High dose anakinra for treatment of severe neonatal Kawasaki disease: a case report

BACKGROUND:Kawasaki disease is an acute vasculitis of childhood that leads to coronary artery aneurysms in ≈25% of untreated cases. It has been reported worldwide and is the leading cause of acquired heart disease in children in developed countries. METHODS AND RESULTS:To revise the previous American Heart Association guidelines, a multidisciplinary writing group of experts was convened to review and appraise available evidence and practice-based opinion, as well as to provide updated recommendations for diagnosis, treatment of the acute illness, and long-term management. Although the cause remains unknown, discussion sections highlight new insights into the epidemiology, genetics, pathogenesis, pathology, natural history, and longterm outcomes. Prompt diagnosis is essential, and an updated algorithm defines supplemental information to be used to assist the diagnosis when classic clinical criteria are incomplete. Although intravenous immune globulin is the mainstay of initial treatment, the role for additional primary therapy in selected patients is discussed. Approximately 10% to 20% of patients do not respond to initial intravenous immune globulin, and recommendations for additional therapies are provided. Careful initial management of evolving coronary artery abnormalities is essential, necessitating an increased frequency of assessments and escalation of thromboprophylaxis. Risk stratification for long-term management is based primarily on maximal coronary artery luminal dimensions, normalized as Z scores, and is calibrated to both past and current involvement. Patients with aneurysms require life-long and uninterrupted cardiology follow-up. CONCLUSIONS:These recommendations provide updated and best evidence-based guidance to healthcare providers who diagnose and manage Kawasaki disease, but clinical decision making should be individualized to specific patient circumstances. K awasaki disease (KD) is an acute, self-limited febrile illness of unknown cause that predominantly affects children <5 years of age. When initially described, the potential for coronary artery complications was not appreciated. KD is now the most common cause of acquired heart disease in children in developed countries. In the absence of pathognomonic tests, the diagnosis continues to rest on the identification of principal clinical findings and the exclusion of other clinically similar entities with known causes. Timely initiation of treatment with intravenous immunoglobulin (IVIG) has reduced the incidence of coronary artery aneurysms defined from absolute luminal dimensions from 25% to ≈4%. Ongoing studies with additional therapies have not substantially reduced this residual risk. The long-term prognosis is determined by the initial and current level of coronary artery involvement. Certain subsets of patients are at risk for myocardial ischemia from coronary artery thrombosis and stenoses. Medical management of such patients hinges on judicious use of thromboprophylaxis and vigilance to identify evolving stenoses. Invasive revascul...

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“…217,218 Clinical trials are in progress to evaluate the efficacy of IL-1 blockade in children with acute KD.…”

Section: Other Monoclonal Antibody Therapymentioning

confidence: 99%

Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association

McCrindle¹,

Rowley²,

Newburger³

et al. 2017

Circulation

2,870

4,124

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“…At least 52 pregnant women, infants and children < 2 years of age have been treated with anakinra with doses ranging from 1 to 20 mg/kg without serious adverse events (Matsubara, Hasegawa et al 2006, Aksentijevich, Masters et al 2009, Hoffman 2009, Neven, Marvillet et al 2010, Nigrovic, Mannion et al 2011, Record, Beukelman et al 2011, Stenerson, Dufendach et al 2011, Cohen, Tacke et al 2012, Minkis, Aksentijevich et al 2012, Ruiz Gomez, Couce et al 2012, Sibley, Plass et al 2012, Rossi-Semerano, Piram et al 2013, Chang, Spong et al 2014, Paccaud, Berthet et al 2014, Shafferman, Birmingham et al 2014). In addition, through an informal survey of rheumatologists belonging to the Childhood Arthritis and Rheumatology Research Alliance (CARRA) Network, I was notified of an additional 10 infants (2 to 11 months old) who received anakinra (maximum dose ranging from 3 to 9 mg/kg) for inflammatory disorders without major adverse events.…”

Section: Discussionmentioning

confidence: 99%

Rationale and study design for a phase I/IIa trial of anakinra in children with Kawasaki disease and early coronary artery abnormalities (the ANAKID trial)

Tremoulet

Jain

Kim

et al. 2016

Contemporary Clinical Trials

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Background Although Kawasaki disease (KD) is the most common cause of acquired heart disease in children and may result in coronary artery aneurysms (CAA) with an attendant risk of myocardial infarction, there is no recommended therapy to halt progression of arterial wall damage and prevent aneurysm formation in the acute phase of the vasculitis. While intravenous immunoglobulin (IVIG) reduces the risk of CAA, up to 20% of KD patients are IVIG resistant and have a higher risk for developing CAA. The IL-1 pro-inflammatory pathway is upregulated in children with acute KD and plays a critical role in the experimental animal model of KD. Thus, IL-1 is a logical therapeutic target. Objectives The goal of this study is to determine the safety, tolerability, pharmacokinetics, and immunomodulatory effects of anakinra, a recombinant human IL-1 receptor antagonist, in acute KD patients with coronary artery abnormalities on the baseline echocardiogram. Design This is a two-center dose-escalation Phase I/IIa trial in 30 acute KD patients ≥8 months old with a coronary artery Z score ≥3.0 in the right coronary artery and/or left anterior descending artery or an aneurysm. Subjects will receive a 2- to 6-week course of anakinra by daily subcutaneous injection and will be assessed for resolution of inflammation and dose limiting toxicities (leukopenia, anaphylactoid reaction, or severe infection). Conclusion The safety and tolerability of blocking both IL-1α and Il-1β by anakinra will be evaluated as a strategy to prevent or attenuate coronary artery damage in infants and children with acute KD.

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“…While no animal model can fully mimic human disease, the LCWE-induced KD mouse model, has been accepted by many in the Kawasaki research community, as a reliable experimental model with the goal to provide novel insights that can be tested in children. The translational value of this animal model has recently been shown again when discovery for the role of IL-1 signaling in the development of the coronary arteritis/stenosis and myocarditis associated with this KD mouse model 25 has led to successful treatment of several IVIG-resistant KD cases with the IL-1 R antagonist (Anakinra) 26, 27 and most importantly to the initiation of two Phase II clinical trials with Anakinra in KD patients.…”

Section: Introductionmentioning

confidence: 99%

Role of Interleukin-1 Signaling in a Mouse Model of Kawasaki Disease–Associated Abdominal Aortic Aneurysm

Wakita

Kurashima

Crother

et al. 2016

ATVB

127

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Objective Kawasaki disease (KD) is the most common cause of acquired cardiac disease in US children. In addition to coronary artery abnormalities and aneurysms, it can be associated with systemic arterial aneurysms. We evaluated the development of systemic arterial dilatation and aneurysms, including abdominal aortic aneurysm (AAA) in the Lactobacillus casei cell wall extract (LCWE)-induced KD vasculitis mouse model. Methods and Results We discovered that in addition to aortitis, coronary arteritis and myocarditis, the LCWE-induced KD mouse model is also associated with abdominal aorta dilatation and AAA, as well as renal and iliac artery aneurysms. AAA induced in KD mice was exclusively infrarenal, both fusiform and saccular, with intimal proliferation, myofibroblastic proliferation, break in the elastin layer, vascular smooth muscle cell loss, and inflammatory cell accumulation in the media and adventitia. Il1r−/−, Il1a−/−, and Il1a−/− mice were protected from KD associated AAA. Infiltrating CD11c+ macrophages produced active caspase-1 and caspase-1 or NLRP3 deficiency inhibited AAA formation. Treatment with IL-1R antagonist (Anakinra), anti-IL-1α, or anti-IL-1β mAb blocked LCWE-induced AAA formation. Conclusions Similar to clinical KD, the LCWE-induced KD vasculitis mouse model can also be accompanied by AAA formation. Both IL-1α and IL-1β play a key role, and that use of an IL-1R blocking agent that inhibits both pathways may be a promising therapeutic target not only for KD coronary arteritis, but also for the other systemic arterial aneurysms including AAA that maybe seen in severe cases of KD. The LCWE-induced vasculitis model may also represent an alternative model for AAA disease.

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High dose anakinra for treatment of severe neonatal Kawasaki disease: a case report

Cited by 96 publications

References 28 publications

Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association

Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association

Rationale and study design for a phase I/IIa trial of anakinra in children with Kawasaki disease and early coronary artery abnormalities (the ANAKID trial)

Role of Interleukin-1 Signaling in a Mouse Model of Kawasaki Disease–Associated Abdominal Aortic Aneurysm

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