The concept of autoinflammation was initially developed about 10 years ago after the genetic causes of 2 hereditary fever syndromes, familial Mediterranean fever (FMF)1,2
and the former familial Hibernian fever,3
were identified by means of positional cloning. The FMF mutations occurred in a novel gene, Mediterranean fever gene (MEFV)
, which encodes the protein pyrin. Mutations in the p55 TNF receptor led to the renaming of familial Hibernian fever as TNF receptor–associated periodic syndrome (TRAPS). Both diseases present with episodic occurrences of fever, sterile serositis, and other more variable inflammatory manifestations but lack the clinical and laboratory markers that indicate adaptive immune dysregulation, such as autoantibodies and antigen-specific T cells. There is no evidence of infection, allergy, or immunodeficiency; disease triggers in these 2 disorders are not obvious, but nonspecific factors, such as stress and minor infections, are often reported to induce flares.
In subsequent years, the genes causing at least 10 Mendelian autoinflammatory diseases have been described and are listed in . In 1999, 2 Dutch groups independently reported that mutations in the mevalonate kinase gene cause hyperimmunoglo-bulinemia D with periodic fever syndrome.4,5
In 2001, mutations in another previously unknown gene that encodes the then-novel protein cryopyrin were found to cause the autosomal dominant disorders familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS).6
The following year, mutations in this same gene were identified in patients with neonatal-onset multisystem inflammatory disease (NOMID; also known as chronic infantile neurologic, cutaneous, and arthritis [CINCA] syndrome),7,8
which occurs as a sporadic disease because of the reduced reproductive fitness often associated with these severe mutations. The discovery of the genes underlying pyogenic arthritis, pyoderma gangrenosum, and acne9
; Blau syndrome10
; early-onset sarcoidosis11
; Majeed syndrome12
; and, most recently, the deficiency of the IL-1 receptor antagonist (DIRA)15,16
have opened our awareness to yet more genes and pathways, many of which have not been fully characterized.
Monogenic autoinflammatory syndromes
Other systemic autoinflammatory diseases with presumed more complex modes of inheritance include systemic-onset juvenile idiopathic arthritis; adult-onset Still disease; the syndrome of periodic fever with aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA); Behçet disease; and chronic recurrent multifocal osteomyelitis (CRMO). The discovery that gout is caused by increased activation of the NALP3 (NLRP3) inflammasome by uric acid crystals has illustrated the role of the NALP3 (NLRP3) inflammasome in common diseases. The concept of autoinflammation is currently evolving, and the ongoing discovery that innate immune dysregulation is also seen in patients who were thought to have classical autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, indicates that in many polygenic/complex inflammatory diseases, abnormalities in the innate immune system and adaptive system jointly contribute to disease.17
A recent extensive review explores the concept of autoinflammation in diseases with mutations or immune dysregulation not only involving inflammasome components with aberrations in the IL-1 pathway but also involving nuclear factor κB activation, protein misfolding, complement regulation, cytokine signaling, and macrophage activation, reflecting the growing list of diseases that are thought to have evidence of autoinflammation.18
A major conceptual breakthrough in understanding auto-inflammatory diseases has come from Hoffman et al’s 2001 discovery6
that mutations in the cryopyrin gene cause FCAS and MWS.6
The gene that encodes cryopyrin is variously called CIAS1
, and, rarely, PYPAF1
and is a major component in the assembly of the NALP3 (NLRP3) inflammasome, an intracellular molecular complex that links the immune system’s ability to sense danger to a first response to such challenges by activating the crucial proinflammatory cytokine IL-1β. Despite the pivotal role of IL-1 in a number of autoinflammatory diseases, it is by no means the only cytokine pathway involved, but its exploration has certainly been aided by the availability of IL-1–inhibiting drugs for therapy. Thus this review will focus on the description of 2 autoinflammatory syndromes in which the significant contribution of IL-1 to the disease’s pathogenesis has been confirmed in clinical trials with IL-1 inhibition.