Autoinflammatory disorders are caused by dysregulation of the innate immune system.
Although many of the symptoms of autoinflammatory disorders, such as fever, skin lesions, and joint pain, mimic infection, the inflammation is sterile.
Interleukin (IL)-1 plays a prominent role in a large subset of monogenic autoinflammatory disorders.
Monogenic autoinflammatory disorders typically present in childhood but sometimes occur neonatally.
Monogenic autoinflammatory disorders are mostly inherited in an autosomal-recessive or autosomal-dominant pattern, but there are a considerable number of sporadic cases.
Characteristic skin eruptions are associated with a number of these disorders, including neutrophilic urticarial skin lesions, pustulosis, cellulitis-like skin lesions, erythematous and maculopapular eruptions. Skin lesions can be the sole remarkable disease manifestation in some disorders.
Specific treatments exist, including IL-1 antagonists for cryopyrin-associated periodic syndromes (CAPS), Schnitzler syndrome, and deficiency of the interleukin (IL)-1 receptor antagonist (DIRA), and colchicine for familial Mediterranean fever (FMF). IL-1 antagonists have also been used with variable efficacy in FMF and hyperimmunoglobulinemia D with periodic fever syndrome (HIDS)/mevalonate kinase deficiency (MKD).
An online database for autoinflammatory mutations is available at Infevers (http://fmf.igh.cnrs.fr/ISSAID/infevers/).
This chapter focuses on the clinical aspects and known pathogenesis of autoinflammatory disorders (Table 39-1). Most of these disorders present with recurrent fevers and involvement of the skin, the joints, the gastrointestinal tract, the bones, and serosal surfaces that mimic infectious disease, collagen-vascular disease, or malignant disease. Autoinflammatory disorders are, however, diseases of the innate immune system, characterized by recurrent episodes of systemic inflammation without the usual hallmarks of autoimmunity such as high autoantibody titers and the presence of antigen-specific T cells.1,2 Although a delay in diagnosis is unfortunately common because of their rarity, the characteristic clinical features can help the clinician to make a diagnosis, which is confirmed by genetic testing.
Table 39-1Autoinflammatory Disorders ||Download (.pdf) Table 39-1 Autoinflammatory Disorders
|PATHOGENESIS ||DISEASE ||GENE ||INHERITANCE PATTERN ||PROTEIN ||FLARE/FEVER PATTERN ||INVOLVED ORGAN(S) |
|IL-1 mediated || |
Skin, eyes, joints
Skin, eyes, joints, inner ears, meninges
Skin, eyes, joints, inner ears, meninges, bones
|Schnitzler syndrome ||NLRP3/CIAS1a ||De novo ||NLRP3/Cryopyrin ||Variable ||Skin, bones, joints, blood (IgM gammopathy) |
|DIRA ||IL1RN ||AR ||IL-1 receptor antagonist ||Continuous ||Skin, bones, lungs (rare), vasculitis (rare) |
|Partially IL-1 mediated ||FMF ||MEFV ||AR/ADb ||Pyrin ||1-3 days ||Skin, joints, peritoneum, pleura |
|HIDS/MKD ||MVK ||AR ||Mevalonate kinase ||3-7 days ||Skin, mucosa, eyes, joints, prominent lymph nodes |
|PAPA syndrome ||PSTPIP1/CD2BP1 ||AD ||PSTPIP1 ||Common ||Skin, joints |
|SAPHO syndrome ||– ||– ||– ||Uncommon ||Skin, joints, bones |
|IL-36 mediated ||DITRA ||IL36RN ||AR ||IL-36 receptor antagonist ||Common ||Skin |
|Partially IL-36 mediated ||CAMPS/PSORS2 ||CARD14 ||AD ||CARD14 ||Variable ||Skin |
|Other pathways ||TRAPS ||TNFRSF1A ||AD ||TNF receptor 1 ||1-4 weeks ||Skin, eyes, joints, peritoneum, pleura |
|HA20 ||TNFAIP3 ||AD ||A20/TNFAIP3 ||Common ||Skin, mucosa, eyes, joints, vasculitis, GI tract |
|Otulipenia/ORAS ||OTULIN ||AR ||OTULIN ||Weeks...|