Autoinflammatory Diseases as an Important Differential Diagnosis in Rheumatology - An Update

Autoinflammatory syndromes are a group of disorders with a genetic predisposition for an intermittent or chronic multisystemic inflammation, which often involves joints and skin. They are caused by a dysregulation of the innate immune response with a subsequently increased production of proinflammatory cytokines and neutrophilic inflammation. Central players are so-called inflammasomes, intracellular macromolecular protein complexes, which mediate especially the activation of interleukin (IL)-1 beta. Prototypic representatives are the monogenic autoinflammatory diseases familial Mediterranean fever (FMF), tumour necrosis factor receptor 1-associated periodic syndrome (TRAPS), hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS), and the cryopyrin-associated periodic syndromes (CAPS) which characteristically present with recurrent fever episodes. A long-term complication can be the development of a systemic amyloidosis. Fever, however, does not need to be present in each case, as demonstrated by the recently discovered deficiency of the IL-1 receptor antagonist (DIRA) and the functional deficiency of the IL-10 receptor, which are caused by an inherited imbalance of pro-and anti-inflammatory cytokines and mainly present with skin or joint and gastrointestinal manifestations, respectively. Our increasing knowledge of exogenous and endogenous triggers of inflammasomes and of the molecular pathways involved have led to the unexpected discovery that a growing number of genetically complex conditions such as, e. g., gout, pseudogout, diabetes mellitus type 2, systemic onset juvenile idiopathic arthritis, adultonset Still's disease and the most common fever syndrome in childhood, PFAPA (periodic fever, aphthous stomatitis, pharyngitis and adenitis) syndrome, are also autoinflammatory diseases. These insights have already resulted in an effective treatment of a variety of these disorders by anti-IL-1 blockade and will most certainly lead to the identification of further target molecules for a rational drug therapy.