TY - JOUR
T1 - Free IL-18 in NLRC4-associated autoinflammatory disease without macrophage activation syndrome
AU - Willemsen, Mathijs
AU - Schoonbrood, Thea H.M.
AU - Rodriguez, Emiliana
AU - Roosens, Willem
AU - De Langhe, Ellen
AU - Schrijvers, Rik
AU - Gabay, Cem
N1 - Funding Information:
Supported by the Fonds Wetenschappelijk Onderzoek\u2014Flanders National Fund for Scientific Research fellowship 11PDZ24N (to W.R.) and senior Clinical Investigator Fellowship 1805523N (to R.S.). R.S. was recipient of an FWO Junior Research Project Grant (G0AHL25N). C.G. was supported by a grant from the Swiss National Science Foundation (310030B-201269) and the ERARE2 Cure-AID Grant from the European Union ERA-Net for Research Programs on Rare Diseases.
Publisher Copyright:
© The Author(s) 2026. Published by Oxford University Press on behalf of the British Society for Rheumatology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
PY - 2026/7/1
Y1 - 2026/7/1
N2 - Objectives: 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. Methods: 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-?, total IL-18, IL-1ß, TNF-a and IL-1Ra were assessed using a bead-based assay. Free IL-18 was assessed using a proprietary ELISA. Results: 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-?, CXCL9 and CXCL10 were not elevated in NLRC4-AID patients without MAS. Conclusion: 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.
AB - Objectives: 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. Methods: 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-?, total IL-18, IL-1ß, TNF-a and IL-1Ra were assessed using a bead-based assay. Free IL-18 was assessed using a proprietary ELISA. Results: 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-?, CXCL9 and CXCL10 were not elevated in NLRC4-AID patients without MAS. Conclusion: 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.
KW - autoinflammatory disease
KW - IL-18
KW - macrophage activation syndrome
KW - NLRC4
U2 - 10.1093/rheumatology/keag363
DO - 10.1093/rheumatology/keag363
M3 - Article
SN - 1462-0324
VL - 65
JO - Rheumatology
JF - Rheumatology
IS - 7
M1 - keag363
ER -