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Chapter 134. Systemic Autoinflammatory Diseases

Chyi-Chia Richard Lee; Raphaela Goldbach-Mansky

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Systemic Autoinflammatory Diseases at a Glance
  • Autoinflammatory diseases are disorders of the innate immune system. Excessive, innate immune responses lead to uncontrolled systemic and organ inflammation.
  • Although these syndromes can mimic infections clinically, the inflammatory lesions in autoinflammatory disorders are aseptic. Fever typically accompanies some autoinflammatory diseases but is not present in all disorders.
  • A number of pediatric autoinflammatory syndromes are caused by single gene mutations that have been crucial in pointing to key proinflammatory pathways, in particular the regulation of the cytokine interleukin-1 (IL-1).
  • Most monogenic autoinflammatory syndromes typically present in childhood and can be differentiated on the basis of their clinical features.
  • These disorders present with evidence of systemic inflammation often accompanied by generalized lymphadenopathy. Organ-specific inflammation can affect the skin, the joints/bones, serosal surfaces, the eyes, cochlea, meninges, but are often specific for one of the syndromes.
  • Autosomal recessive autoinflammatory syndromes include: familial Mediterranean fever (FMF) and hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), Majeed syndrome, deficiency of the IL-1 receptor antagonist (DIRA), and deficiency of the IL-10 receptor.
  • Autosomal dominant autoinflammatory syndromes include: i) tumor necrosis factor receptor-associated periodic syndrome (TRAPS) and the spectrum of the cryopyrinopathies or cryopyrin-associated periodic syndromes (CAPS)—familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID); ii) pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome; and iii) pediatric granulomatous arthritis (PGA).
  • Characteristic skin eruptions are associated with a number of these disorders and include, neutrophilic urticaria, skin erythema, macular papular eruptions, and pustulosis.
  • Colchicine effectively prevents the inflammatory attacks and the development of amyloidosis in FMF.
  • Anti-IL-1 therapy is the standard of care in treating the cryopyrinopathies (CAPS), and DIRA. Anti-IL-1 therapy is also used to treat syndromes with more variable responses to IL-1 blockade such as resistant patients with HIDS, TRAPS, FMF, PAPA, and PGA.
  • Mutations for these disorders are available in an online database called Infevers: available at http://fmf.igh.cnrs.fr/ISSAID/infevers/).

This chapter focuses on the clinical and immunologic description of the currently known monogenic autoinflammatory syndromes. Most of these syndromes present with predominantly neutrophilic skin eruptions and either fever or systemic inflammation, with elevation of acute-phase reactants during the attacks. Disease-specific organ inflammation often involves the skin, serosal surfaces, the eyes, the inner ear the meninges, the bones, the gastrointestinal tract, lymphadenopathy and more rarely, the vasculature. The characteristic clinical pattern of organ-specific inflammation in the various syndromes can, in most cases, be used to make a clinical diagnosis, which is then confirmed by genetic testing. The syndromes are summarized in this chapter.

image Autoinflammatory diseases are clinical disorders marked by episodic flares of abnormally increased systemic and organ-specific inflammation, mediated predominantly by the cells and molecules of the innate immune system, with a significant host predisposition.1 Historically, the term autoinflammatory diseases was first applied to two periodic fever syndromes that are caused by two single gene mutations encoding molecules involved in innate immune pathways. Both disorders lack the presence of ...

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