Fifteen years have elapsed since the identification of MEFV as the gene responsible for familial Mediterranean fever (FMF)(1, 2). This finding was the first step forward in the identification of the molecular defect in a number of other genetic diseases, which are collectively known as the autoinflammatory diseases and are characterized by chronic inflammation secondary to a marked dysregulation of the innate immune system. The identification of autoinflammatory diseases represents a major recent advance in clinical medicine for several reasons. First, it is very probable that in the years to come, many other rare inflammatory syndromes of unknown cause will turn out to be autoinflammatory diseases with a defined genetic etiology and, therefore, with potential targeted therapies. Second, the discovery of the genetic basis of these diseases has proven to be a powerful tool for discovering new mechanisms that regulate innate immunity and that can be involved in many other inflammatory conditions. Third, it has become increasingly clear that several common multifactorial diseases have a strong autoinflammatory component that can be successfully targeted with the same therapies that are used in autoinflammatory diseases.

The most typical clinical feature associated with the autoinflammatory diseases that was initially identified was the occurrence of recurrent bouts of fever followed by symptom-free periods of variable duration. For this reason, these disorders were generically defined as periodic fevers. The first studies on the functional consequences of these disorders revealed the primary pathogenic role of an abnormal activation of the cells of the innate immune system by endogenous and exogenous stimuli. Compared to autoimmune rheumatic conditions, this group of diseases is characterized by an apparent secondary role of the adaptive branch of the immune response, as suggested by the lack of circulating autoantibodies and/or self-reactive T cells and by the absence of a clear association with class II major histocompatibility complex molecules (3). As we will discuss below, a prototype of these diseases was a small group of disorders occurring secondary to mutations in the NLRP3 gene (or cryopyrin), a pivotal component of the NLRP3 inflammasome. The study of the mechanisms of activation of this multiprotein intracellular complex represented a milestone for the understanding of the development of inflammation not only in rare inherited diseases, but also in a large spectrum of multifactorial disorders. During the last 15 years, many other autoinflammatory diseases and their associated gene defects have been identified (Table 1). The clinical heterogeneity of the new diseases showed that, besides the “classic” phenotype of periodic fevers (skin rash, arthralgia/myalgia, and chest/abdominal pain), a variety of clinical manifestations may be associated with this group of conditions (Table 2). These different manifestations depend on the gene that is involved and on the cells and tissues in which that gene