Curr Opin Immunol. 2026 Jan 13;99:102722. doi: 10.1016/j.coi.2025.102722. Online ahead of print.

ABSTRACT

Primary Sjögren’s disease (SjD) is a systemic autoimmune disorder where diagnosis relies on the presence of Ro/SS-A and La/SS-B autoantibodies. However, approximately one-third of SjD patients are seronegative, often requiring an invasive minor salivary gland biopsy, which can lead to significant diagnostic delays. This review comprehensively evaluates a wide array of novel autoantibodies to determine their potential as diagnostic biomarkers for Ro/SS-A-negative SjD patients. While many newly identified autoantibodies, such as those targeting ASCA, TRIM38, and PUF60, were found to be strongly associated with Ro/SS-A positivity and thus offer limited utility for seronegative diagnosis, several others show significant promise. Notably, autoantibodies targeting functional proteins like the muscarinic M3 receptor (anti-M3R) have demonstrated high diagnostic sensitivity and specificity. Furthermore, systematic screenings have uncovered highly specific markers. One panel of 12 autoantigens (including GMNN, GRAMD1A, and NUP50) identified by human proteome arrays exhibited 54% sensitivity with 100% specificity for Ro/SS-A-negative SjD. Another validated panel combining immunoglobulin G autoantibodies against FNBP4, SNRPC, CCL4, M3R, and KDM6B achieved 46% sensitivity with 95% specificity. Other individual markers, such as anti-NA14 and anti-calponin-3, also show potential for identifying seronegative SjD subsets. In conclusion, a growing body of evidence supports the clinical utility of several novel autoantibodies in diagnosing Ro/SS-A-negative SjD. The integration of these biomarkers into clinical practice could significantly improve early and accurate diagnosis, reduce the reliance on invasive procedures, and potentially aid in patient stratification for targeted therapies. Further validation of these markers in large cohorts is warranted.

PMID:41534451 | DOI:10.1016/j.coi.2025.102722