The knowledge on systemic autoinflammatory disorders (SAID) is expanding rapidly 
and new signalling pathways are being decrypted. The concept of autoinflammation 
has been proposed since 1999, to define a group of diseases with abnormal innate 
immunity activation. Since then, more than 30 monogenic SAID have been 
described. In this review, we first describe inflammasomopathies and SAID 
related to the interleukin-1 pathway. Recent insights into the pathogenesis of 
familial Mediterranean fever and the function of Pyrin are detailed. In 
addition, complex or polygenic SAID, such as Still's disease or PFAPA syndrome, 
are also discussed. Then, major players driving autoinflammation, such as type-1 
interferonopathies (including the recently described haploinsuffiency in A20 and 
otulipenia), TNF-associated periodic syndromes, defects in ubiquitination, and 
SAID with overlapping features of autoimmunity or immunodeficiency. Discoveries 
of the pathogenic role of mosaicism, intronic defects coupled to the likelihood 
to identify digenic or polygenic diseases are providing new challenges for 
physicians and geneticists. This comprehensive review depicts the various SAID, 
presenting them according to their predominant pathophysiological mechanism, 
with a particular emphasis on recent findings. Epidemiologic data are also 
presented. Finally, we propose a practical diagnostic approach to the most 
common monogenic SAID, based on the most characteristic clinical presentation of 
these disorders.