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Abstract & Commentary
Synopsis: Recurrent febrile episodes with localized myalgia and an erythematous, tender skin eruption overlying the painful muscle group are among the most common manifestation of the tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS).
Source: Hull KM, et al. The TNF receptor-associated periodic syndrome (TRAPS). Medicine. 2002;81:349-368.
Hull and colleagues review the available data from their cohort of more than 50 patients with the tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS), an autosomal dominantly inherited illness that occurs in individuals of diverse ethnicities. Twenty disease-associated mutations in genes encoding the TNF receptor super family 1A (TNFRSF1A) have been detected in association with this syndrome; nineteen of these are single nucleotide missense mutations, 18 of which account for amino acid substitutions within the first 2 cysteine-rich domains of the extracellular portion of the receptor. Most, but not all, of these mutations are associated with a specific defect in shedding of soluble TNFRSF1A.
The age of onset of illness in the cohort ranged from 2 weeks to 53 years of age, while the median age at onset was 3 years. The frequency and duration of symptoms were highly variable, but attacks occurred an average of every 5-6 weeks and were present an average of 21 days per month.
Attacks most commonly had a gradual onset, often with a sensation of deep muscle cramping, reaching a maximum intensity over 1-3 days and then persisting at this level for a minimum of an additional 3 days, but most often much longer. Symptoms then gradually resolved. Some patients, rather then suffering from episodic attacks, have continuing symptoms on a daily basis that vary in severity. Fever is invariably present during attacks in adults but sometimes absent in children.
Skin eruption is frequent. While quite varied, the most commonly observed cutaneous manifestation is a centrifugal migratory, erythematous patch that may overlie a localized area of myalgia. The rash is tender, blanchable, and warm to the touch and ranges from 1 to 28 cm in size and is usually single, being present on the limbs or trunk. Some patients have, instead, urticarial-like plaques or generalized erythematous serpiginous patches and plaques.
Myalgia is almost invariably present often, together with fever, heralding the onset of an attack. Only a single area of the body is usually involved but, like the rash, migrates centrifugally. Serum creatine kinase and aldolase concentrations remain normal. MRI shows focal areas of edema. Histological examination of biopsy specimens demonstrates a monocytic fasciitis; myositis is absent.1 Arthritis, which infrequently occurs, is nonerosive, asymmetric, and monoarticular, primarily involving large joints.
Ninety-two percent of the cohort had abdominal pain during attacks. Testicular or scrotal pain may occur. Eighty-two percent had ocular symptoms including conjunctivitis, periorbital edema, and/or periorbital pain; these may be bilateral or unilateral.
During an acute attack, ESR, CRP, and other markers of acute inflammation are elevated. A polyclonal gammopathy is usually present.
The administration of nonsteroidal anti-inflammatory agents may control fever but usually are not effective in controlling muscle, abdominal, and other pain complaints. Corticosteroids are more effective in reducing the severity of symptoms, but chronic administration does not reduce the frequency of attacks. Etanercept appears to decrease the frequency of attacks. Among agents that do not appear to provide benefit are colchicines, thalidomide, dapsone, methotrexate, and IVIG.
Comment By Stan Deresinski, MD, FACP
TRAPS is one of a number of periodic fever syndromes that has been genetically defined in recent years. Three of these, like TRAPS, are inherited in an autosomally dominant fashion: the neonatal onset multisystem inflammatory disorder/chronic infantile neurological cutaneous and articular syndrome, the familial cold autoinflammatory syndrome, and the Muckle-Wells syndrome—each of which is associated with mutations in the gene encoding copyrin. Familial Mediterranean fever, an autosomal recessive disease, is associated with mutations in the gene encoding pyrin, and hyperimmunoglobulinemia D with periodic fever, also autosomal recessive, is associated with altered mevalonate kinase. In children, nonhereditary causes of "autoinflammatory disease" include systemic juvenile idiopathic arthritis and the periodic fever, aphthous stomatis, pharyngitis adenitis (PFAPA) syndrome.2
TRAPS was first described among Irish and Scottish individuals and was originally called familial Hibernian fever. While most cases have a family history of compatible illness, cases may also occur sporadically. Although the pathogenesis of TRAPS remains undefined, the alteration in TNFRSF1A and the apparent efficacy of etanercept appears to implicate the TNF receptor.
Hull et al point out that the diagnosis of TRAPS should be considered in a patient of any ethnicity, usually with other affected family members, with recurrent febrile episodes lasting more than 5 days, occurring over a period of at least 6 months characterized by the presence of focal myalgia with an overlying erythematous rash, often with abdominal pain and ocular involvement with response to corticosteroids but not colchicine. The diagnosis is confirmed by genetic analysis.
Dr. Deresinski, Clinical Professor of Medicine, Stanford; Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor of Infectious Disease Alert.
1. Hull KM, et al. Arthritis Rheum. 2002;46:2189-2194.
2. Frenkel J, Kuis W. Overt and occult rheumatic diseases: The child with chronic fever. Best Pract Clin Rheumatol. 2002;16:443.