Free IL-18 in NLRC4-associated autoinflammatory disease without macrophage activation syndrome

NLRC4-associated autoinflammatory diseases (NLRC4-AID) cover a clinical spectrum from relatively mild familial cold autoinflammatory syndrome 4 (FCAS4) to life-threatening macrophage activation syndrome (MAS). Free IL-18 has been shown to pathogenically promote MAS, but the pathological relevance of free IL-18 in NLRC4-AID without MAS has not been explored. We investigated free IL-18 and related cytokines in five germline p.S445P and one somatic p.V341L NLRC4-AID patients without MAS.

Clinical, genetic and laboratory data, as well as serum samples were obtained from NLRC4-AID patients without MAS. Human IL-6, soluble CD25, CXCL9, CXCL10, IL-12p70, IFN-γ, total IL-18, IL-1β, TNF-α and IL-1Ra were assessed using a bead-based assay. Free IL-18 was assessed using a proprietary ELISA.

Total and free IL-18 were elevated both in the FCAS4 patients and the NLRC4-AID patient harbouring a heterozygous somatic NLRC4 variant restricted to the haematopoietic compartment. Despite the association between free IL-18 and MAS, we found no relevant correlation between total and free IL-18 and laboratory markers of inflammation or MAS. Accordingly, MAS-associated cytokines IFN-γ, CXCL9 and CXCL10 were not elevated in NLRC4-AID patients without MAS.

Germline and somatic NLRC4-AID without MAS are associated with elevated levels of both total and free IL-18. Our findings in the somatic NLRC4-AID patient suggest that free IL-18 originating from the haematopoietic system alone is not sufficient to drive MAS. Our findings indicate that IL-18 is necessary but not sufficient to drive MAS and suggest a pathological role of IL-18 beyond MAS in NLRC4-AID.