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

Koga, Tomohiro; Sumiyoshi, Remi; Furukawa, Kaori; Sato, Shuntaro; Migita, Kiyoshi; Shimizu, Toshimasa; Umeda, Masataka; Endo, Yuichi; Fukui, Shoichi; Kawashiri, Shin‐ya; Iwamoto, Naoki; Ichinose, Kunihiro; Tamai, Mami; Nakamura, Hideki; Origuchi, Tomoki; Nonaka, Fumiaki; Yachie, Akihiro; Kondo, Hideaki; Maeda, Takahiro; Kawakami, Atsushi

doi:10.1186/s13075-020-02200-4

Cited by 24 publications

(16 citation statements)

References 35 publications

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“…Besides, IL-18 showed the highest discriminating ability between AOSD and COVID-19 in the ROC analysis of the putative markers. These findings suggest that exaggerated production of IL-18 is highly characteristic of active AOSD, resonating with previous reports showing IL-18 as a diagnostic marker and indicator of disease activity in AOSD (16,48,49). Blocking IL-18 with recombinant IL18 BP (tadekinig alfa) has therapeutic efficacy for AOSD (22) but has yet to be applied to COVID-19 treatment now.…”

Section: Discussionsupporting

confidence: 84%

Interleukin-18 Is a Potential Biomarker to Discriminate Active Adult-Onset Still’s Disease From COVID-19

et al. 2021

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BackgroundHyperinflammation with dysregulated production of galectins and cytokines may develop in COVID-19 or adult-onset Still’s disease (AOSD). Given the similar clinical features in both diseases, it is necessary to identify biomarkers that can differentiate COVID-19 from AOSD. However, the related data remain scarce currently.MethodsIn this cross-sectional study, plasma levels of galectin-3, galectin-9, and soluble TIM-3 (sTIM-3) were determined by ELISA in 55 COVID-19 patients (31 non-severe and 24 severe), 23 active AOSD patients, and 31 healthy controls (HC). The seropositivity for SARS-CoV-2 was examined using an immunochromatographic assay, and cytokine profiles were determined with the MULTIPLEX platform.ResultsSignificantly higher levels of galectin-3, galectin-9, IL-1β, IL-1Ra, IL-10, IFN-α2, IL-6, IL-18, and TNF-α were observed in severe COVID-19 and active AOSD patients compared with HC (all p<0.001). AOSD, but not COVID-19, showed significantly higher IFN-γ and IL-17A compared with HC (both p<0.01). Moreover, active AOSD patients had 68-fold higher IL-18 levels and 5-fold higher ferritin levels than severe COVID-19 patients (both p<0.001). IL-18 levels at the cut-off value 190.5pg/mL had the highest discriminative power for active AOSD and severe COVID-19, with AUC 0.948, sensitivity 91.3%, specificity 95.8%, and accuracy of 91.5% (p<0.005). Multivariate regression analysis revealed IL-18 as a significant predictor of active AOSD (p<0.05).ConclusionActive AOSD patients share features of hyperinflammation and cytokine storm with severe COVID-19 patients but possess a distinct cytokine profile, including elevated IL-18, IL-6, IFN-γ, and IL-17A. IL-18 is a potential discriminator between AOSD and COVID-19 and may significantly predict active AOSD.

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Section: Discussionsupporting

confidence: 84%

Interleukin-18 Is a Potential Biomarker to Discriminate Active Adult-Onset Still’s Disease From COVID-19

et al. 2021

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“…To assess the diagnostic ability of IL-18 in AOSD, it is necessary to conduct comparative studies with control diseases that have pathologies and clinical findings similar to those of AOSD. Between 2001, when Kawashima et al were the first to report that serum IL-18 was markedly elevated in patients with AOSD, and the present investigation's writing, several studies have compared serum IL-18 levels in AOSD and other inflammatory diseases in adults (8,10,12,(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32). The most common control group in those reports was rheumatic diseases, mainly such as rheumatoid arthritis, SLE, and Sjogren's syndrome.…”

Section: Discussionmentioning

confidence: 75%

“…those studies. The control disease in the remaining studies was infection, especially sepsis in two studies (30,31), which is categorized as 'hyperferritinemic syndrome,' similar to MAS or Still's disease (33). These studies also showed that the serum IL-18 levels in patients with sepsis were approximately 100 pg/mL, which is significantly lower than the levels in AOSD patients.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2021

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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.

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“…Serum IL-18 levels have been shown to be significantly higher in patients with AOSD than in other inflammatory diseases, and its concentration correlates with disease activity. IL-18 may therefore be a useful therapeutic target for AOSD as well as a biomarker for differential diagnosis between AOSD and sepsis (35)(36)(37)(38)(39). Until now, there were no other biomarkers with high sensitivity and specificity.…”

Section: Discussionmentioning

confidence: 99%

“…Grouping AOSD disease activity status by our method was somewhat arbitrary and divergent, so it may cause the results to be biased with other research units. Last, previous studies had proposed that PCT, IL-18 combined with fibroblast growth factor 2 (FGF 2) and modified Pouchot Score including elevated serum ferritin levels ( 12 , 33 , 36 ) could be a useful diagnostic tool to distinguish AOSD and sepsis. However, as our study was a retrospective design, many laboratory values such as ferritin, PCT, serum cytokine levels such as IL-18, IL-6 and interferon were not performed in all patients at that time.…”

Section: Discussionmentioning

confidence: 99%

Serum Heparin-Binding Protein as a Potential Biomarker to Distinguish Adult-Onset Still’s Disease From Sepsis

et al. 2021

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Adult-onset Still’s disease (AOSD) is a systemic, multifactorial, autoinflammatory disease for which the etiopathogenesis is not well understood. Given the similarities in clinical and laboratory features between this disease and sepsis, and the differences in treatment strategies for these two diseases, specific diagnostic markers are crucial for the correct diagnosis and management of AOSD. Previous studies have shown plasma heparin-binding protein (HBP) is a promising potential biomarker for AOSD; thus, this study aimed to detect serum HBP levels in patients with AOSD or sepsis to assess its potential as a biomarker for differential diagnosis. We found that serum HBP levels were significantly higher in patients with active AOSD than that in those with inactive AOSD. Patients with sepsis had higher serum HBP levels compared with those who had active or inactive AOSD. We calculated the area under the receiver operating characteristic (ROC) curve to assess whether HBP could be used to differentiate active from inactive AOSD; this was 0.811 with sensitivity 0.650, specificity 0.811, and cutoff HBP value of 35.59 ng/ml. The area under the ROC curve for HBP as a biomarker to differentiate AOSD from sepsis was 0.653, with sensitivity 0.759, and specificity 0.552, and cutoff HBP value of 65.1 ng/ml. Taken together, the results of our study suggest that serum HBP could be a useful diagnostic biomarker to evaluate disease activity in patients with AOSD, and to differentiate AOSD from sepsis.

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

Cited by 24 publications

References 35 publications

Interleukin-18 Is a Potential Biomarker to Discriminate Active Adult-Onset Still’s Disease From COVID-19

Interleukin-18 Is a Potential Biomarker to Discriminate Active Adult-Onset Still’s Disease From COVID-19

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

Serum Heparin-Binding Protein as a Potential Biomarker to Distinguish Adult-Onset Still’s Disease From Sepsis

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