Systematic review and meta-analysis of ENA seropositivity in ANA-IIF-negative connective tissue disease populations
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Key Takeaway
Note that negative ANA-IIF results do not reliably exclude connective tissue disease.
This systematic review and meta-analysis assessed the frequency of extractable nuclear antigen (ENA) seropositivity among ANA-IIF-negative individuals. The analysis included 28,552 samples and examined associated clinical and methodological determinants. The primary outcome measured the pooled proportion of ENA-positive results in this specific population.
The pooled proportion of ENA-positive individuals among ANA-IIF-negative samples was 14.1% (95% CI: 10%–18.7%). Frequency varied by clinical context: 1.4% (95% CI: 1.1%–1.9%) in unspecified indications, 8.1% (95% CI: 6%–10.5%) in suspected connective tissue disease, and 44.1% (95% CI: 32.3%–54.6%) in confirmed connective tissue disease. Multivariable meta-regression identified the IIF cut-off dilution, anti-SSA/Ro antibodies, and anti-tRNA synthetase antibodies as significant determinants of ENA-positive frequency.
The authors acknowledge substantial heterogeneity (I² = 99%) among studies. Safety data, adverse events, and discontinuations were not reported. The study setting was not reported. The authors conclude that findings support a targeted, clinically driven ENA testing strategy, particularly for conditions such as Sjögren syndrome and inflammatory myopathies. However, the high heterogeneity and lack of reported certainty notes warrant cautious interpretation of these pooled estimates.
View Original Abstract ↓
BackgroundThe 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. MethodsA 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.ResultsTwenty-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.DiscussionThis 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 Registrationhttps://www.crd.york.ac.uk/PROSPERO/view/, identifier CRD420250654499.
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