Clinical application of several rapidly evolving technologies—next-generation DNA sequencing, biomarker discovery, and targeted cytokine blockade—has been particularly beneficial to understanding an expanding spectrum of genetically defined autoinflammatory diseases. 1 Our understanding of the pathways that cause hemophagocytic disorders, such as macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH), is evolving similarly. MAS and HLH are life-threatening sepsis-like conditions notable for hyperferritinemia, acute cytopenias, and hepatitis. If not promptly recognized and treated, they can progress to consumptive coagulopathy, hemophagocytosis, multiorgan failure, and high mortality. HLH is classically associated with genetic defects in cytotoxicity, whereas MAS is observed as a complication of rheumatic diseases. 1

We recently implicated gain-of-function mutations in NLRC4, a protein that activates the inflammasome, in a syndrome of recurrent MAS with early-onset enterocolitis (NLRC4-MAS, OMIM# 616050). 2, 3 Inflammasomes are large innate immune complexes that quickly and exponentially catalyze the activation of pro–IL-1β and pro–IL-18. Although IL-1β blockade is effective in many “inflammasomopathies,” 1, 2 the role of IL-1β in MAS is controversial. IL-1 blockade is effective in treating MAS-prone diseases, but was not protective against the development of MAS. The effects of blocking IL-18 are unknown. Patients with NLRC4-MAS have extraordinary and chronic elevation of serum IL-18 2, 3; and although extraordinary IL-18 levels are a feature of MAS more generally, IL-18 is only modestly elevated in other genetic inflammasomopathies.