Comparison of serum cytokine profiles in macrophage activation syndrome complicating different background rheumatic diseases in children

Abstract Objectives To compare the cytokines involved in the development of macrophage activation syndrome (MAS) in different background rheumatic diseases and to identify serum biomarkers for MAS diagnosis. Methods Serum neopterin, IL-6, IL-18 and soluble TNF receptor (sTNFR) type I (sTNFR-I) and type II (sTNFR-II) levels were determined using ELISA in 12 patients with SLE, including five with MAS; 12 patients with JDM, including four with MAS; 75 patients with Kawasaki disease (KD), including six with MAS; and 179 patients with systemic JIA (s-JIA), including 43 with MAS. These results were compared with the clinical features of MAS. Results Serum neopterin, IL-18 and sTNFR-II levels were significantly higher during the MAS phase than during the active phase in patients with all diseases. Furthermore, serum sTNFR-I levels were significantly higher during the MAS phase than during the active phase in patients with SLE, KD and s-JIA. Receiver operating characteristic (ROC) curve analysis revealed that serum sTNFR-I levels for SLE, serum IL-18 levels for JDM, and serum sTNFR-II levels for KD and s-JIA had the highest areas under the ROC curve. Serum levels of these cytokines were significantly and positively correlated with serum ferritin levels. Conclusions Overproduction of IFN-γ, IL-18 and TNF-α might be closely related to the development of MAS. Serum levels of sTNFR-I for SLE, IL-18 for JDM, and sTNFR-II for KD and s-JIA might be useful diagnostic markers for the transition from active phase to MAS.

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Cytokine Profiles of Macrophage Activation Syndrome Associated with Rheumatic Diseases

The Journal of Rheumatology ◽

10.3899/jrheum.090662 ◽

2010 ◽

Vol 37 (5) ◽

pp. 967-973 ◽

Cited By ~ 56

Author(s):

JUNKO MARUYAMA ◽

SHIGEKO INOKUMA

Keyword(s):

Rheumatic Diseases ◽

Lupus Erythematosus ◽

Macrophage Activation Syndrome ◽

Macrophage Activation ◽

Laboratory Data ◽

Serum Levels ◽

Interferon Γ ◽

Cytokine Profiles ◽

Factor Α ◽

Activation Syndrome

Objective.To elucidate the cytokine profiles of macrophage activation syndrome (MAS) in relation to underlying rheumatic diseases and prognosis.Methods.The clinical features and laboratory data of 18 patients with MAS and rheumatic diseases were retrospectively analyzed. Serum levels of macrophage colony-stimulating factor (M-CSF), interleukin 18 (IL-18), tumor necrosis factor-α, interleukin 6, interferon-γ, ferritin, and ß2-microglobulin (ß2m) were measured. These data were compared between underlying diseases and between those who died and those who recovered.Results.Of the 18 patients with MAS, 9 had underlying systemic lupus erythematosus (SLE), 7 had adult-onset Still’s disease (AOSD), 1 had rheumatoid arthritis (RA), and 1 had antiphospholipid syndrome. Three patients with SLE and 1 patient with RA died. The serum M-CSF and IL-18 levels were substantially elevated in all the patients. In the patients with SLE, the M-CSF level was higher than the IL-18 level (median: 4879 vs 1341 pg/ml, p = 0.0054), and it was the reverse in the patients with AOSD (5883 vs 228,350 pg/ml, p = 0.0017). The serum M-CSF and ß2m levels were significantly higher in the patients who died than in those who recovered (M-CSF: 18,245 vs 3404 pg/ml, p = 0.019; ß2m: 18.8 vs 5.4 mg/dl, p = 0.0058).Conclusion.The cytokine profiles associated with MAS differed between patients with SLE and patients with AOSD. The patients with SLE showed a prominent increase in serum M-CSF levels, as did the patients with AOSD in serum IL-18 level. Patients who died had higher serum M-CSF and ß2m levels, and this suggests that aggressive treatment for patients with MAS and these profiles should be promptly started.

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FRI0509 COMPARISON OF MS SCORE AND HSCORE FOR THE DIAGNOSIS OF ADULT-ONSET STILL’S DISEASE ASSOCIATED MACROPHAGE ACTIVATION SYNDROME

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.4303 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 853.1-853

Author(s):

L. Zhang ◽

X. Yang ◽

T. LI ◽

S. Liu

Keyword(s):

Roc Curve ◽

Macrophage Activation Syndrome ◽

Macrophage Activation ◽

Adult Onset Still’S Disease ◽

Adult Onset ◽

Still’S Disease ◽

Roc Curve Analysis ◽

Still's Disease ◽

Adult Onset Still's Disease ◽

Activation Syndrome

Background:Adult-onset Still’s disease (AOSD) is a rare multisystemic auto-inflammatory disease.Macrophage activation syndrome (MAS) is a life-threatening complication of rheumatic disorders, including sJIA, adult-onset Still’s disease (AOSD) and lupus. Many tools have been developed for the diagnosis of MAS, including HScore and MS score. Although some authors have tried to apply these tools for the diagnosis of ASOD-associated MAS, there are no studies comparing the diagnostic ability of HScore and MS score.Objectives:We aimed to compare the capacity of HS score and MS score for the diagnosis of AOSD-associated MAS.Methods:Patients diagnosed as AOSD during January,2012 and October,2019 in our hospital were retrospectively analyzed. Clinical and laboratory data were compared between patients with pure AOSD and those with AOSD associated MAS. HScore and MS score were calculated respectively and the diagnostic capacity of MAS was compared by means of receiver operating characteristic (ROC) curve analysis.Results:We included 174 patients with pure AOSD and 35 patients with AOSD-associated MAS. Patients with AOSD-associated MAS were younger than those with pure AOSD (32+/-11.4 yrs vs 36.9+/-13.5 yrs, P=0.028). More death were observed among patients with AOSD-associated MAS (17.1% vs 3.4%, P=0.001). Patients with AOSD-associated MAS had higher HScore (median[range] 196[98-333] vs 68[33-156], P<0.001) and higher MS score (median[range] 1.05[-1.26-26.55] vs -1.17[-1.26-2.52],P<0.001) than those with pure AOSD.The difference of different parameters of these two groups of patients were detailed in Table 1 and Table 2. ROC curve analysis (Figure 1) revealed that HScore has stronger ability to diagnose AOSD-associated MAS compared with MScore (AUC=0.973 and 0.865 for HScore and MS score repectively, P<0.001). HScore≥120 perform best (sensitivity 90.6% and specificity 89.6%). MS score≥-0.25 yielded a sensitivity of 75% and a specificity of 73%.Figure 1.ROC curve of HScore and MS score. HScore=120, sensitivity=90.6%, specificity= 89.6%. MS score=-0.45,sensitivity=75%, specificity=73%. AUC-HScore=0.973, AUC-MS score=0.865, P<0.001Conclusion:HScore seems to perform much better than MS score for the diagnosis of AOSD-associated MAS in our cohort.References:[1] Siddiqui M, Putman MS, Dua AB. Adult-Onset still’s disease: current challenges and future prospects. Open Access Rheumatol 2016;8:17–22.[2] Bracaglia C, Prencipe G, De Benedetti F. Macrophage activation syndrome: different mechanisms leading to a one clinical syndrome. Pediatr Rheumatol Online J 2017;15.[3] Guilpain P, Le Quellec A. About the complexity of adult onset still’s disease... and advances still required for its management. BMC Med 2017;15:5.[4] Minoia F, Bovis F, Davì s, et al. Development and initial validation of the MS score for diagnosis of macrophage activation syndrome in systemic juvenile idiopathic arthritis.Ann Rheum Dis 2019;78:1357–1362.[5] Fardet L, Galicier L, Lambotte O, et al. Development and validation of the HScore, a score for the diagnosis of reactive hemophagocyticsyndrome. Arthritis Rheumatol. 2014 Sep;66(9):2613-20.[6] ED Batu, A Erden, E Seyhoğlu, etal. Assessment of the HScore for reactive haemophagocytic syndrome in patients with rheumatic diseases.Scand J Rheumatol. 2017 Jan;46(1):44-48.[7] Wang R,Li T, Ye S, et al. Application of MS score in macrophage activation syndrome patients associated with adult onset Still’s disease. Ann Rheum Dis. 2019 Oct 14. pii: annrheumdis-2019-216286.Disclosure of Interests:None declared

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Macrophage Activation Syndrome in Childhood Rheumatic Diseases

Current Rheumatology Reviews ◽

10.2174/157339707781387617 ◽

2007 ◽

Vol 3 (3) ◽

pp. 225-230 ◽

Cited By ~ 1

Author(s):

Angelo Ravelli ◽

Clara Malattia ◽

Ilaria Sala ◽

Alberto Martini

Keyword(s):

Rheumatic Diseases ◽

Macrophage Activation Syndrome ◽

Macrophage Activation ◽

Activation Syndrome

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PReS-FINAL-2154: The early predictors of fatal outcome of macrophage activation syndrome in pediatric rheumatic diseases

Pediatric Rheumatology ◽

10.1186/1546-0096-11-s2-p166 ◽

2013 ◽

Vol 11 (S2) ◽

Author(s):

MM Kostik ◽

NN Abramova ◽

LS Snegireva ◽

LI Vasykina ◽

MF Dubko ◽

...

Keyword(s):

Rheumatic Diseases ◽

Macrophage Activation Syndrome ◽

Macrophage Activation ◽

Fatal Outcome ◽

Early Predictors ◽

Activation Syndrome

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THU0565 Macrophage activation syndrome in adults with inflammatory rheumatic diseases

10.1136/annrheumdis-2017-eular.5784 ◽

2017 ◽

Author(s):

M Olejárová ◽

K Jarošová

Keyword(s):

Rheumatic Diseases ◽

Macrophage Activation Syndrome ◽

Macrophage Activation ◽

Inflammatory Rheumatic Diseases ◽

Activation Syndrome

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Macrophage Activation Syndrome in Rheumatic Diseases (MAS-HLH)

Histiocytic Disorders ◽

10.1007/978-3-319-59632-7_13 ◽

2017 ◽

pp. 233-246 ◽

Cited By ~ 1

Author(s):

Alexei A. Grom ◽

AnnaCarin Horne ◽

Fabrizio De Benedetti

Keyword(s):

Rheumatic Diseases ◽

Macrophage Activation Syndrome ◽

Macrophage Activation ◽

Activation Syndrome

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SOLUBLE ST2 AND CD163 AS POTENTIALBIOMARKERS TO DIFFERENTIATE PRIMARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS FROM MACROPHAGE ACTIVATION SYNDROME

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2019.008 ◽

2019 ◽

Vol 11 (1) ◽

Cited By ~ 2

Author(s):

Zhuo Gao ◽

Yini Wang ◽

Jingshi Wang ◽

Jia Zhang ◽

Zhao Wang

Keyword(s):

Healthy Subjects ◽

Macrophage Activation Syndrome ◽

Macrophage Activation ◽

Serum Levels ◽

Haemophagocytic Lymphohistiocytosis ◽

Soluble St2 ◽

Tnf Α ◽

Significant Difference ◽

Ifn Γ ◽

Activation Syndrome

Abstract Background and Objective: The differentiation of primary haemophagocytic lymphohistiocytosis (pHLH) and macrophage activation syndrome (MAS) poses a challenge to hematologists. The aim of this study was (1) to compare the levels of soluble ST2 (sST2), sCD163, IL-10, IFN-γ, TNF-α and IL-18 in patients with pHLH and MAS and (2) to investigate whether they can help differentiate the two diseases. Methods: A total of 54 participants were recruited in this study, including 12 pHLH patients, 22 MAS patients and 20 healthy subjects. We measured the levels of sST2 and sCD163 in serum by ELISA. The serum levels of IL-10, IFN-γ, TNF-α and IL-18 were detected using a Luminex 200 instrument. Results: The serum levels of sST2 and sCD163 in MAS patients were markedly higher than that in pHLH patients (363.13 ± 307.24 ng/ml vs 80.75 ± 87.04 ng/ml, P = 0.004; 3532.72 ± 2479.68 ng/ml vs 1731.96 ± 1262.07 ng/ml, P = 0.046). There was no significant difference in the expression of IFN-γ (306.89 ± 281.60 pg/ml vs 562.43 ± 399.86 pg/ml), IL-10 (20.40 ± 30.49 pg/ml vs 8.3 ± 13.14 pg/ml), IL-18 (463.33 ± 597.04 pg/ml vs 1247.82 ± 1318.58 pg/ml) and TNF-α (61.48 ± 84.69 pg/ml vs 106.10 ±77.21 pg/ml) between pHLH and MAS. Conclusion: Patients with pHLH and MAS show some differences in cytokine profiles. The elevated levels of IFN-γ, IL-10, IL-18 and TNF-α can contribute to the diagnosis of HLH, but may not discriminate pHLH from MAS. Levels of sST2 and sCD163 may serve as markers to distinguish pHLH from MAS.

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Elevated circulating levels of interferon-γ and interferon-γ-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2015-209020 ◽

2016 ◽

Vol 76 (1) ◽

pp. 166-172 ◽

Cited By ~ 98

Author(s):

Claudia Bracaglia ◽

Kathy de Graaf ◽

Denise Pires Marafon ◽

Florence Guilhot ◽

Walter Ferlin ◽

...

Keyword(s):

Juvenile Idiopathic Arthritis ◽

Macrophage Activation Syndrome ◽

Macrophage Activation ◽

Systemic Juvenile Idiopathic Arthritis ◽

Serum Levels ◽

Interferon Γ ◽

Mrna Levels ◽

Circulating Levels ◽

Activation Syndrome

ObjectivesInterferon-γ (IFNγ) is the pivotal mediator in murine models of primary haemophagocytic lymphohistiocytosis (pHLH). Given the similarities between primary and secondary HLH (sec-HLH), including macrophage activation syndrome (MAS), we investigate the involvement of the IFNγ pathway in MAS by evaluating levels of IFNγ and of the induced chemokines, and their relation with laboratory parameters of MAS in systemic juvenile idiopathic arthritis (sJIA) patients with MAS and in a murine MAS model.MethodsThe Luminex multiplexing assay was used to assess serum levels of interleukin (IL)-1β, IL-6, IFNγ and of the IFNγ-induced chemokines CXCL9, CXCL10 and CXCL11 in patients with sec-HLH (n=11) and in patients with sJIA (n=54), of whom 20 had active MAS at sampling. Expression of IFNγ-induced chemokines was assessed in IL-6 transgenic mice in which MAS is induced by TLR4 stimulation with lipopolysaccharide.ResultsLevels of IFNγ and of IFNγ-induced chemokines were markedly elevated during active MAS and sec-HLH and were significantly higher in patients with MAS compared with active sJIA without MAS. Levels in patients with active sJIA without MAS were comparable to those of patients with clinically inactive sJIA. During MAS, ferritin and alanine transferase levels and neutrophil and platelet counts were significantly correlated with serum levels of IFNγ and CXCL9. In murine MAS, serum levels of ferritin were significantly correlated with mRNA levels of Cxcl9 in liver and spleen.ConclusionsThe high levels of IFNγ and of IFNγ-induced chemokines and their correlation with the severity of laboratory abnormalities of MAS suggest a pivotal role of IFNγ in MAS.

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Macrophage Activation Syndrome in Pediatric Systemic Lupus Erythematosus: A Systematic Review of the Diagnostic Aspects

Frontiers in Medicine ◽

10.3389/fmed.2021.681875 ◽

2021 ◽

Vol 8 ◽

Author(s):

Altynay Abdirakhmanova ◽

Vitaliy Sazonov ◽

Zaure Mukusheva ◽

Maykesh Assylbekova ◽

Diyora Abdukhakimova ◽

...

Keyword(s):

Systematic Review ◽

Systemic Lupus Erythematosus ◽

Diagnostic Criteria ◽

Rheumatic Diseases ◽

Lupus Erythematosus ◽

Macrophage Activation Syndrome ◽

Macrophage Activation ◽

Systemic Lupus ◽

Pediatric Systemic Lupus Erythematosus ◽

Activation Syndrome

Macrophage Activation Syndrome (MAS) is a very severe complication of different rheumatic diseases, including pediatric Systemic Lupus Erythematosus (pSLE). MAS is not considered as a frequent complication of pSLE; however, its occurrence could be under-estimated and the diagnosis can be challenging. In order to address this issue, we performed a systematic review of the available medical literature, aiming to retrieve all those papers providing diagnostic (clinical/laboratory) data on patients with pSLE-related MAS, in individual or aggregated form. The selected case reports and series provided a pool of 46 patients, accounting for 48 episodes of MAS in total. We re-analyzed these patients in light of the diagnostic criteria for MAS validated in systemic Juvenile Idiopathic Arthritis (sJIA) patients and the preliminary diagnostic criteria for MAS in pSLE, respectively. Five clinical studies were also selected and used to support this analysis. This systematic review confirms that MAS diagnosis in pSLE patients is characterized by several diagnostic challenges, which could lead to delayed diagnosis and/or under-estimation of this complication. Specific criteria should be considered to diagnose MAS in different rheumatic diseases; as regards pSLE, the aforementioned preliminary criteria for MAS in pSLE seem to perform better than the sJIA-related MAS criteria, because of a lower ferritin cut-off.

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