IL-1 Inhibition May Have an Important Role in Treating Refractory Kawasaki Disease

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.

IL-1 receptor antagonist, anakinra, prevents myocardial dysfunction in a mouse model of Kawasaki disease vasculitis and myocarditis

“…These observations further support that interventions blocking IL-1β and its receptor could be more broadly utilized as a front-line agent to treat KD, a concept that is now readily entertained [6,7]. These observations further support that interventions blocking IL-1β and its receptor could be more broadly utilized as a front-line agent to treat KD, a concept that is now readily entertained [6,7].…”

“…In summary, while IL-1Ra is now in two Phase II clinical trials in IVIG-non-responsive acute KD patients, our findings indicate a potential benefit of IL-1 receptor blockade on the long-term cardiovascular consequences of KD by inhibiting acute KD myocarditis and cardiac dysfunction. These observations further support that interventions blocking IL-1β and its receptor could be more broadly utilized as a front-line agent to treat KD, a concept that is now readily entertained [6,7].…”

“…With high-dose intravenous immunoglobulin (IVIG) treatment, this number falls to ~5% [2], but IVIG resistance is a growing problem, with approximately 25-30% of KD patients IVIG-resistant and thus at higher risk of developing CAA [3][4][5]. Therefore, alternative therapies, including blocking interleukin (IL)-1 signaling, are being investigated [6,7].…”

Monocyte‐Derived Interleukin‐1β As the Driver of S100A12‐Induced Sterile Inflammatory Activation of Human Coronary Artery Endothelial Cells: Implications for the Pathogenesis of Kawasaki Disease

“…A single infusion of 2 gm/kg of intravenous immunoglobulins (IVIGs), administered in conjunction with aspirin, has reduced the frequency of coronary artery aneurysms in patients with KD from 25% to 5%. However, 10–20% of patients are unresponsive to IVIG treatment, and thus present with persisting fever and inflammation and have an increased risk of cardiac complications and death .…”

Treatment Options for Refractory Kawasaki Disease

“…Initial reports suggesting these drugs are safe to children but data regarding their efficacy is still not available [32]. In a study conducted by Dusser P et al [33] IL-1 blockade treatment such as anakinra showed successful improvement in myocarditis and aneurysm that was formed in a mouse model of KD.…”