Transcript What’s new in the aetiopathogenesis of vasculitis?

Kawasaki Disease
Dr Paul A Brogan
Senior Lecturer in vasculitis
Department of Rheumatology ICH/GOSH
[email protected]
Overview
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History and Epidemiology
Clinical features
Pathogenesis
Treatment
Outcome
Research at GOSH: Long term KD follow up
study
What time is dinner?
The first case of Kawasaki
disease: London 1870
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Epidemiology
KD epidemiology
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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
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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
Incidenc
e 8/100
000
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
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Oropharyngeal changes
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(90%+ of cases)
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Changes in peripheral
extremities
Bilateral non-purulent
conjunctival injection
(90%+ of cases)
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Polymorphous rash
(95%+ of cases)
(90%+ of cases)
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Cervical
lymphadenopathy
(~75% of cases)
KD differential diagnosis
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Toxic shock syndrome (streptococcal and
staphylococcal)
Staphylococcal scalded skin syndrome
Scarlet fever
Infection with viruses
enterovirus, adenovirus, measles, parvovirus, Epstein–Barr virus,
cytomegalovirus
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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
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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 against
Studies for
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.
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.
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:
1. Subclinical endothelial injury
2. Sub-clinical inflammation
3. Arterial stiffness (vicorder PWV)
4. 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?