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The pathogenesis of macrophage activation syndrome

The term macrophage activation syndrome (MAS) identifies a severe and potentially fatal complication of s-JIA, and, more rarely of other rheumatic diseases. MAS share similarities in clinical features and laboratory abnormalities with primary and secondary heamophagocytic lymphohystiocytosis (HLH). Indeed it is currently classified among secondary HLH and the term rheuma-HLH has been used to indicate this condition. The clinical and laboratory similarities with primary genetic- caused HLH led to the hypothesis that pathogenic mechanisms leading to the typical features of MAS/rheuma-HLH are similar to those involved in primary HLH. We will review the evidence supporting this hypothesis; particularly the role of hyper-responses to TLR activation, of subclinical variants of genes involved in the cytotoxic pathways, and of the transient NK cytotoxicity defect induced by inflammatory cytokines. We will also present evidence on the role of IL-6, IL-1 and IFN-g in this syndrome and discuss the potential benefits of therapies targeted to these cytokines.

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F. De Benedetti Grant / Research Support from: Sobi, Novimmune, Novartis, Roche, Pfizer, Abbvie

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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

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De Benedetti, F. The pathogenesis of macrophage activation syndrome. Pediatr Rheumatol 12 (Suppl 1), I7 (2014).

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