ReviewThe use of interleukin 1 receptor antagonist (anakinra) in Kawasaki disease: A retrospective cases series
Introduction
Kawasaki disease (KD) is the most frequent vasculitis of children aged <5 years, and the main cause of acquired heart disease in developed countries. KD has also been seldom reported in young adults at a mean age of 30 years [1]. Epidemiologic data strongly suggest an infectious aetiology, although the causative agent has yet to be identified. Genetic factors also increase susceptibility to KD, as indicated by its strikingly high incidence in children of Asian ethnicity, both in and outside the Far East, and by an increased incidence in first-degree family members [2,3]. KD is a self-limited illness that results in coronary artery aneurysms in up to 25% of untreated children. Giant aneurysms, myocardial infarction and myocarditis are present in a minority of KD cases, and rarely lead to early death [4]. Administration of high-dose intravenous immunoglobulin (IVIG) in combination with aspirin results in dramatic clinical improvement and reduced incidence of coronary artery aneurysms in the majority of patients with KD [5,6]. A subset (20%) of patients have persistence or recrudescence of fever following IVIG treatment, and are at increased risk for coronary vasculitis. The American heart association (AHA) has recommended administering a second dose of IVIG (2 g/kg) to patients who fail to become afebrile within 48 h after completion of the first infusion, even though the benefits of this approach may be limited, especially in terms of efficacy on coronary abnormalities [7]. Identifying patients at risk for IVIG resistance is difficult outside the Asian population, and there remains a critical unmet need to identify an anti-inflammatory treatment that is efficacious in all KD patients. Some clinical features of KD are similar to those observed in systemic autoinflammatory diseases (SAID), including systemic-onset juvenile idiopathic arthritis (soJIA): abrupt and seemingly unprovoked onset of fever at a young age, skin rash, eye and mouth inflammation, cervical adenitis, and pericarditis. Marked elevation of acute phase reactants: e.g. CRP and neutrophils, elevated platelets, hypoalbuminemia without evidence of autoantibodies are also very concordant with soJIA. Intriguingly, transient coronary abnormalities have also been noticed in patients with soJIA [8]. Recent evidence from studies in animals and humans suggest a critical role for interleukin-1 (IL-1) α and β in the pathogenesis of KD. For example, IL-1 polymorphisms could be associated either to response or resistance to IVIG treatment. Interestingly elevated transcripts have been shown in IVIG-resistant KD patients, those carrying the highest risk for coronary aneurysms [9,10]. Of particular note, only blockade of IL-1, but not of tumour necrosis factor (TNF) α, reduced the myocarditis in the LCWE (Lactobacillus casei cell wall extract)-injected mice and TNFα blockade as adjunctive therapy to IVIG gave success regarding fever and inflammatory parameters but with no differences in coronary artery evolution in a controlled trial in humans [[11], [12], [13], [14]]. Anakinra has been reported to successfully treat KD in 3 patients not responding to standard treatment with IVIG [[15], [16], [17], [18]].
Due to its availability and its safety of use, anakinra is increasingly used off label to treat patients with other IL-1 related diseases [19,20]. Here, we present further experience of anakinra use in order to identify the clinical characteristics, reasons for use and response to treatment with anakinra in a retrospective series of patients with KD.
Section snippets
Patients and methods
We collected retrospective data from KD patients treated with anakinra using a dedicated questionnaire. Patients were recruited in France through the SOFREMIP (SOciété Francophone de Rhumatologie Et de Médecine Interne Pédiatriques) network, and other European countries (Italy, Spain, United Kingdom) through an established international network on KD. Inclusion criteria were a diagnosis of KD according to the American Heart association (AHA) criteria for complete or incomplete KD, treatment
Clinical, biological and cardiologic characteristics
Eleven patients, 8 boys and 3 girls, were included. Age at symptom onset ranged from 4 months to 9 years [median 22 months], and included 4 patients under 6 months. Nine patients fulfilled AHA criteria for complete KD and two for incomplete KD. The median delay to diagnosis was 8 days [mean 13 days; 3 to 50 days]. The mean disease follow-up from diagnosis was 8 months [1 to 31 months]. In addition to major AHA criteria, 90% of patients (9/10) were irritable, 70% had hepatomegaly (7/10), 3/11had
Discussion
We have presented the largest published case-series so far of patients with KD treated with anakinra. Common characteristics of these patients were IVIG resistance, cardiac complications (with cardiogenic shock in 2 cases), and at least two lines of other treatment before anakinra. It is well known that IVIG resistance is associated with coronary vasculitis and genetic studies have identified the inositol 1,4,5‑trisphosphate 3-kinase C, (ITPKC) as a susceptibility factor for both KD and
Abbreviations
- KD
Kawasaki disease
- IVIG
intravenous immunoglobulin
- soJIA
systemic onset juvenile idiopathic arthritis
- IL-1
interleukin 1
- AHA
American Heart association
- CRP
C-reactive protein
- ESR
erythrocyte sedimentation rate
Conflicts of interest
MP has no conflict of interest related to this study.
RC has no conflict of interest related to this study.
JH has no conflict of interest related to this study.
OB has no conflict of interest related to this study.
AC has no conflict of interest related to this study.
JPS has no conflict of interest related to this study.
MCM has no conflict of interest related to this study.
JA has no conflict of interest related to this study.
IKP: has received a research grant from SOBI, which is not related to the
Acknowledgements
Edoardo Marrani, MD, Firenze, Corinne Guitton, MD, Kremlin-Bicêtre, Bilade Cherqaoui, MD, Kremlin-Bicêtre, Michael Levine, MD, PHD, London, Sheatha Latif, MD.
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