Autoinflammatory syndromes are defined as recurrent attacks of systemic inflammation that are often unprovoked (or triggered by a minor event) related to a lack of adequate regulation of the innate immune system. Unlike autoimmune diseases, there is a relative lack of autoantibodies or autoreactive T cells. In recent years there has been a substantial increase in the diseases classified (at least partially) as autoinflammatory because of better understanding of pathways of immune activation and regulation of the innate immune system ( Box 1 ). Much of this understanding was obtained from knowledge gained from rare autoinflammatory diseases with a genetic etiology ( Table 1 ). Periodic fever syndromes, the former term for this group of diseases, is not adequate because most syndromes are not truly periodic, and fever is not a necessary feature. This article includes those autoinflammatory syndromes (especially genetic) that do not fall into other diagnostic categories (eg, systemic juvenile idiopathic arthritis, vasculitis, and crystal disease).

These syndromes should be suspected in patients, mainly young children, with recurrent fever unexplained by infections and/or with episodic symptoms in various systems, especially the skin, gastrointestinal tract, chest, eyes, musculoskeletal, and central nervous system. These syndromes should also be suspected in patients with unexplained increased laboratory indices of inflammation even if the patient is asymptomatic. A family history of these syndromes is often but not always obtained, including a history of unexplained deafness, renal failure, or amyloidosis.

Most autoinflammatory syndromes have common clinical features including recurrent fevers, serositis, rashes, musculoskeletal manifestations, and increased laboratory markers of inflammation. However, a complete history and physical examination is crucial and often the correct diagnosis can be attained before more genetic or sophisticated tests are used. Syndromes can be differentiated by age of onset, ethnicity, attack triggers, duration of attacks, disease-free intervals between attacks, clinical manifestations, and the response to therapy ( Tables 2–4 ). It is very useful to examine patients during an attack, or alternately to ask parents to record attacks carefully and take photos of relevant physical findings. It is also useful to obtain laboratory markers of inflammation during and between attacks, because in some syndromes attacks are only the “tip of the inflammatory iceberg” and patients consistently have increased inflammatory indices. These patients are at higher risk of developing Amyloid A (AA) amyloidosis, the major adverse outcome of the autoinflammatory syndromes.

The innate immune system as it relates to the pathogenesis of autoinflammatory syndromes

The initial response to pathogens and damaged cells is mediated by the innate immune system ( Fig. 1 ). The cells of the innate immune system, primarily epithelial, dendritic, polymorphonuclear, and macrophage cells, act not only as an immediate barrier, but also as effectors in the evolution of the inflammatory response. The innate immune system recognizes pathogen-associated molecular patterns and damage-associated molecular patterns by several complex mechanisms, involving cell-associated pattern recognition receptors and soluble recognition molecules. These receptors, such as toll-like receptors, are present on the surface of the cell. Nucleotide oligomerization domain–like receptors (NLRs) within the cell and other receptors further mediate intracellular innate immune system processes and development of the inflammatory response. NLRPs (NLRs with pyrin-domain–containing proteins) are a subfamily of the NLRs. NLRP3 assembles other proteins to form the inflammasome complex in response to cytoplasmatic pathogen-associated molecular patterns and damage-associated molecular patterns, which also triggers the expression of proinflammatory genes by transcription factors (eg, nuclear factor-κB). The inflammasome complex involving NLRP3 recruits and activates caspase 1, a protease that cleaves prointerleukin (IL)-1β and IL-18 to their active forms. The common pathogenic pathway of the autoinflammatory syndromes involves the excessive production and activity of these proinflammatory cytokines and molecules, not as a result of external stimuli but as a result of mutations in different proteins that regulate these pathways.

Schema of selected innate immune inflammatory pathways related to the autoinflammatory syndromes. The schema demonstrates the effect of external stimuli on the development of inflammation and the relationship of several regulatory proteins (pyrin, NLRP3, NLRP12, and PSTPIP1) that when mutated result in the development of autoinflammatory diseases. DAMP, damage-associated molecular patterns; IL, interleukin; NF-κB, nuclear factor-κB; NLR, nucleotide oligomerization domain–like receptors; NLRPs, NLRs with pyrin-domain-containing proteins; PAMP, pathogen-associated molecular patterns; PSTPIP, proline-serine-threonine phosphatase-interacting protein; ROS, reactive oxygen species; TLR, toll-like receptors.