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IL-1 Inhibition May Have an Important Role in Treating Refractory Kawasaki Disease
Perrine Dusser1, Isabelle Koné-Paut1
1Department of Pediatric Rheumatology, Reference Centre for Autoinflammatory Diseases, Le Kremlin-Bicêtre Hospital, Assistance Publique-Hôpitaux de Paris, Paris-Sud University Hospital Paris, France.
Insights
Kawasaki disease (KD) treatment may improve with interleukin-1 (IL-1) blockade. Targeting IL-1 signaling offers new hope for children unresponsive to standard therapies, potentially reducing cardiac complications.
Area of Science:
- Pediatric Rheumatology
- Immunology
- Vascular Biology
Background:
- Kawasaki disease (KD) is a leading cause of acquired heart disease in young children.
- Standard treatment with intravenous immunoglobulin and aspirin is effective but fails in 10-20% of cases.
- KD shares features with autoinflammatory diseases, suggesting novel therapeutic targets.
Purpose of the Study:
- To investigate the role of interleukin-1 (IL-1) signaling in Kawasaki disease pathogenesis.
- To evaluate the potential of IL-1 blockade as a therapeutic strategy for KD.
- To identify genetic factors associated with treatment resistance in KD.
Main Methods:
- Analysis of genetic and transcriptomic data in KD patients.
- Investigated IL-1α and IL-1β roles in a mouse model of KD.
- Examined intracellular calcium levels and cytokine production in treatment-resistant patients.
Main Results:
- IL-1 signaling is a key pathway in KD pathogenesis.
- IL-1 blockade, demonstrated in a mouse model, improved disease markers.
- Treatment failure in specific genotypes correlated with elevated calcium and IL-1β/IL-18 levels.
Conclusions:
- IL-1 blockade represents a promising therapeutic avenue for Kawasaki disease.
- Targeting IL-1 may benefit patients unresponsive to current treatments.
- Ongoing clinical trials are crucial to confirm the efficacy of IL-1 blockade in KD.
Abstract:
Kawasaki disease (KD) is an acute inflammatory vasculitis occurring in young children before 5 years and representing at this age, the main cause of acquired heart disease. A single infusion of 2 g/kg of intravenous immunoglobulins along with aspirin has reduced the frequency of coronary artery aneurysms from 25 to 5%. However, 10-20% of patients do not respond to standard treatment and have an increased risk of cardiac complications and death. The development of more potent therapeutic approaches of KD is an urgent need. Phenotypical and immunological similarities between KD and systemic juvenile idiopathic arthritis led to the hypothesis that KD could be considered as an autoinflammatory disease. New insights regarding KD's pathogenesis have merged from the combination of genetic and transcriptomic data revealing the key role of interleukin-1 (IL-1) signaling in the pathogenesis of the vasculitis. Once activated, IL-1α and IL-1β trigger a local proinflammatory environment-inducing vasodilatation and attracting monocytes and neutrophils to sites causing tissue damage and stress. Both IL-1α and IL-1β have been shown to induce myocarditis and aneurysm formation in Lactobacillus casei cell-wall extract mouse model of KD; both being successfully improved with IL-1 blockade treatment such as anakinra. Treatment failure in patients with the high-risk inositol-triphosphate 3-kinase C genotype was associated with highest basal and stimulated intracellular calcium levels, increased cellular production of IL-1β, and IL-18, and higher circulating levels of both cytokines. Three clinical trials of IL-1 blockade enrolling KD patients are currently being conducted in Western Europe and in USA, they could change KD outcome.