Autoantibodies to 14-3-3η: A Novel Diagnostic Biomarker for Axial Spondyloarthritis

Objectives There is a high clinical unmet need in primary care, to differentiate patients with axial spondyloarthritis (axSpA) who require a referral to a rheumatologist from those with mechanical backpain (MBP). According to the Spondyloarthritis Research and Treatment Network (SPARTAN), identifying 1 axSpA patient of 3 referred, could meaningfully reduce diagnostic delay. This study examines the discriminative performance of autoantibodies to 14-3-3η in patients with axSpA, including those with radiographic (r-) and nonradiographic (nr-) disease, compared to people with MBP. Methods Serum samples (n=160) from the Bath Spondyloarthritis Biobank were selected based on availability. All patients had rheumatologist-confirmed diagnoses and met criteria for r-axSpA (n=55), nr-axSpA (n=54), or MBP (n=51). 14-3-3η autoantibody levels were measured using a multiplex assay. Nominal regression modeled the relationship between predictors and diagnosis, generating a probability-based linear score for 3 models: (1) axSpA (n=109), (2) r-axSpA, and (3) nr-axSpA vs MBP. Predictors included age, sex, CRP, and HLA-B27. The r-axSpA vs MBP model was also applied to healthy controls (n=100) for comparison. Statistical significance was set at p < 0.05. Results Mean age (SD) was 55 (23) yrs for r-axSpA, 42 (14) yrs for nr-axSpA, and 30 (14) yrs for MBP. Male percentages were 67%, 41%, and 59%, respectively. Disease duration averaged 13 years for r-axSpA and 5 years for nr-axSpA. HLA-B27+ rates were 69% (r-axSpA), 72% (nr-axSpA), and 18% (MBP). ROC AUCs for the 14-3-3η AAb model were 0.77 (all axSpA), 0.78 (r-axSpA), and 0.73 (nr-axSpA). At ~90% specificity, sensitivities were 42%, 47%, and 38%, with PPVs of 88%, 83%, and 83% - all exceeding the SPARTAN target of 33.3%. Adding age and sex to the model improved the diagnostic odds ratio (DxOR) from 5.4 to 18.4, rising to 23.4 with CRP and 63.7 with HLA-B27 (Table 1). Scores for healthy controls matched MBP (p > 0.99). Table 1. 14-3-3η AAb Model Performance by axSpA Subset Conclusion Autoantibodies to 14-3-3η AAb differentiates radiographic and nonradiographic-axSpA from MBP, achieves a high PPV and its discrimination improves when age, sex, CRP, and HLA-B27 are added. Alongside these clinical variables, autoantibodies to 14-3-3η may reduce the diagnostic delay at primary care and complement HLA-B27.