IL-18 as a biomarker linking systemic juvenile idiopathic arthritis and macrophage activation syndrome

Abstract

Objectives Systemic juvenile idiopathic arthritis (sJIA) is a childhood arthritis with features of autoinflammation and high risk of macrophage activation syndrome (MAS). IL-18 has been shown to have key roles in sJIA and MAS. We aimed to examine IL-18 levels in sJIA in relation to disease activity and history of MAS and other disease biomarkers namely S100 proteins and CXCL9. Methods Total IL-18, CXCL9 and S100 proteins levels were determined in 40 sJIA patients, and IL-18 levels were compared between patients with regards to disease activity, history of MAS, and other biomarkers. Results Total IL-18 levels were significantly higher in patients with active sJIA (median 16 499 pg/ml; interquartile range (IQR) 4816–61 839), and remained persistently elevated even in the majority of patients with inactive disease (1164 pg/ml; IQR 587–3444). Patients with history of MAS had significantly higher IL-18 levels (13 380 pg/ml; IQR 4212–62 628) as compared with those without MAS history (956.5 pg/ml; IQR 276.3–4262.5). Total IL-18 performed well with area under the curve of 0.8145 and 0.84 in predicting disease activity and history of MAS, respectively. We observed moderate correlation between IL-18 and CXCL9 (R = 0.56), S100A8/A9 (R = 0.47) and S100A12 (R = 0.46). The correlation was stronger for ferritin (R = 0.74) and overall for those with active disease. Conclusion Total IL-18 levels were elevated in the majority of sJIA patients regardless of clinical features, but were higher in patients with active disease and history of MAS. Change in IL-18 may reflect increased disease activity or development of MAS.

The role of interleukin-18 in the diagnosis and monitoring of hemophagocytic lymphohistiocytosis/macrophage activation syndrome – a systematic review

“…Study characteristics are displayed in Table 1. Briefly, nine studies included MAS patients [15,16,18,20,23–27], eight included patients with sHLH of other causes [15,17,20,24,28–31] and six studies included pHLH [15,16,23,29–31]. Other inflammatory conditions included were EBV infection ( n = 5) [20,24,29–31], Kawasaki’s disease ( n = 2) [20,28], sJIA/AOSD ( n = 4) [18,20,25,26] and patients with other infectious, inflammatory or malignant disorders [15,17,23].…”

“…Three studies investigated patients with a history of recurrent MAS, and found that IL‐18 was significantly elevated in sJIA patients with history of MAS compared with sJIA with no history of MAS, regardless of whether or not the patients were in the active or inactive phase of sJIA [15,26,27].…”

Tocilizumab modifies clinical and laboratory features of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis

“…Recent studies revealed some biomarkers including IL-18, CXCL9, neopterin and soluble tumor necrosis factor receptor type II might be useful for the prediction of the development of MAS and the diagnosis of the transition from active phase of s-JIA to MAS [14][15][16][17][18][19][20][21]. Recent studies revealed that high levels of free IL-18 (that is, IL-18 not bound to IL-18 binding protein) increases the risk of developing MAS [15,22].…”

Dietary Short-Term Fiber Interventions in Arthritis Patients Increase Systemic SCFA Levels and Regulate Inflammation

“…In addition to its costimulatory functions on Th1 cytokines, IL-18 acts directly as a proinflammatory cytokine [ 46 ]. The level of IL-18 reportedly increased in both the serum and synovial fluid samples of RA patients [ 39 , 47 , 48 , 49 ], and IL-18-deficient mice were shown to have a reduced incidence and severity of arthritis in preclinical models [ 50 , 51 ]. IL-33, another proinflammatory cytokine that was shown to exacerbate inflammation in preclinical arthritis models [ 9 , 52 , 53 ] but that, at the same time, harbors direct effects on bone homeostasis [ 54 , 55 ], was significantly reduced in RA patients following short-term high-fiber dietary interventions.…”