30 years hids-Travels between bedside and bench.

In this paper I describe more than 30 years of investigations of the autoinflammatory syndrome hyper-IgD syndrome (HIDS). In the first paper after the recognition of the syndrome published in 1984, we described the characteristics of this periodic fever syndrome. The hypotheses regarding the pathogenesis of the fever and the acute phase response in these patients prompted us to study interleukin-1 (IL-1), the cytokine formerly described as endogenous pyrogen and lymphocyte activating factor. Although we were unable to find elevated concentrations of IL-1 in the circulation, we discovered that white blood cells spontaneously produced elevated amounts of IL-1b. A major next discovery was the identification of the gene defect by us and others in 1999: quite unexpectedly the mevalonate kinase, an enzyme in the cholesterol synthesis pathway was found to be mutated. We were able to describe a founder effect and a phenotypic continuum with the classical mevalonate aciduria in the years to follow. A major step forward was the finding that recombinant interleukin-1 receptor antagonist (anakinra) was an effective treatment for the majority of patients. Thus, research over a period of three decades after the first recognition of the syndrome, has yielded much insight into the pathogenesis as well as an effective therapy for HIDS.