Soluble ST2 and its association with disease activity in adult-onset Still’s disease

Abstract

Objectives: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disorder of unknown etiology. Although the precise pathogenesis of AOSD remains unknown, many important inflammatory cytokines, including interleukin (IL)-1, IL-6, IL-18, and TNF-alpha contribute to the many clinical manifestations and laboratory abnormalities. The aim of this study was to investigate the associations between serum IL-33, soluble ST2 (sST2), serum macrophage migration inhibitory factor (MIF) and disease activity in patients with AOSD. Methods: Fifty-two patients meeting Yamaguchi’s criteria for AOSD were evaluated. Serum levels of IL-33, sST2 and MIF were measured by enzyme-linked immunosorbent assay. All patients with AOSD were evaluated longitudinally on a second occasion. Thus, 104 serum samples were obtained from patients with AOSD and compared with 26 age- and sex-matched normal controls. AOSD disease activity was evaluated with mPouchot’s score. Serum levels of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and ferritin were clinically used as indicators of disease activity in patients with AOSD, and were compared with sST2 and MIF concentrations. The Kruskal–Wallis and Wilcoxon’s signed rank-sum tests were used to compare continuous variables in patients with active and inactive AOSD and healthy controls. Correlation coefficients were obtained by Spearman’s correlation test. Results: Active patients with AOSD [338.9 (207.5–1107.1) pg/mL] had significantly higher serum sST2 concentrations than those in patients with inactive AOSD [196.6 (58.7–437.8) pg/mL, p = 0.01], and also than control subjects [46.6 (10.1–119.2) pg/mL, p = 0.002].Serum sST2 levels changed according to the trend in the mPouchot’s disease activity score (p = 0.03, r = 0.44). sST2 levels were positively correlated with clinical parameters of disease activity, such as ESR, CRP, and ferritin. The 23 patients with initially active AOSD improved clinically at the time of the second examination. sST2 levels decreased significantly after resolution of the active phase [338.9 (207.5–1107.1) to 155.5 (43.7–260.6) pg/mL, p < 0.001]. Serum IL-33 levels were not different between patients with active AOSD [31.4 (13.0–61.8) pg/mL], those with inactive AOSD [22.9 (14.7–44.9) pg/mL], and healthy controls [26.2 (13.8–179.5) pg/mL, p = 0.75]. The IL-33/sST2 ratio decreased significantly in patients with AOSD [0.1 (0.04–0.29)] compared to that in healthy controls [1.01 (0.21–3.89), p < 0.001], and was negatively correlated with conventional disease activity parameters. Serum levels of MIF were higher in patients with active AOSD than those with inactive disease [25.0 (12.6–33.7) ng/mL vs. 12.6 (7.8–25.1) ng/mL, p = 0.06]; however, no significant difference was observed between inactive patients and normal controls. Serum MIF levels changed according to the trend in the mPouchot’s disease activity score (p = 0.006, r = 0.26).The cutoff points to distinguish patients and activity of AOSD from healthy controls were determined by receiver operator characteristic (ROC) curves. Sensitivity and specificity were 53.6% and 90.0% when using a 191.5 pg/mL sST2 level as an AOSD cutoff value. Sensitivity was 51.9% and specificity was 96.2% when using a 19.1 ng/mL MIF level as a AOSD cutoff value. A cutoff value of 0.35 for the IL-33/sST2 ratio showed most reliable sensitivity (80.0%) and specificity (72.2%) for differentiating patients with AOSD from healthy controls. Sensitivities were 72.4% and 56.7and specificities were 70.6% and 68.9% when using levels of 232.9 pg/mL for serum sST2 and 24.7 ng/mL for MIF as an active AOSD cutoff point, respectively, Conclusions: The IL-33/sST2 ratio decreased significantly in patients with AOSD compared with that in healthy controls. Therefore, the IL-33/sST2 ratio was reliable for differentiating patients with AOSD from healthy controls. Serum sST2 level increased significantly in patients with AOSD compared to that in controls, and sST2 levels were much higher in patients with active AOSD than in patients with inactive AOSD. Serum sST2 levels correlated positively with the parameters of disease activity. These findings suggest that the IL-33/sST2 ratio is useful for differentiating AOSD and healthy controls and that sST2 level may be a promising surrogate marker of disease activity in patients with AOSD.