The use of interleukin 1 receptor antagonist (anakinra) in Kawasaki disease: A retrospective cases series

Abstract

Objectives

To identify the clinical characteristics, reasons for use and response to treatment with anakinra in a series of patients with Kawasaki Disease (KD).

Study design

A retrospective chart review of patients treated with anakinra for KD diagnosed according to the AHA criteria. We compared clinical, biological and echocardiographic characteristics of KD before and after anakinra use. We analysed reasons for use of anakinra, and compared treatment regimens used in 7 European KD referral centres.

Results

Eight boys and 3 girls with treatment-refractory KD, aged 4 months to 9 years old, received at least 2 different KD treatments prior to anakinra, which was given on mean at 25 days after disease onset (8 to 87 days). The main reasons for use of anakinra were clinical and biological inflammation, progression of coronary dilatations, and severe myocarditis with cardiac failure. Doses of anakinra ranged from 2 to 8 mg/kg and duration varied from 6 to 81 days. Efficacy of anakinra was judged in terms of fever resolution (100%), decrease of CRP (100%), and in terms of its effect on coronary artery dilatation Z scores, which decreased in 10/11 patients and increased in one who died suddenly of pericardial hemorrhage.

Conclusion

Anakinra used late in the disease course led to a rapid and sustained improvement in clinical and biological inflammation. Our retrospective analysis did show neither a striking nor a rapid decrease of coronary dilatations and we cannot determine if anakinra itself had an effect on coronary artery dimensions.

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.