Clinical Information

Systemic autoinflammatory disorders result from dysregulation of the innate immune system and are characterized by a hyperinflammatory state with elevated acute phase reactants. These disorders may present at any age, but symptoms often begin in childhood with unexplained fever that may be accompanied by a rash. While these features can mimic infections or hematological neoplasias, the inflammatory lesions are noncancerous and sterile. Additional features may be present and highly variable, depending on the organ or organs impacted by cytokine amplification loops and sterile inflammation. Symptoms may involve the gastrointestinal (GI) tract (eg, serositis, abdominal pain, early-onset inflammatory bowel disease), bone, eyes (eg, uveitis), musculoskeletal system (eg, arthritis and arthralgias), central nervous system (eg, meningitis), or other tissues. Some autoinflammatory disorders are also associated with an increased risk of developing AA amyloidosis. These disorders include familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), cryopyrin-associated autoinflammatory syndrome (CAPS), and hyper-IgD syndrome/mevalonate kinase deficiency (HIDS/MKD).

Autoinflammatory disorders are classified by molecular pathogenesis or clinical features. Pathophysiologic classification is based on the pathway or cytokine that drives disease, such as interleukin (IL)-1, interferon, nuclear factor kappa B, and IL-18. Disease classification based on clinical features often focuses on skin involvement or fever duration and frequency. Age of onset, triggers, and additional organ system involvement are also used to classify these disorders and aid clinical diagnosis.

The genetic basis of many heritable autoinflammatory disorders has been identified. Autoinflammatory disorders may be inherited in an autosomal recessive, autosomal dominant, or X-linked manner. Disease-causing variants may also arise de novo. The inheritance pattern appears more complicated for some disorders. For example, FMF is typically inherited in an autosomal recessive manner. However, some affected individuals appear to have only one disease-causing alteration. For other autoinflammatory disorders, cases of digenic and oligogenic inheritance have also been described. Inheritance may also be multifactorial, requiring an environmental component along with low-penetrance variants. One example is Yao syndrome, a recently described clinical entity characterized by recurrent fever, dermatitis, inflammatory arthritis, and GI symptoms in most affected individuals. While some variants in NOD2 have been reported in association with Yao syndrome, they are relatively common among the general population. They may confer an increased risk for developing Yao syndrome but are not diagnostic and appear insufficient to cause disease by themselves. Some disorders such as PFAPA (periodic fever, aphthous stomatitis, pharyngitis, adenitis) syndrome, systemic juvenile idiopathic arthritis, adult-onset Still disease, and Behcet disease have significant phenotypic overlap with monogenic autoinflammatory conditions, but a genetic cause of these disorders has not been identified.

Finally, several examples of post-zygotic (mosaic or somatic) genetic alterations causing autoinflammatory disorders have been described. While it may be possible to identify mosaic variants, this test is primarily intended for the identification of germline variants and the diagnosis of inherited monogenic autoinflammatory disorders.

Determining the underlying genetic cause of an autoinflammatory condition may help guide treatment decisions. For example, colchicine is an effective therapy for many patients with FMF, but some patients may not respond. Instead, these individuals, and others affected by a subset of autoinflammatory disorders, may respond to IL-1 blocking therapies. Anakinra, rilonacept, and canakinumab are several examples of medications that target IL-1. However, another subset of autoinflammatory disorders is not responsive to IL-1 blockade, such as proteasome-associated autoinflammatory syndromes (PRAAS), CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy), deficiency of IL-36 receptor antagonist, and CAMPS (CARD14-mediated psoriasis). Medications that target other components of the IL-1 pathway are under development. In addition, medications that target other pathways (eg, anti-tumor necrosis factor, anti-IL-6, and JAK-inhibitors) have demonstrated efficacy in some patients.