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. 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 proinflammatory 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.

A xenograft model of macrophage activation syndrome amenable to anti-CD33 and anti–IL-6R treatment

“…It also occurs in Kawasaki disease and systemic lupus erythematosus and sporadically in a myriad of other syndromes (5). MAS is the result of an uncontrolled, hyperactive immune response, often to an identifiable infection but in many cases lacking a known trigger (6). High levels of T cell-produced cytokines such as IFNγ, TNFα, and GM-CSF result, activating macrophages and other myeloid cells.…”

“…These treatments may thus not be appropriate for MAS (7). Newer therapies such as the IL-6 receptor (IL-6R) inhibitor tocilizumab, the IL-1 receptor antagonist anakinra, and TNFα inhibitors are all being evaluated for efficacy and safety in patients with HLH or MAS (6).…”

How I treat hemophagocytic lymphohistiocytosis in the adult patient

“…MAS is most commonly seen in association with adult-onset Still disease, systemic juvenile idiopathic arthritis, and systemic lupus erythematosus but has also been described in other rheumatologic conditions. 33- 35 The common malignancies associated with HLH include non-Hodgkin lymphoma and acute leukemia. Various infections have been described as triggers, including viral, bacterial, fungal, and parasitic infections.…”

UnMASking the diagnosis: Acute severe necrotizing pancreatitis in the setting of systemic lupus erythematosus complicated by macrophage activation syndrome

“…[15] In AOSD complicated by MAS, anakinra resulted in complete resolution of MAS symptoms. [16] MAS itself is associated with a tremendous "cytokine storm" including IL-1. This provides a mechanistic explanation for the efficacy of anakinra in such patients.…”