear; D015415:Biomarkers; D009707:Nucleosomes; D012330:RNA, Double-Stranded