TUMOR NECROSIS FACTOR RECEPTOR–ASSOCIATED PERIODIC SYNDROME

Tumor necrosis factor receptor–associated periodic syndrome (TRAPS) results from alterations in the gene encoding the TNF cell surface receptor. TRAPS has a widely variable phenotypic presentation. Febrile attacks in TRAPS typically last for 7 or more days, differentiating TRAPS from FMF and HIDS. The median age at onset in TRAPS is 3 years, yet adolescent and adult onset cases have been reported. Intense myalgias are characteristic of TRAPS attacks. TRAPS patients may have an erythematous rash that usually occurs on an extremity and travels in a distal-to-proximal fashion in association with myalgias. Abdominal pain and pleuritic chest pain are common. Painful conjunctivitis and periorbital edema are also frequently observed. Genetic testing can be used to confirm the diagnosis of TRAPS.

Treatment for TRAPS is reliant on use of TNF-α antagonists. Systemic corticosteroids are also effective but require ever-increasing doses and unacceptable systemic adverse effects. Overall, the prognosis of TRAPS is quite good. The risk of amyloidosis is lower than that of FMF.

CRYOPYRIN-ASSOCIATED PERIODIC SYNDROME

The most diverse hereditary autoinflammatory syndrome is the cryopyrin-associated periodic syndrome (CAPS). CAPS encompasses three overlapping phenotypes: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal onset multisystemic inflammatory disorder (NOMID). In CAPS, mutations in the NLRP3 (NOD-like receptor family, pyrin domain containing 3) gene result in increased IL-1β production. Inheritance patterns for CAPS appear to be autosomal dominant, but spontaneous mutations are common.

The physical manifestations of CAPS vary widely. Common findings in CAPS patients include recurrent fevers, urticarial rash, and joint pain. When exposed to sudden drops in ambient temperature, FCAS patients develop symptoms that resolve in less than 24 hours. Patients with MWS have more frequent and prolonged attacks that may or may not be related to changes in ambient temperature. In addition to fever and urticarial rash, MWS patients may develop arthritis and headaches due to aseptic meningitis. NOMID is the most severe CAPS phenotype, presenting shortly after birth as fever and persistent urticarial rash. Patients with NOMID suffer from chronic aseptic meningitis, papilledema, and optic nerve atrophy in addition to frontal bossing of the skull. Overgrowth of the epiphyseal regions of long bones and growth delay are characteristic of NOMID (see Plate 5-47).

Control of IL-1β activity is key to successful treatment of CAPS. Many patients with FCAS do not require treatment and may move to warmer climates to avoid the rapid swings in ambient temperature. Patients with MWS and NOMID require therapy with IL-1 antagonists. Overall prognosis for CAPS is largely dependent on phenotype. Patients with FCAS generally have a progressive improvement in attack frequency and severity over time. Patients with symptoms more consistent with MWS also have a relatively good prognosis and low likelihood of amyloidosis and sensorineural hearing loss, especially when treated with IL-1 antagonists. Finally, patients with NOMID carry the greatest risk of sensorineural hearing loss, growth delay, and amyloidosis.