Kawasaki Disease Dr Paul A Brogan Senior Lecturer in vasculitis Department of Rheumatology ICH/GOSH P.brogan@ich.ucl.ac.uk

Overview History and Epidemiology Clinical features Pathogenesis Treatment Outcome Research at GOSH: Long term KD follow up study

NEW GENERAL CLASSIFICATION OF CHILDHOOD VASCULITIS 1 Predominantly large vessel vasculitis Takayasu arteritis 2 Predominantly medium-sized vessel vasculitis Childhood polyarteritis nodosa Cutaneous polyarteritis Kawasaki disease

NEW GENERAL CLASSIFICATION OF CHILDHOOD VASCULITIS 3 Predominantly small vessel vasculitis (A) GRANULOMATOUS Wegener granulomatosis Churg-Strauss syndrome (B) NON GRANULOMATOUS Microscopic polyangiitis HSP Isolated cutaneous leukocytoclastic vasculitis Hypocomplementemic urticarial vasculitis

What time is dinner?

The first case of Kawasaki disease: London 1870 B                    C

Epidemiology

KD epidemiology World wide distribution Male preponderance Commoner in oriental children Some seasonality and occasional epidemics The incidence of KD is rising world-wide, including the UK. Incidence in the UK is 8.1 /100 000 children aged less than 5 years old

Epidemiology Japan: Incidence 220 per hundred thousand children under the age of five peak age onset 9-11 months 70% of all cases younger than 3 years 240 00 cases in Japan Increased cases in winter Epidemics moving from adjoining region Risk higher in siblings of index cases

Hawaii Mean 40 per 100 000 360 for Japanese 95 for Chinese 77 for Hawaiians 56 for Filipino 7 for Caucasians

Race-specific incidence of Kawasaki disease Davis RL , Waller PL , Mueller BA , et al. Kawasaki syndrome in Washington State. Race-specific incidence rates and residential proximity to water. Arch Pediatr Adolesc Med 1995; 149:66-69

Rising incidence of Kawasaki disease in the UK Harnden A et al. BMJ 2002; 324: 1424-1425

Clinical features

Kawasaki disease - AHA diagnostic criteria Fever of  5 days duration + four of five criteria Oropharyngeal changes (90%+ of cases) 1. Bilateral non-purulent conjunctival injection (90%+ of cases) 3. 2. Polymorphous rash (95%+ of cases) 4. Changes in peripheral extremities (90%+ of cases) Cervical lymphadenopathy (~75% of cases) 5.

KD differential diagnosis Toxic shock syndrome (streptococcal and staphylococcal) Staphylococcal scalded skin syndrome Scarlet fever Infection with viruses enterovirus, adenovirus, measles, parvovirus, Epstein–Barr virus, cytomegalovirus Mycoplasma pneumoniae Rickettsiae Leptospirosis The differential diagnosis of IVIG (intravenous immunoglobulin) resistant KD includes polyarteritis nodosa, systemic onset juvenile idiopathic arthritis, and malignancy (particularly lymphoma).

The cause of KD is…

… nature & nurture

Genetics

Genetics of KD

KD is polygenic Mannose binding lectin: ambiguous role ACE MMP TNF alpha (IVIG resistance) IL-10 promoter Chemokines (CCR5) IL-18 promoter (Taiwanese) IL 1 beta- no association eNOS/iNOS not associated with CAA in Japanese Fc gamma so far not associated

No infectious cause yet found

For and against Superantigens in KD Studies for Studies against Seroconvert (IgG and IgM) for SAgs (Matsubara et al 2006, CEI) T cell activation consistent with SAg mediated disease (Brogan et al 2008, CEI)

A new RNA virus? Rowley et al PIDJ 2011

Treatment

Treatment IVIG 2g/kg over 12 hours Aspirin 30-50 mg/kg/day (4 divided doses) Then 2-5 mg/kg/od 48 hours after fever settles Fever recrudescence/IVIG resistance: Repeat IVIG OR corticosteroids OR Infliximab

Recent developments in KD Rx

Corticosteroids as adjunctive first line Rx? Inoue Y et al. A multicenter prospective randomized trial of corticosteroids in primary therapy for Kawasaki disease: clinical course and coronary artery outcome. 2006; J Pediatr; 149: 336-341 Prospective RCT of 178 patients Fewer CAA at 1 month in those receiving IVIG AND prednisolone (11.2% versus 2.4%)

Corticosteroids as adjunctive first line Rx? Newburger JW et al. Randomized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease. NEJM 2007; 356: 663-675 No effect on CAA

Rationale for blocking TNF-α in KD Murine model of KD: Production of TNF- α in the peripheral immune system Response site directed, migration to the coronary arteries Mice treated with etanercept and TNFRI knockout mice resistant to development of both coronary arteritis and coronary aneurysm formation. Our results suggest that blocking TNF- or its downstream functions, such as leukocyte recruitment or matrix degradation, may be exciting new options in the battle against coronary artery damage in children with Kawasaki disease. Kawasaki disease is the most common cause of multisystem vasculitis in childhood. The resultant coronary artery lesions make Kawasaki disease the leading cause of acquired heart disease in children in the developed world. TNF- is a pleiotropic inflammatory cytokine elevated during the acute phase of Kawasaki disease. In this study, we report rapid production of TNF- in the peripheral immune system after disease induction in a murine model of Kawasaki disease. This immune response becomes site directed, with migration to the coronary arteries dependent on TNF--mediated events. Production of TNF- in the heart is coincident with the presence of inflammatory infiltrate at the coronary arteries, which persists during development of aneurysms. More importantly, inflammation and elastin breakdown in the coronary vessels are completely eliminated in the absence of TNF- effector functions. Mice treated with the TNF--blocking agent etanercept, as well as TNFRI knockout mice, are resistant to development of both coronary arteritis and coronary aneurysm formation. Taken together, TNF- is necessary for the development of coronary artery lesions in an animal model of Kawasaki disease. These findings have important implications for potential new therapeutic interventions in children with Kawasaki disease. Hui-Yuen JS et al J Immunol. 2006;176:6294-301

Evidence for infliximab Burns JC et al 2005 J Pediatr 2005; 146:662–667. 13 patients with IVIG resistant KD, good response Burns JC et al 2008 J Pediatr 2008; 153:833–838 24 patients 2nd IVIG vs infliximab (non inferior) Case reports: O‘Connor MJ, Saulsbury FT. Incomplete and atypical Kawasaki disease in a young infant: severe, recalcitrant disease responsive to infliximab. Clin Pediatr 2007; 46:345-8 Zulian F et al. Efficacy of infliximab in long-lasting refractory Kawasaki disease. Clin Exp Rheumatol. 2006; 24: 453 Brogan RJ et al Pediatr Rheumatol Online J. 2009 Jan 21;7:3. TNF-a blocking agents ? part of the therapeutic arsenal combating life-threatenig primary vascular inflammation

Infliximab Chimeric monoclonal antibody against TNFα Dose 6mg/kg IV ?repeat after 2 weeks if ongoing inflammation (consider differential diagnosis)

KD outcome 25 % CAA untreated 4-9% CAA with IVIG and aspirin IVIG resistance 15-20% V high risk of CAA: 20-30% The acute mortality rate due to myocardial infarction <1%

Follow up Stop aspirin if echo at 6/52 normal Continue if CAA present Giant aneurysms (>8mm) never resolve: Aspirin and warfarin (heparin until INR 2-3) Long term follow up

Prognosis for those with giant CAA (>8mm) 76 patients from 1972 Median observational period 19 years 61% required surgical coronary intervention At one month to 21 years Mode time of intervention: one month Survival rate: 10 yrs: 95% 20 yrs: 88% 30 years: 88% Suda et al 2011 Circulation

Does KD cause premature atherosclerosis?

GOSH KD follow up study

Hypothesis: KD predisposes to premature atherosclerosis (or vasculopathy) in UK patients We are studying: Subclinical endothelial injury Sub-clinical inflammation Arterial stiffness (vicorder PWV) Carotid intimal medial thickness Years after KD

Take home messages HSP and KD are the commonest paediatric vasculitides KD still kills children- limited window of opportunity to influence outcome: switch off the inflammation ASAP Earlier use of steroids and infliximab ie after 1 dose of IVIG Polygenic and no infectious cause yet found Does KD predispose to premature atherosclerosis?