Receptor activator of nuclear factor kappa-Β ligand (RANKL) serum levels are associated with progression to seropositive/negative rheumatoid arthritis

Objective The aim of this study was to establish whether serum RANKL levels in early inflammatory arthritis (IA) were associated with rheumatoid arthritis (RA) diagnosis at follow-up, and to evaluate the added value of RANKL for RA diagnosis. Methods Serum from 298 patients was collected. Demographic and clinical (swollen/tender joint counts, CRP, DAS28-CRP, RF, ACPA and shared-epitope data were recorded. Baseline ultrasound of 26 joints was performed, including total power Doppler (PD). An ELISA was used to measure RANKL. Predictors of progression were identified using multivariable logistic regression analysis. Area under the receiver operating characteristics (AUROC) was used to assess the performance of the prediction models and quantify the added value of RANKL in RA diagnosis. Results 151 patients developed RA and 147 were non-RA (undifferentiated IA, other inflammatory diagnoses or non-persistent inflammation). RANKL levels were significantly higher in RA (median [IQR]: 474.1 [270.8–1430.6]) than in non-RA (median [IQR]: 301.0 [174.1–477.5]. Three clinical factors (age, SJC and PD) were identified by multivariable logistic regression with model performance AUROC of 77.9% (95% CI 72.1–83.8%). Adding RANKL resulted in a relative increase of 6.5% in the model classification performance of an AUROC of 83.0% (95% CI 77.9–88.1%). In ACPA-negative patients, the model performance increased from 77.6% (95% CI 69.5–85.7%) with clinical data only to 81.9% (95% CI 73.7–89.8%) with added value of RANKL and imaging. Conclusion RANKL levels can predict RA diagnosis over clinical biomarkers alone, both seropositive and particularly in seronegative IA patients.