Background/Purpose: Systemic juvenile idiopathic arthritis (sJIA) is a childhood arthritis with features of autoinflammation, and is associated with high risk of macrophage activation syndrome (MAS). IL-18 has been increasingly shown to have key roles in linking sJIA and MAS, in particular due to an imbalance between IL-18 and its natural inhibitor IL-18 binding protein (IL-18 BP). Therefore, we hypothesized that free(unbound) IL-18, rather than total IL-18, might be a more accurate biomarker for sJIA disease activity and emerging MAS.

Methods: Serum samples were obtained from 43 established sJIA patients, free and total IL-18 (pg/ml), CXCL9, and S100 protein levels were determined. Free IL-18 levels were compared between patients with regards to clinical and laboratory features, including disease activity, history of MAS, and other emerging biomarkers for sJIA and MAS.

Results: Median free IL-18 level for the cohort was 2.03 pg/ml (IQR: 0-35.68). Free IL-18 levels were significantly higher in patients with active disease (median 25.96, IQR 16.89-66.52) compared to those with clinically inactive disease (CID) (0, IQR -1.29-7.79; p=0.0002). Likewise, those with history of MAS had significantly higher free IL-18 levels (29.55, IQR 16.14-67.51) when compared to those without MAS history (0, IQR -0.29-15.07; p=< 0.0001).Of note, Patients with active disease and history of MAS had higher free IL-18 than in patients with active disease and no history of MAS (0=0.01). Patients with fever, arthritis, systemic features or elevated inflammatory markers (ESR/CRP) had significantly higher free IL-18 levels (p= 0.001, 0.318,0.0003 and < 0.0001, respectively). Notably, free IL-18 levels were undetectable in the majority (78%) of patients with CID. This is in marked contrast to total IL-18, where a majority (83%) of CID still had high levels (median 956.5, IQR 458-2682, upper limit normal 540 pg/ml) (Figure 1).

Free IL-18 performed well as a biomarker for disease activity with AUC of 81% (p=0.0006). There was a strong correlation between free and total IL-18 levels (r=0.87, p< 0.0001)), with sustained significance when restricted to patients with only active disease or CID (r=0.81 and 0.73 respectively). Correlation was moderate with CXCL9 (r=0.57, p< 0.0001)), S100A8/9 (r=0.50, p=0.0022)) and S100 A12 (r=0.38, p=0.0228)). Interestingly, correlations between free IL-18 and S100 A8/9 and A12 were stronger in patients with active disease (r=0.68 and 0.58), but weak and statistically insignificant for patients in CID.

Conclusion: Free IL-18 levels were significantly higher in sJIA patients with active disease, fever, systemic features and arthritis. Levels were undetectable in the majority of patients with CID. Free IL-18 correlated well with other disease biomarkers particularly when disease was active, indicating that free IL-18 is a promising new sensitive biomarker for sJIA disease activity. It also supports the role of IL-18/IL-18 BP imbalance in the pathogenesis of sJIA and MAS.

Figure 1

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/free-interlukin-18-a-new-promising-biomarker-for-systemic-juvenile-idiopathic-arthritis-and-macrophage-activation-syndrome/