Macrophage activation syndrome in the era of biologic therapy

Abstract

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.

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

“…Identification of patients carrying heterozygous variants of the same genes involved in pHLH,5–9 and the transient defect in cytotoxic NK activity secondary to active inflammation,32 suggests that mechanisms, at least in part, similar to those of pHLH may contribute 33. An additional contribution may be represented by high levels of IL-18 that have been suggested to predispose to MAS during sJIA:34 IL-18 is a well-known IFNγ-inducing cytokine 35.…”

Fire behind the fury: IL-18 and MAS

“…4 There are no tests proven to distinguish HLH from MAS (or from severe sepsis or other mimics). Perforin-deficient mouse models suggest interferon-g (IFN-g) production as the critical driver of HLH, with activation of multiple downstream pathways that regulate and respond to inflammation.…”

“…Loss of 9p, the locus for cyclin-dependent kinase inhibitor 2 A and B (CDKN2A/2B), has already been associated with a poorer relapse-free survival in 3 clinical studies of Ph 1 ALL. [3][4][5] Pfeifer et al used single nucleotide polymorphism arrays and multiplex ligation-dependent probe amplification to uncover the impact of…”

Serum soluble VSIG4 as a surrogate marker for the diagnosis of lymphoma‐associated hemophagocytic lymphohistiocytosis

“…Activated CTLs and macrophages are two crucial players in HLH. During the development and progression of HLH, impaired cytotoxicity leads to prolonged stimulation of CTLs and natural killer (NK) cells secreting large amounts of pro‐inflammatory cytokines, including IFN‐γ, which causes macrophage activation and expansion, further resulting in subsequent overproduction of other pro‐inflammatory cytokines and ultimately the cytokine storm (Lehmberg & Ehl, ; Grom et al ., ; Al‐Samkari & Berliner, ). The soluble interleukin‐2 receptor alpha (sIL‐2Rα; also termed sCD25) is a truncated protein shed from the surface of activated CTLs.…”