ArticleRheumatology (Oxford, England)2026
Free IL-18 in NLRC4-associated autoinflammatory disease without macrophage activation syndrome.
Article in Rheumatology (Oxford, England), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
objectivesNLRC4-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.
methodsClinical, 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.
resultsTotal 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.
conclusionGermline 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.
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