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

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.