SynthesisFrontiers in immunology2026
Frequency of extractable nuclear antigen seropositivity among individuals seronegative for antinuclear antibodies on indirect immunofluorescence: a systematic review and meta-analysis.
Synthesis in Frontiers in immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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1 citing paper in PubMed.
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11 authors.
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Abstract
Background: The frequency of extractable nuclear antigen (ENA) seropositivity in patients with negative antinuclear antibodies (ANA) by indirect immunofluorescence (IIF) remains insufficiently characterized. We aimed to estimate the frequency of ENA seropositivity among ANA-IIF-negative individuals (ENA+/IIF-), and to identify associated clinical and methodological determinants. Methods: A systematic search of PubMed, EMBASE, Web of Science, and Scopus was conducted for studies published up to January 31, 2025. Studies evaluating ENA seropositivity in ANA-IIF-negative patients using HEp-2 or HEp-2000 substrates were included. Meta-analysis was performed using the Freeman-Tukey double arcsine transformation and random-effects models. Results: Twenty-eight studies, comprising 33 distinct patient groups and 28,552 ANA-IIF-negative samples, were included. The pooled proportion of ENA+/IIF- was 14.1% (95% CI: 10%-18.7%), with substantial heterogeneity (I² = 99%). Subgroup analysis demonstrated significant variation according to clinical indication: 1.4% (95% CI: 1.1%-1.9%) in unspecified indications, 8.1% (95% CI: 6%-10.5%) in suspected connective tissue disease (CTD), and 44.1% (95% CI: 32.3%-54.6%) in confirmed CTD (p < 0.0001). Multivariable meta-regression identified the IIF cut-off dilution, anti-SSA/Ro antibodies, and anti-tRNA synthetase antibodies as significant determinants of ENA+/IIF- frequency. Discussion: This meta-analysis confirmed that ENA seropositivity is not uncommon in ANA-IIF-negative individuals, and it varies according to clinical context. A negative ANA-IIF result does not reliably exclude CTD, particularly in patients with strong clinical suspicion of CTD. These findings support a targeted, clinically driven ENA testing strategy, especially in conditions such as Sjögren syndrome and inflammatory myopathies. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/view/, identifier CRD420250654499.
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