Within 5 years of the discovery of the FMF gene, three additional genes causing five other hereditary recurrent fever syndromes were identified, catalyzing a paradigm shift in diagnosis and treatment of these disorders.
TNF RECEPTOR-ASSOCIATED PERIODIC SYNDROME (TRAPS)
TRAPS is caused by dominantly inherited mutations in the extracellular domains of the 55-kDa TNF receptor (TNFR1, p55). Although originally described in a large Irish family (and hence the name familial Hibernian fever), TRAPS has a broad ethnic distribution. TRAPS episodes often begin in childhood. The duration of attacks ranges from 1–2 days to as long as several weeks, and in severe cases symptoms may be nearly continuous. In addition to peritoneal, pleural, and synovial attacks similar to FMF, TRAPS patients frequently have ocular inflammation (most often conjunctivitis and/or periorbital edema), and a distinctive migratory myalgia with overlying painful erythema may be present. TRAPS patients generally respond better to glucocorticoids than to prophylactic colchicine. Untreated, about 15% develop amyloidosis. The diagnosis of TRAPS is based on the demonstration of TNFRSF1A mutations in the presence of characteristic symptoms. Two particular variants, R92Q and P46L, are common in certain populations and may act more as functional polymorphisms than as disease-causing mutations. In contrast, pathogenic TNFRSF1A mutations, including a number of substitutions at highly conserved cysteine residues, are associated with intracellular TNFR1 misfolding, aggregation, and retention, with consequent ligand-independent kinase activation, mitochondrial reactive oxygen species production, and proinflammatory cytokine release. Etanercept, a TNF inhibitor, ameliorates TRAPS attacks, but the long-term experience with this agent has been less favorable. Perhaps because of the ligand-independent signaling abnormalities in TRAPS, IL-1 inhibition has been beneficial in a large percentage of the patients in whom it has been used. Monoclonal anti-TNF antibodies should be avoided, because they may exacerbate TRAPS attacks.
HYPERIMMUNOGLOBULINEMIA D WITH PERIODIC FEVER SYNDROME (HIDS)
HIDS is a recessively inherited recurrent fever syndrome found primarily in individuals of northern European ancestry. It is caused by mutations in mevalonate kinase (MVK), encoding an enzyme involved in the synthesis of cholesterol and nonsterol isoprenoids. Attacks usually begin in infancy and last 3–5 days. Clinically distinctive features include painful cervical adenopathy, a diffuse maculopapular rash sometimes affecting the palms and soles, and aphthous ulcers; pleurisy is rare, as is amyloidosis. Although originally defined by the persistent elevation of serum IgD, disease activity is not related to IgD levels, and some patients with FMF or TRAPS may have modestly increased serum IgD. Moreover, occasional patients with MVK mutations and recurrent fever have normal IgD levels. For these reasons, some have proposed renaming this disorder mevalonate kinase deficiency (MKD). All patients with mutations have markedly elevated urinary mevalonate levels during their febrile attacks, although the inflammatory manifestations are likely to be due to a deficiency of isoprenoids rather than an excess of mevalonate. There is currently no established treatment for HIDS/MKD, although intermittent or continuous IL-1 inhibition and TNF inhibitors have been effective in small series.
THE CRYOPYRINOPATHIES, OR CRYOPYRIN-ASSOCIATED PERIODIC SYNDROMES (CAPS)
Three hereditary febrile syndromes, familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID), are all caused by mutations in NLRP3 (formerly known as CIAS1), the gene encoding cryopyrin (or NLRP3), and represent a clinical spectrum of disease. FCAS patients develop chills, fever, headache, arthralgia, conjunctivitis, and an urticaria-like rash in response to generalized cold exposure. In MWS, an urticarial rash is noted, but it is not usually induced by cold; MWS patients also develop fevers, abdominal pain, limb pain, arthritis, conjunctivitis, and, over time, sensorineural hearing loss. NOMID is the most severe of the three disorders, with chronic aseptic meningitis, a characteristic arthropathy, and rash. Like the FMF protein, pyrin, cryopyrin has an N-terminal PYRIN domain. Cryopyrin regulates IL-1β production through the formation of a macromolecular complex termed the inflammasome. Peripheral blood leukocytes from patients with FCAS, MWS, and NOMID release increased amounts of IL-1β upon in vitro stimulation, relative to healthy controls. Macrophages from cryopyrin-deficient mice exhibit decreased IL-1β production in response to certain gram-positive bacteria, bacterial RNA, and monosodium urate crystals. Patients with all three cryopyrinopathies show a dramatic response to injections of IL-1 inhibitors. Approximately one-third of patients with clinical manifestations of NOMID do not have germline mutations in NLRP3, but have been found to be mosaic for somatic NLRP3 mutations. Such patients also respond dramatically to IL-1 inhibition. Similarly, somatic mosaicism in NLRP3 has been found in Schnitzler’s syndrome, which presents in middle age with recurrent fever, urticarial rash, elevated acute phase reactants, monoclonal IgM gammopathy, and abnormal bone remodeling. IL-1 inhibition is the treatment of choice for Schnitzler’s syndrome.