Comparative study of Interleukin-18 (IL-18) serum levels in adult onset Still’s disease (AOSD) and systemic onset juvenile idiopathic arthritis (sJIA) and its use as a biomarker for diagnosis and evaluation of disease activity

Abstract

Background Signs and symptoms establish the diagnosis of adult onset Still’s disease (AOSD) as well as of systemic onset juvenile idiopathic arthritis (sJIA). The published data regarding the importance of IL-18 as a marker for diagnosis and disease activity so far are conflicting. The aim of this study was to clarify the role of IL-18 as a diagnostic and disease activity marker in AOSD and sJIA. Methods Thirty adult patients diagnosed with AOSD and twenty children diagnosed with sJIA were included in the study. Clinical and laboratory data were obtained retrospectively for each patient visit whenever IL-18 serum levels were determined. IL-18 levels were determined by ELISA. Sixty-five adults and twenty-three children presenting with fever and/or arthritis who did not meet the criteria for a diagnosis of AOSD or sJIA served as comparison groups. Rau’s criteria and CRP values were used to evaluate disease activity. Results IL-18 levels were significantly elevated in patients with active AOSD compared to AOSD patients in remission and to the comparison group with a median of 16,327 pg/ml, 470 pg/ml, and 368 pg/ml, respectively ( p < 0.001). Analogous to AOSD in active sJIA, the median IL-18 serum level was significantly higher with 21,512 pg/ml than in the comparison group with 2580 pg/ml ( p < 0.001). At our cut-off point of 5000 pg/ml, the calculated specificity of IL-18 to establish the diagnosis of AOSD was 96.9%, and the sensitivity 63.3% (AUC = 0.870, p < 0.001). For the diagnosis of sJIA, a cut-off value of 10,000 pg/ml was chosen with a specificity of 100% and a sensitivity of 60% (AUC = 0.774, p = 0.003). At a cut-off value of 5000 pg/ml, the specificity was 62% and the sensitivity 65%. Conclusions This study gives further evidence to earlier publications of elevated IL-18 serum levels in active AOSD and sJIA, with up to 1000-fold higher concentrations compared to other rheumatic diseases. A clear association of IL-18 serum levels with disease activity in AOSD was found. The results support the use of IL-18 as an important biomarker in AOSD and sJIA. Electronic supplementary material The online version of this article (10.1186/s41927-019-0053-z) contains supplementary material, which is available to authorized users.

Interleukin-18 and fibroblast growth factor 2 in combination is a useful diagnostic biomarker to distinguish adult-onset Still’s disease from sepsis

“…Previous studies showed that serum IL-18 levels in patients with AOSD varied widely, from 788 pg/mL (mean value) to 16,327 pg/mL (median value) [7,9,16,17,23,[26][27][28]. The median IL-18 level in this study was 12,070 pg/mL, which was higher than that reported in some studies [7,9,16,17,23,26,27].…”

“…The cross-sectional design and use of serum samples from patients with untreated AOSD mean that continuous serum samples were not used in this study. Although it has been suggested that IL-18 is useful as a biomarker to reflect the therapeutic response and disease activity of AOSD [28,31,37] and a phase II clinical trial showed that IL-18 inhibition by administration of recombinant human IL-18BP is effective in the treatment of AOSD [38], further longitudinal studies are needed to verify whether the cytokines identified in this study are associated with therapeutic responses. In addition, the cytokine profiles presented here for patients with sepsis may differ from those of normal populations of patients with sepsis because we included patients admitted for evaluation of FUO who were subsequently diagnosed with sepsis.…”

Biomarker Significance of Interleukin-18 in Juvenile Idiopathic Arthritis

“…Most of medium-high JADAS27 patients were presented with a level higher than the median of IL-18 (76.7%). These results complement an existing body of publications in JIA in general or specifically in sJIA, adult-onset Still's disease (AOSD) and macrophage activation syndrome (MAS) [11,[13][14][15]. Accordingly, the key role of IL-18 in the pathogenesis of JIA, as well as its biomarker significance in the disease, is augmented.…”

“…It has also been demonstrated that IL-18 can be counterbalanced by the naturally occurring IL-18BP (IL-18 binding protein), which is an IL-18 endogenous antagonist with a high-affinity [22]. Several publications have addressed using exogenous IL-18BP as a novel therapeutic approach for inflammatory diseases; including sJIA, AOSD and MAS, and encouraging results have been gained [15,23,24].…”

Anakinra in children and adults with Still’s disease

“…Nevertheless, when measured, IL-1β concentrations appear significantly higher in patients with active sJIA [46, 47] or AOSD [17, 48] compared with patients with inactive disease or healthy controls. IL-18 has repeatedly been found to be elevated in peripheral blood of patients with sJIA and AOSD [3, 49, 50], distinguishing them from many other rheumatic diseases. For this reason, IL-18 has been regarded as a potential biomarker, mostly with regard to its association with macrophage activation.…”