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Adenosine deaminase 2 as a biomarker of macrophage activation syndrome in systemic juvenile idiopathic arthritis.

ABSTRACT: OBJECTIVE:Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile idiopathic arthritis (sJIA) characterised by a vicious cycle of immune amplification that can culminate in overwhelming inflammation and multiorgan failure. The clinical features of MAS overlap with those of active sJIA, complicating early diagnosis and treatment. We evaluated adenosine deaminase 2 (ADA2), a protein of unknown function released principally by monocytes and macrophages, as a novel biomarker of MAS. METHODS:We established age-based normal ranges of peripheral blood ADA2 activity in 324 healthy children and adults. We compared these ranges with 173 children with inflammatory and immune-mediated diseases, including systemic and non-systemic JIA, Kawasaki disease, paediatric systemic lupus erythematosus and juvenile dermatomyositis. RESULTS:ADA2 elevation beyond the upper limit of normal in children was largely restricted to sJIA with concomitant MAS, a finding confirmed in a validation cohort of sJIA patients with inactive disease, active sJIA without MAS or sJIA with MAS. ADA2 activity strongly correlated with MAS biomarkers including ferritin, interleukin (IL)-18 and the interferon (IFN)-?-inducible chemokine CXCL9 but displayed minimal association with the inflammatory markers C reactive protein and erythrocyte sedimentation rate. Correspondingly, ADA2 paralleled disease activity based on serial measurements in patients with recurrent MAS episodes. IL-18 and IFN-? elicited ADA2 production by peripheral blood mononuclear cells, and ADA2 was abundant in MAS haemophagocytes. CONCLUSIONS:These findings collectively identify the utility of plasma ADA2 activity as a biomarker of MAS and lend further support to a pivotal role of macrophage activation in this condition.

SUBMITTER: Lee PY

PROVIDER: S-EPMC7385992 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Adenosine deaminase 2 as a biomarker of macrophage activation syndrome in systemic juvenile idiopathic arthritis.

Lee Pui Y PY Schulert Grant S GS Canna Scott W SW Huang Yuelong Y Sundel Jacob J Li Ying Y Hoyt Kacie J KJ Blaustein Rachel B RB Wactor Alexandra A Do Thuy T Halyabar Olha O Chang Margaret H MH Dedeoglu Fatma F Case Siobhan M SM Meidan Esra E Lo Mindy S MS Sundel Robert P RP Richardson Edward T ET Newburger Jane W JW Hershfield Michael S MS Son Mary Beth MB Henderson Lauren A LA Nigrovic Peter A PA

Annals of the rheumatic diseases 20191109 2

<h4>Objective</h4>Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile idiopathic arthritis (sJIA) characterised by a vicious cycle of immune amplification that can culminate in overwhelming inflammation and multiorgan failure. The clinical features of MAS overlap with those of active sJIA, complicating early diagnosis and treatment. We evaluated adenosine deaminase 2 (ADA2), a protein of unknown function released principally by monocytes and macrophages, ...[more]

PMID: 31707357

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Project description:Macrophage activation syndrome (MAS) is a severe and potentially lethal complication of several inflammatory diseases but seems particularly linked to systemic juvenile idiopathic arthritis (sJIA). Standardized diagnostic and treatment guidelines for MAS in sJIA are currently lacking. The aim of this systematic literature review was to evaluate currently available literature on diagnostic criteria for MAS in sJIA and provide an overview of possible biomarkers for diagnosis, disease activity and treatment response and recent advances in treatment.A systematic literature search was performed in MEDLINE, EMBASE and Cochrane. 495 papers were identified. Potentially relevant papers were selected by 3 authors after which full text screening was performed. All selected papers were evaluated by at least two independent experts for validity and level of evidence according to EULAR guidelines.27 papers were included: 7 on diagnosis, 9 on biomarkers and 11 on treatment. Systematic review of the literature confirmed that there are no validated diagnostic criteria for MAS in sJIA. The preliminary Ravelli criteria, with the addition of ferritin, performed well in a large retrospective case-control study. Recently, an international consortium lead by PRINTO proposed a new set of diagnostic criteria able to distinguish MAS from active sJIA and/or infection with superior performance. Other promising diagnostic biomarkers potentially distinguish MAS complicating sJIA from primary and virus-associated hemophagocytic lymphohistiocytosis. The highest level of evidence for treatment comes from case-series. High dose corticosteroids with or without cyclosporine A were frequently reported as first-line therapy. From the newer treatment modalities, promising responses have been reported with anakinra.MAS in sJIA seems to be diagnosed best by the recently proposed PRINTO criteria, although prospective validation is needed. Novel promising biomarkers for sJIA related MAS are in need of prospective validation as well, and are not widely available yet. Currently, treatment of MAS in sJIA relies more on experience than evidence based medicine. Taking into account the severity of MAS and the scarcity of evidence, early expert consultation is recommended as soon as MAS is suspected.

Project description:Objective. Follistatin-like protein 1 (FSTL-1) is a secreted glycoprotein that is over-expressed in certain inflammatory diseases. Our objective in this study was to correlate FSTL-1 levels with measures of clinical disease activity in systemic juvenile idiopathic arthritis (sJIA), including macrophage activation syndrome (MAS). Methods. FSTL-1 serum levels were measured by ELISA in 28 patients with sJIA, including 7 patients who developed MAS, as well as in 30 normal controls. Levels were correlated with erythrocyte sedimentation rate (ESR), ferritin and sIL-2Rα expression. Differential gene expression based on FSTL-1 levels was analyzed in peripheral blood mononuclear cells (PBMCs). Results. FSTL-1 serum levels were elevated at time of presentation (pre-treatment) of sJIA (mean 200.7 ng/ml) and decreased to normal (mean 133.7 ng/ml) over 24 months (p<0.01). FSTL-1 levels were markedly elevated during acute MAS (mean 279.8 ng/ml) and decreased to normal (mean 120.3 ng/ml) following treatment (p<0.001). FSTL-1 levels correlated with serum markers of inflammation, including sIL-2Rα and ferritin, in patients with MAS. PBMCs from patients with FSTL-1 levels >200 ng/ml showed an increase in expression of genes related to innate immunity and erythropoiesis, and decrease in NK cell function. Patients with the highest FSTL-1 levels at disease onset (>300 ng/ml) ultimately required cyclosporine treatment. Conclusion. In patients with sJIA, serum FSTL-1 is a biomarker for MAS and FSTL-1 levels at presentation may predict subsequent disease course. Patients with FSTL-1 levels >200 ng/ml had altered gene expression patterns suggestive of subclinical MAS and may represent a subgroup of sJIA with more severe disease. FSTL-1 serum levels were measured by ELISA in 28 patients with sJIA, including 7 patients who developed MAS, as well as in 30 normal controls. Levels were correlated with erythrocyte sedimentation rate (ESR), ferritin and sIL-2Rα expression. Differential gene expression based on FSTL-1 levels was analyzed in peripheral blood mononuclear cells (PBMCs). Only 11 patients were run on microarray.

Dataset Information

Adenosine deaminase 2 as a biomarker of macrophage activation syndrome in systemic juvenile idiopathic arthritis.

Publications

Adenosine deaminase 2 as a biomarker of macrophage activation syndrome in systemic juvenile idiopathic arthritis.

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