Autoinflammatory syndromes are a rare group of conditions caused by an exaggerated innate immune response, resulting in recurrent episodes of spontaneous inflammation affecting multiple organs. An autoinflammatory syndrome can only be diagnosed when infective conditions, malignancy, allergic conditions, and immunodeficiency disorders have been excluded.
Compared to classical autoimmune diseases, autoinflammatory syndromes lack pathogenic autoantibodies and antigen-specific T cells. The clinical presentation of autoinflammatory syndromes can vary but often includes recurrent fevers, rashes, joint inflammation, and other systemic symptoms.
Autoinflammatory syndromes may be inherited through mutations in a single gene (monogenic autoinflammatory syndromes). More commonly, they are polygenic immune conditions that resemble autoimmune collagen disorders. The number of conditions included is increasing as molecular and genetic studies reveal disease mechanisms.
A classification system, with examples of syndromes with dermatologic manifestations, follows.
The innate immune system is a primitive inherited system that recognises danger in the form of injury or infection. Macrophages and dendritic cells carry receptors that bind to pathogen-associated molecular patterns (PAMPs), which are microbial cell wall components consistently expressed by bacteria and viruses, or danger-associated molecular patterns (DAMPs), which are produced by the body in response to injury or infection. Pattern recognition receptors are inherited and do not adapt or change with experience. Binding of these receptors coordinates an initial inflammatory response involving neutrophils and monocytes and the production of cytokines such as interleukin 1 (IL-1). IL-1 is activated within the cytoplasm of neutrophils and monocytes by inflammasomes, large protein complexes that include the activating enzyme caspase-1. Activated IL-1 is the most potent known trigger for producing fever. It also activates lymphocytes and promotes white blood cell infiltration into sites of injury or infection.
Genetic mutations affecting components of the inflammasome or IL-1-activated inflammatory response have been found in several of the monogenic autoinflammatory syndromes. Mutations may result in overactivity of the inflammasome or failure to limit IL-1-mediated inflammation. Autoinflammatory diseases that are not thought to be genetic are associated with inherited polymorphisms of proteins such as gamma-secretase and Notch-associated proteins, which result in dysregulation of inflammasomes when exposed to certain trigger factors. These include hormones, smoking, and adipokines associated with insulin resistance and obesity.
In autoinflammatory syndromes, the effector pathways are either hypersensitive to endogenous (DAMPs) or exogenous (PAMPs) molecular patterns, or are constitutively overactive, resulting in uncontrolled cytokine-mediated inflammation.
Treatment varies by condition, and systemic corticosteroids have only a modest effect in many instances. Biologic agents such as anakinra and canakinumab (IL-1 inhibitors) produce dramatic and consistent improvements in syndromes where a clear link to IL-1 has been demonstrated eg, TRAPS, CAPS, DIRA, PAPA syndrome.
Janus kinase inhibitors and type I interferon receptor antagonists show efficacy for autoinflammatory syndromes mediated by interferons, such as SAVI and CANDLE syndrome.
Refer to the individual disease-specific pages for more detail on treatment.
