The challenge of autoinflammatory syndromes: with an emphasis on hyper-IgD syndrome

Autoinflammatory syndromes are disorders with an exaggerated inflammatory response, mostly in the absence of an appropriate trigger. Prototypic autoinflammatory syndromes are FMF, hyper-IgD syndrome (also known as mevalonate kinase deficiency), TNF receptor-associated periodic syndrome and cryopyrin-associated periodic syndrome. The clinical phenotypes partly overlap (with fever and acute phase response), but also differ between the various syndromes (e.g. regarding fever pattern, episodic vs chronic inflammation and accompanying clinical signs). In recent years, the genetic basis of quite a number of these relatively rare and mostly hereditary disorders has been elucidated. These genetic defects lead to either enhanced production of inflammatory mediators or to a lack of inhibition of these components of the innate immune system. Among these dysregulated inflammatory mediators, the pro-inflammatory cytokine IL-1β stands out. Hence, targeted treatment with blockers of IL-1 action, such as recombinant IL-1 receptor antagonist (IL-1Ra, anakinra) and mAb against IL-1β has met with impressive clinical results. In this article, hyper-IgD syndrome is discussed in more detail, based on 30 years of experience with this syndrome.