Kawasaki disease, a multi-system vasculitis, is a leading cause of acquired heart disease in the developed world – but more than 40 years since it was first described, its cause is still not known.
At the American College of Rheumatology annual meeting in Atlanta, Dr Rae Yeung from the University of Toronto described the immunobiology of the paediatric disease and argued for IL-1b as a promising target for intervention.
“It’s damage to the coronary arteries we need to prevent,” Dr Yeung said.
Kawasaki’s aetiology appeared to be genetic with an infectious trigger or triggers, she said.
This was suggested by the fact that the disease appears endemic in Japan and Korea – Japan has a prevalence of 280 per 100,000 compared to Denmark’s five – punctuated by epidemics.
The age profile of between six months and five years also suggested that there was protection in utero and that immunity developed in later childhood.
Dr Yeung presented a slide with 20 diverse potential triggers including adenovirus, herpes, Epstein Barr, measles and other viruses, various streptococci and staphylococci, as well as dust mites, carpet shampoo, mercury and living near water.
She said Kawasaki children showed markedly elevated levels of IL-1b and IL-18 and their natural antagonists.
The likelihood of going on to develop diseases featuring IL-1b – systemic juvenile idiopathic arthritis and macrophage activation syndrome in adulthood – made it likely that these conditions would in future be referred to as an IL-1b-mediated disease spectrum, Dr Yeung said, rather than as discrete diseases.
Two genes implicated in Kawasaki were the calcium and sodium ion channel regulators ITPKC and SLC8A1. The high-risk allele for ITPKC gave children dramatically higher intracellular calcium, more IL-1b and IL-18, and a higher non-response rate to the standard treatment, intravenous immune globulin (IVIG).
The high-risk allele for SLC8A1 – which occurs in 70% of the Japanese population compared to 30% in the general population – put children at increased risk of coronary aneurysms.
High intracellular calcium, which results from low sodium, fits with hyponatraemia as a clinically recognised risk for coronary artery lesions.
Dr Koichi Miyata, from Tokyo Metropolitan Children’s Medical Centre, presented studies showing that adding prednisolone to IVIG improved response rates and rapidity, reduced the need for additional rescue therapy and was better than IVIG alone for preventing coronary artery abnormalities – but the safety and effectiveness in a real-world setting was yet to be demonstrated.
Dr Susan Kim from UCSF Benioff Children’s Hospital followed Dr Miyata’s presentation with guidelines that strongly recommended IVIG over glucocorticoids such as prednisolone.
She said aspirin was recommended along with IVIG, but the best dose was not yet established.