Macrophage activation syndrome and cytokine-directed therapies

Abstract

Macrophage activation syndrome (MAS) is an episode of overwhelming inflammation that occurs most commonly in children with systemic juvenile idiopathic arthritis (SJIA). It is characterized by expansion and activation of T lymphocytes and hemophagocytic macrophages and bears great similarity to hemophagocytic lymphohistiocytosis (HLH). This disorder has substantial morbidity and mortality, and there is frequently a delay in recognition and initiation of treatment. Here, we will review what is known about the pathogenesis of MAS and, in particular, its similarities to HLH. The development of MAS is characterized by a cytokine storm, with the elaboration of numerous pro-inflammatory cytokines. We will examine the evidence for various cytokines in the initiation and pathogenesis of MAS and discuss how new biologic therapies may alter the risk of MAS. Finally, we will review current treatment options for MAS and examine how cytokine-directed therapy could serve as novel treatment modalities.

Keywords: Hemophagocytic lymphohistiocytosis; IFNγ; IL-1; IL-18; IL-6; Macrophage activation syndrome; Still's disease; Systemic juvenile idiopathic arthritis.

Figure 1

“Cytokine storm” and the development of MAS. MAS can develop in the setting of high SJIA disease activity, which is associated with increased cytokine levels including IL-1, IL-6, IL-18 and TNFα. MAS can also be triggered by viral infections, wherein pathogen-associated molecular patterns (PAMPs) are recognized by toll-like receptors (TLR) and trigger further secretion of inflammatory cytokines. Notably the proinflammatory environment including elevated IL-6 can enhance signaling through TLR. Infection also leads to activation and proliferation of CD8+ T cells and NK cells, including secretion of IFNγ. Increased IL-18 levels further drive IFNγ production by these activated lymphocytes. This surge in IFNγ leads to activation of macrophages that acquire a proinflammatory phenotype and generate high levels of chemokines and cytokines. These activated macrophages, along with CD8+ T cells, traffic to tissue including the bone marrow and liver and lead to the cytopenia, liver dysfunction and coagulopathy associated with MAS.