Interferon-gamma (IFNy) in macrophage activation syndrome (MAS) associated with systemic juvenile idiopathic arthritis (sJIA). High levels in patients and a role in a murine mas model

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

doi:10.1186/1546-0096-12-s1-o3

Cited by 7 publications

(11 citation statements)

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“…Serum IFN-γ levels in patients with MAS are markedly high compared with patients with active sJIA without MAS 52,53 . The emergence of clinical features of MAS in sJIA patients often corresponds to an increase in levels of IFN-γ-induced chemokines 53 and neopterin, a catabolic product of guanosine triphosphate released by IFN-γ activated macrophages 54 .…”

Section: Proposed Mas Pathophysiology Modelmentioning

confidence: 93%

“…Furthermore, IFN-γ and IFN-γ-induced chemokines (CXCL9 in particular) strongly correlated with many laboratory features of MAS. Neutralization of IFN-γ in the MAS model using IL-6 transgenic mice led to a great improvement in survival and a considerable decrease in ferritin levels 53 . Collectively, these observations raise the question of whether IFN-γ could also be an appropriate therapeutic target in MAS.…”

Section: Pathophysiological Implicationsmentioning

confidence: 96%

“…The emergence of clinical features of MAS in sJIA patients often corresponds to an increase in levels of IFN-γ-induced chemokines 53 and neopterin, a catabolic product of guanosine triphosphate released by IFN-γ activated macrophages 54 . Furthermore, extremely high serum levels of soluble IL-2 receptor subunit-α (sIL2Rα), presumably shed by cytotoxic CD8 T lymphocytes, are a consistent finding in patients with MAS that could be a useful diagnostic marker 55 .…”

Section: Proposed Mas Pathophysiology Modelmentioning

confidence: 99%

“…Furthermore, children with MAS exhibit increased levels of neopterin, a product normally released by macrophages stimulated with interferons 52 . Another 2015 study, focused on longitudinal cytokine changes in serum of patients with sJIA, showed that IFN-γ itself and IFN-γ-induced chemokines increased markedly with the emergence of clinical features of MAS, and returned to normal ranges after resolution of this complication 53 . Furthermore, IFN-γ and IFN-γ-induced chemokines (CXCL9 in particular) strongly correlated with many laboratory features of MAS.…”

Section: Pathophysiological Implicationsmentioning

confidence: 99%

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Macrophage activation syndrome in the era of biologic therapy

2016

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Macrophage activation syndrome (MAS) refers to acute overwhelming inflammation caused by a ‘cytokine storm’. Although increasingly recognized as a life-threatening complication of various rheumatic diseases, clinically, MAS is strikingly similar to primary and secondary forms of haemophagocytic lymphohistiocytosis (HLH). Not surprisingly, many rheumatologists prefer the term secondary HLH rather than MAS to describe this condition, and efforts to change the nomenclature are in progress. The pathophysiology of MAS remains elusive, but observations in animal models, as well as data on the effects of new anticytokine therapies on rates and clinical presentations of MAS in patients with systemic juvenile idiopathic arthritis (sJIA), provide clues to the understanding of this perplexing clinical phenomenon. In this Review, we explore the latest available evidence and discuss potential diagnostic challenges in the era of increasing use of biologic therapies.

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Section: Proposed Mas Pathophysiology Modelmentioning

confidence: 93%

Section: Pathophysiological Implicationsmentioning

confidence: 96%

Section: Proposed Mas Pathophysiology Modelmentioning

confidence: 99%

Section: Pathophysiological Implicationsmentioning

confidence: 99%

See 2 more Smart Citations

Macrophage activation syndrome in the era of biologic therapy

2016

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“…IFNγ appears central to the pathogenesis of FHLH. First, IFNγ expression is highly elevated in these patients, out of proportion to other proinflammatory cytokines such as TNFα and IL-6, and rapidly returns to normal upon effective treatment (42, 84, 85). These children also exhibit increased levels of the IFNγ-induced chemokines IP-10 and MIG (86).…”

Section: Pathophysiologymentioning

confidence: 99%

Pathogenesis of Macrophage Activation Syndrome and Potential for Cytokine- Directed Therapies

Schulert

Grom²

2015

Annu. Rev. Med.

325

274

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Macrophage activation syndrome (MAS) is an acute episode of overwhelming inflammation characterized by activation and expansion of T lymphocytes and hemophagocytic macrophages. In rheumatology, it occurs most frequently in patients with systemic juvenile idiopathic arthritis (SJIA) and systemic lupus erythematosus. The main clinical manifestations include cytopenias, liver dysfunction, coagulopathy resembling disseminated intravascular coagulation, and extreme hyperferritinemia. Clinically and pathologically, MAS bears strong similarity to hemophagocytic lymphohistiocytosis (HLH), and some authors prefer the term secondary HLH to describe it. Central to its pathogenesis is a cytokine storm, with markedly increased levels of numerous proinflammatory cytokines including IL-1, IL-6, IL-18, TNFα, and IFNγ. Although there is evidence that IFNγ may play a central role in the pathogenesis of MAS, the role of other cytokines is still not clear. There are several reports of SJIA-associated MAS dramatically benefiting from anakinra, a recombinant IL-1 receptor antagonist, but the utility of other biologics in MAS is not clear. The mainstay of treatment remains corticosteroids; other medications, including cyclosporine, are used in patients who fail to respond.

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Rate and Clinical Presentation of Macrophage Activation Syndrome in Patients With Systemic Juvenile Idiopathic Arthritis Treated With Canakinumab

Grom

Ilowite

Pascual

et al. 2015

Arthritis & Rheumatology

112

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Objective In pivotal trials, canakinumab has been shown to be effective in the treatment of systemic juvenile idiopathic arthritis (JIA), but reported adverse events have included macrophage activation syndrome (MAS). This study was undertaken to assess the impact of canakinumab on MAS incidence. Methods An independent MAS Adjudication Committee (MASAC), consisting of 3 of the authors, was convened, and a search of databases from clinical studies of canakinumab treatment in systemic JIA was performed using MASAC‐specified adverse event terms to identify potential MAS events. These were then adjudicated as “probable MAS,” “possible MAS,” or “MAS unlikely,” using criteria developed by the MASAC. MAS rates were expressed as numbers of cases per 100 patient‐years. Results Of 72 potential MAS cases identified, 21 events (19 with canakinumab treatment; 2 with placebo treatment) in 19 patients were adjudicated as being probable MAS and 10 events in 9 patients as being possible MAS. Systemic JIA was well controlled in the majority of canakinumab‐treated patients at the time of MAS. The time period between initiation of canakinumab treatment and onset of MAS ranged from 3 to 1,358 days (median 292 days). When the rates of probable MAS events were compared between canakinumab‐treated patients (2.8 per 100 patient‐years) and placebo‐treated patients (7.7 per 100 patient‐years), the difference was not significant (−4.9 [95% confidence interval −15.6, 5.9]). There were 3 deaths due to MAS‐related complications (2 in patients receiving canakinumab; 1 in a patient receiving placebo); full recovery was reported in all other patients. Infections were the most common trigger of MAS, and the clinical features of MAS were not modified by canakinumab. Conclusion Canakinumab does not have a significant effect on MAS risk or its clinical features in patients with systemic JIA. Infections are the most common trigger, and MAS occurs even in patients whose systemic JIA is well controlled with this treatment.

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Interferon-gamma (IFNy) in macrophage activation syndrome (MAS) associated with systemic juvenile idiopathic arthritis (sJIA). High levels in patients and a role in a murine mas model

Cited by 7 publications

References 0 publications

Macrophage activation syndrome in the era of biologic therapy

Macrophage activation syndrome in the era of biologic therapy

Pathogenesis of Macrophage Activation Syndrome and Potential for Cytokine- Directed Therapies

Rate and Clinical Presentation of Macrophage Activation Syndrome in Patients With Systemic Juvenile Idiopathic Arthritis Treated With Canakinumab

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