Autoinflammatory syndromes

What are autoinflammatory syndromes?

Autoinflammatory syndromes are defined as conditions caused by an exaggerated innate immune system response resulting in episodes of spontaneous inflammation affecting multiple organs. An autoinflammatory syndrome can only be diagnosed when infective conditions, malignancy, allergic and immunodeficiency conditions have been excluded. Compared to classical autoimmune diseases, autoinflammatory syndromes lack pathogenic autoantibodies and antigen-specific T cells.

Classification of autoinflammatory syndromes

Autoinflammatory syndromes may be inherited through mutations to a single gene (monogenic autoinflammatory syndromes), or, more commonly, 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.

Hereditary fever syndromes

• Familial Mediterranean fever (FMF)
• Tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS)
• Hyper-IgD syndrome (HIDS)

Other monogenic autoinflammatory syndromes

• Cryopyrin-associated periodic syndromes (CAPS)
  • Familial cold autoinflammatory syndrome ( FCAS)
  • Muckle-Wells syndrome (MWS)
  • Neonatal onset multisystem inflammatory disease/chronic Infantile neurologic cutaneous arthropathy syndrome (NOMID/CINCA)
• Syndrome of pyogenic arthritis, pyoderma gangrenosum and acne (PAPA syndrome, PAPAS, PAPGA syndrome)
• Juvenile systemic granulomatosis (Blau syndrome, early onset sarcoidosis)
• Deficiency of interleukin-1 receptor antagonist (DIRA)
• Mevalonic aciduria
• Majeed syndrome

Nonhereditary or polygenic disorders

• Schnitzler syndrome
• Crohn disease
• Behcet disease
• Psoriatic arthritis
• Syndrome of periodic fever, aphthous stomatitis, pharyngitis and adenitis (PAPAS, PFAPA syndrome)
• Systemic-onset juvenile idiopathic arthritis
• Adult-onset Still disease

Innate immune system

The innate immune system is a primitive inherited system for recognising 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 that are expressed consistently 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.

In autoinflammatory syndromes, either the effector pathways are hypersensitive to endogenous (DAMPs) or exogenous (PAMPs) molecular patterns, or are constitutively overactive, resulting in uncontrolled cytokine-mediated inflammation.

Treatment

Treatment varies with the actual syndrome. In many forms, systemic corticosteroids have only a modest effect. Biologic agents such as anakinra (which targets IL-1) result in a dramatic and consistent improvement in those syndromes where a clear link to IL-1 has been shown. There is less consistent benefit in other conditions where a direct link with IL-1 has not been found.