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

Bracaglia, Claudia; Graaf, Kathy de; Marafon, Denise Pires; Guilhot, Joëlle; Ferlin, Walter; Prencipe, Giusi; Caiello, Ivan; Davì, Sergio; Schulert, Grant S.; Ravelli, Angelo; Grom, Alexei A.; Min, Cristina de; Benedetti, Fabrizio

doi:10.1136/annrheumdis-2015-209020

Cited by 249 publications

(190 citation statements)

References 38 publications

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“…IFNγ levels were found to be higher in patients with active MAS at sampling compared to patients with active sJIA without MAS at sampling [41]. Using the above mentioned mouse model of MAS in IL-6 transgenic mice we have also found that neutralization of IFNγ improved survival and reverted biochemical abnormalities (Prencipe G. 2016 submitted).…”

Section: Introductionmentioning

confidence: 99%

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Macrophage Activation Syndrome: different mechanisms leading to a one clinical syndrome

2017

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BackgroundMacrophage activation syndrome (MAS) is a severe complication of rheumatic disease in childhood, particularly in systemic Juvenile Idiopathic Arthritis (sJIA). It is characterize by an uncontrolled activation and proliferation of T lymphocytes and macrophages.Main contentMAS is currently classified among the secondary or acquired forms of haemophagocytic lymphohistiocytosis (sHLH). The reason is that MAS shares clinical and laboratory features with primary genetic HLH (pHLH). In this context is conceivable that some of the pathogenic mechanisms of pHLH may be involved in other forms of HLH. Heterozygosity for mutations of genes involved in pHLH may lead to a cytotoxic defect and to a development of clinical overt disease. But other different contributors might be involved to the development of MAS such as infections or underlying inflammation. In MAS, the inflammatory status of the patient is a major contributor of the disease. Indeed, the majority of the MAS episodes occurs during active disease phases or at disease onset. In addition, recent evidence in animals and humans suggest that genetics may also play a major role in contributing to hyperinflammation and particularly to macrophages hyper-responses.ConclusionsWe hypothesize that HLH may be one unique clinical syndrome, to whose generation different mechanisms may contribute, and maintained by one final effector mechanism.

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Section: Introductionmentioning

confidence: 99%

“…CXCL9 is known to be specifically induced by IFNγ [42]. Indeed in patients with active MAS levels of IFNγ and CXCL9 were strictly related to laboratory features of MAS, including ferritin levels, white blood cell and platelet counts, and LDH [41]. These correlations were not present in patients with active sJIA without MAS.…”

Section: Introductionmentioning

confidence: 99%

Macrophage Activation Syndrome: different mechanisms leading to a one clinical syndrome

2017

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“…5 However, the cytokine storm reflected in plasma of patients with inherited HLH and MAS has been indistinguishable (elevated CXCL9/IFN-g, TNF-a, sIL-2Ra, IL-1, and IL-6). 6,7 Differentiating MAS from HLH is further confounded by recent observations of up to 40% of patients with MAS having monoallelic mutations in the common HLH-associated cytotoxicityregulating genes 8 (with uncertain impact of genetic dosage on pathogenesis). There is a clear need to understand the specific lesions in immune regulatory pathways that underlie unbridled inflammation in critically ill patients with MAS and HLH to facilitate diagnosis and optimize therapy.…”

Section: Texasmentioning

confidence: 99%

Fire behind the fury: IL-18 and MAS

McClain

Allen

2018

Blood

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In this issue of Blood, Weiss et al and Girard-Guyonvarc'h et al demonstrate the ability of free plasma interleukin-18 (IL-18) to distinguish macrophage activation syndrome (MAS) from other inflammatory disorders. Furthermore, with several animal models, they demonstrate that IL-18 is not just a biomarker but rather a driver of inflammation and potential therapeutic target in some patients with MAS.

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“…We did not make any changes in the sJIA classification in this study except for the two patients who were re-categorized to "unclassified arthritis" due to the presence of anti-CCP Ab. sJIA is characterized by prominent systemic features, marked activation of the innate immune system, and important pathogenic roles played by interleukin 1 (IL-1), IL-6, and interferon-γ [12,40]. Adult-onset Still's disease is considered similar to sJIA, but the former is different in terms of arthritis not being an essential diagnostic criterion [12].…”

Section: Discussionmentioning

confidence: 99%

New Provisional Classification of Juvenile Idiopathic Arthritis Applying Rheumatoid Factor and Antinuclear Antibody

2018

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Objective. Previous classification systems for juvenile idiopathic arthritis (JIA) were based on the number of joints involved and did not categorize homogenous disease entities. Therefore, JIA patients were reclassified retrospectively by applying rheumatoid factor (RF) and antinuclear antibody (ANA), which have been proven to constitute a homogenous disease entity. Methods. The medical records of JIA patients were investigated retrospectively and reclassified into six categories using the new provisional classification. The nomenclature was based on Dr. Martini's proposal in the 23rd European Paediatric Rheumatology Congress (2016) at Genoa, Italy. New categories included systemic JIA (sJIA), RF-positive JIA (RF-JIA), early-onset ANA-positive JIA (eoANA-JIA), enthesitis/spondylitis-related JIA (ESR-JIA), "other JIA", and "unclassified JIA". Results. Of a total of 262 JIA patients, 71 (27.1%) were reclassified as sJIA, 31 (11.8%) as RF-JIA, 22 (8.4%) as eoANA-JIA, 63 (24.0%) as ESR-JIA, 65 (24.8%) as "other JIA", and 10 (3.8%) as "unclassified JIA". A comparison of RF-JIA, eoANA-JIA, and ESR-JIA revealed significant differences in the gender ratio, age of disease onset, and the cumulative number and type of joints involved among the three groups. "Other JIA" comprised a significant proportion (24.8%) and warrants the need for further classification. The characteristics of the RF-positive patients were comparable to those of the anti-cyclic citrullinated peptide antibody-positive patients. The ANA positivity was lower (28.2%) than that in Western studies but showed similar clinical features. Conclusion. This is the first study applying RF and ANA to classify JIA without considering the joint counts. The six new categories include sJIA, RF-JIA, eoANA-JIA, ESR-JIA, "other JIA," and "unclassified JIA". (J Rheum Dis 2018;25:34-46)

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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

Abstract: The 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.

Cited by 249 publications

References 38 publications

Macrophage Activation Syndrome: different mechanisms leading to a one clinical syndrome

Macrophage Activation Syndrome: different mechanisms leading to a one clinical syndrome

Fire behind the fury: IL-18 and MAS

New Provisional Classification of Juvenile Idiopathic Arthritis Applying Rheumatoid Factor and Antinuclear Antibody

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