Pathogenesis of macrophage activation syndrome and potential for cytokine- directed therapies

Abstract

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.

Keywords: Still's disease; cytokine storm; hemophagocytic lymphohistiocytosis; hyperferritinemia; systemic juvenile idiopathic arthritis.

Figure 1

“Cytokine storm” and the development of macrophage activation syndrome (MAS). MAS can develop in the setting of high systemic juvenile idiopathic arthritis (SJIA) disease activity, which is associated with increased levels of cytokines 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 (TLRs) and trigger further secretion of inflammatory cytokines. The proinflammatory environment including elevated IL-6 can enhance signaling through TLRs. Infection also leads to activation and proliferation of CD8⁺ T cells and NK cells, including secretion of IFNγ. Defects in the cytolytic activity of these lymphocytes also contribute to hyperinflammation. 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 bone marrow and liver and lead to the cytopenias, liver dysfunction, and coagulopathy associated with MAS.