Usefulness of Interleukin-18 as a Diagnostic Biomarker to Differentiate Adult-Onset Still's Disease With/Without Macrophage Activation Syndrome From Other Secondary Hemophagocytic Lymphohistiocytosis in Adults.

Toshihiko Shiga,Yuji Nozaki,Itaru Matsumura,Kazuya Kishimoto,Yasuaki Hirooka,Masanori Funauchi,Koji Kinoshita,Daisuke Tomita

doi:10.3389/fimmu.2021.750114

Toshihiko Shiga, Yuji Nozaki + Show 6 more

Open Access

https://doi.org/10.3389/fimmu.2021.750114

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Abstract

BackgroundInterleukin (IL)-18 is markedly elevated in systemic inflammatory diseases that cause the ‘cytokine storm’ such as adult-onset Still’s disease (AOSD) and hemophagocytic lymphohistiocytosis (HLH). The differences in IL-18 between AOSD and HLH, especially in adults, is uncertain. Macrophage activation syndrome (MAS), a form of secondary HLH, is often difficult to differentiate cases of AOSD that include MAS from other secondary HLH. In this case-control study, we investigated whether serum IL-18 levels could be a useful biomarker for the differential diagnosis of AOSD with or without MAS (AOSD group) and other secondary HLH in adults (adult HLH group).Patients and MethodsWe enrolled 46 patients diagnosed with AOSD including 9 patients with MAS and 31 patients in the adult HLH group, which excluded AOSD-associated MAS. The clinical features and laboratory data were compared between the AOSD and adult HLH groups. In addition, we subdivided the AOSD group (with or without MAS) and the adult HLH group (whether lymphoma-associated or not) and compared the four groups. A logistic regression analysis was used to identify factors with high efficacy in differentiating the two groups, followed by a receiver operating characteristic (ROC) curve analysis to evaluate the differential diagnostic ability of IL-18. We analyzed the correlation between IL-18 and various laboratory parameters in the AOSD group.ResultsSerum IL-18 levels of patients in the AOSD groups were significantly higher than those of the adult HLH groups, and were closely correlated with ferritin, soluble interleukin-2 receptor (sIL-2R), and other laboratory data. Univariate and multivariate logistic regression analyses revealed that IL-18, sIL-2R, and ‘arthralgia or arthritis’ are independent factors useful in the differential diagnosis of AOSD from adult HLH. In the differential diagnosis of both groups, the area under the curve obtained from the ROC curve of IL-18 with a cutoff value of 18,550 pg/mL was 0.91 (95% confidence interval 0.83–1.00; sensitivity 90.3%, specificity 93.5%), and the differential diagnosis ability of IL-18 was superior to that of other laboratory data.ConclusionsIL-18 could be a useful biomarker for the differential diagnosis of AOSD and adult HLH.

Highlights

Adult-onset Still’s disease (AOSD) is a rare, polygenic, systemic autoinflammatory disease characterized by recurrent fever, skin rash, arthralgia or arthritis, sore throat, leukocytosis with neutrophilia, lymphadenopathy, splenomegaly, and liver dysfunction (1, 2)
The disease activity of the AOSD patients without Macrophage activation syndrome (MAS) was assessed with a modified Pouchot score, and we defined the cases with scores higher than four as having clinically active disease (19, 20)
The results of our analyses demonstrated that serum IL-18 levels could be used as a biomarker with high accuracy for the differential diagnosis of AOSD and adult HLH

Summary

Introduction

Adult-onset Still’s disease (AOSD) is a rare, polygenic, systemic autoinflammatory disease characterized by recurrent fever, skin rash (typically salmon-pink in color), arthralgia or arthritis, sore throat, leukocytosis with neutrophilia, lymphadenopathy, splenomegaly, and liver dysfunction (1, 2). Serum levels of various cytokines and chemokines have been reported to be useful in the diagnosis of AOSD (8), and IL-18 has been found to be markedly elevated in the serum of AOSD patients in several studies (1, 9). Interleukin (IL)-18 is markedly elevated in systemic inflammatory diseases that cause the ‘cytokine storm’ such as adult-onset Still’s disease (AOSD) and hemophagocytic lymphohistiocytosis (HLH). Macrophage activation syndrome (MAS), a form of secondary HLH, is often difficult to differentiate cases of AOSD that include MAS from other secondary HLH In this case-control study, we investigated whether serum IL-18 levels could be a useful biomarker for the differential diagnosis of AOSD with or without MAS (AOSD group) and other secondary HLH in adults (adult HLH group)

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Conclusion