Recurrent Fever Syndromes

Abstract

Recurrent fever syndromes (RFS) are autoinflammatory disorders characterized by self-limited recurrent episodes of fever and systemic inflammation, associated with inflammatory manifestations. Five clinical entities can be considered as the prototypical RFS: familial Mediterranean fever (FMF), tumour necrosis factor (TNF), receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), cryopyrin-associated periodic syndromes (CAPS), and periodic fever, aphthosis, pharyngitis, and adenitis (PFAPA). Genetic testing plays a key role in establishing their diagnosis. In addition, recent development of next-generation sequencing technologies has led to the rapid identification of a number of additional genes responsible for very rare RFS. Since RFS affect multiple organs with potentially severe complications, management of patients is complex and warrants a multidisciplinary approach. The main therapeutic options encompass nonspecific anti-inflammatory approaches, such as corticosteroids and non-steroidal anti-inflammatory drugs, as well as biological agents. The study of the pathophysiology of RFS led to the discovery of multiple receptors of the innate immune system recognizing pathogens and endogenous danger signals. Although a number of pathogenic processes have been demonstrated as underlying these disorders, dysregulation of the interleukin-1β (IL-1β) signalling pathway was found to play a key role in most RFS. This catalysed major advances in the development of targeted biologic therapies, particularly IL-1 blocking treatments. Nevertheless, some patients will require more tailored therapeutic approaches.