Serum ferritin as an independent biomarker of subclinical synovitis in rheumatoid arthritis patients in clinical remission or low disease activity

Abstract

Background Residual synovial inflammation may persist in patients with rheumatoid arthritis (RA) despite clinical remission or low disease activity. Conventional inflammatory markers such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) may not adequately reflect subclinical synovitis detected by musculoskeletal ultrasound. Ferritin, an acute-phase reactant involved in inflammatory signaling, may represent a complementary biomarker of ongoing synovial inflammation. Objective To evaluate the association between serum ferritin levels and Power Doppler (PD)-detected synovitis in patients with RA who were in clinical remission or low disease activity. Methods In this prospective, single-center, cross-sectional study, 188 individuals were enrolled, including 132 patients with RA receiving either conventional synthetic disease-modifying antirheumatic drugs or adalimumab therapy and 56 healthy controls. All patients with RA fulfilled the 2010 ACR/EULAR classification criteria and had DAS28-ESR scores <3.2. Musculoskeletal ultrasound was performed in all patients with RA, and PD positivity was defined as a patient-level PD score of ≥1. Ferritin was analyzed as both a continuous and a categorical variable. To account for potential data separation and model overfitting, Firth's penalized likelihood multivariable logistic regression models were constructed, including adjustments for baseline iron status (serum iron and hemoglobin). Receiver operating characteristic (ROC) analysis was used to assess diagnostic performance, validated internally via 1,000 bootstrap resamples, and compared against CRP and ESR using DeLong tests. Results PD positivity was identified in 40 of 132 patients with RA (30.3%). Ferritin levels were significantly higher in PD-positive than in PD-negative patients (median 117.0 vs. 17.0 ng/mL, p < 0.001), whereas CRP (p = 0.872) and ESR (p = 0.974) did not differ. In univariable Firth logistic regression, each 10 ng/mL increase in ferritin was associated with higher odds of PD positivity (Firth OR 2.49, 95% CI 1.70–3.66; p < 0.001). In the multivariable model adjusted for age, sex, treatment group, CRP, and ESR, ferritin remained independently associated with PD positivity (adjusted Firth OR 2.51 per 10 ng/mL, 95% CI 1.66–3.79; p < 0.001), and this independence persisted after further adjustment for serum iron and hemoglobin (adjusted Firth OR 2.14, 95% CI 1.51–3.05; p < 0.001). ROC analysis demonstrated excellent discriminatory performance for ferritin, with an optimism-corrected AUC of 0.985 (bootstrap 95% CI 0.968–0.997), which was significantly superior to CRP (AUC 0.509, DeLong p < 0.001) and ESR (AUC 0.498, DeLong p < 0.001). An exploratory ferritin threshold of 70 ng/mL yielded 95.0% sensitivity (bootstrap 95% CI 86.7–100.0%), 94.6% specificity (bootstrap 95% CI 89.1–98.9%), 88.4% positive predictive value (bootstrap 95% CI 77.8–97.4%), and 97.8% negative predictive value (bootstrap 95% CI 94.2–100.0%). Conclusion Serum ferritin was independently associated with ultrasound-detected synovial inflammation in patients with RA who were in clinical remission or low disease activity. In this cohort, ferritin showed higher discriminatory performance than CRP and ESR, supporting its potential role as a complementary biomarker of residual synovial inflammation. However, the proposed cutoff of 70 ng/mL must be regarded as exploratory, and independent external validation in longitudinal prospective cohorts is required before clinical implementation.