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TNF Receptor–Associated Periodic Syndrome (TRAPS)

(Familial Hibernian Fever)

By

Apostolos Kontzias

, MD, Stony Brook University School of Medicine

Last full review/revision Mar 2020| Content last modified Mar 2020
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Tumor necrosis factor receptor–associated periodic syndrome is an autosomal dominant disorder causing recurrent fever and painful, migratory myalgias with tender overlying erythema. Diagnosis is clinical and by genetic testing. Treatment is with corticosteroids, etanercept, anakinra, and canakinumab.

Tumor necrosis factor (TNF) receptor–associated periodic syndrome (TRAPS) was originally described in a family of Irish and Scottish pedigree but has been reported in many different ethnic groups. It results from

  • Mutations in the gene coding TNF receptor 1 (TNFR1)

The mutation leads to aberrant inflammation due to accumulation of misfolded TNFR1 in the endoplasmic reticulum, which activates the unfolded protein response. This response is an attempt to correct the abnormal proteins, but it generates reactive oxygen species that trigger inflammation (1).

With treatment, the prognosis is good, but it is more guarded in patients with renal amyloidosis.

General reference

  • 1. Dickie LJ, Aziz AM, Savic S, et al: Involvement of X-box binding protein 1 and reactive oxygen species pathways in the pathogenesis of tumour necrosis factor receptor-associated periodic syndrome. Ann Rheum Dis 71(12):2035–2043, 2012. doi: 10.1136/annrheumdis-2011-201197.

Symptoms and Signs

Attacks of this rare disorder usually begin before age 20. In 70% of patients, attacks last 7 to 21 days (average of 10 days; 1).

The most distinctive features of an attack are fever and migratory myalgia and swelling in the extremities. The overlying skin is red and tender.

Other symptoms of TRAPS may include headache, abdominal pain, diarrhea or constipation, nausea, painful conjunctivitis, periorbital edema, joint pain, rash, and testicular pain. Males are prone to developing inguinal hernias.

Amyloidosis involving the kidneys has been reported in 10% of patients; the median age of presentation is 43 years.

Symptoms and signs reference

  • 1. Lachmann HJ, Papa R, Gerhold K, et al: The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: A series of 158 cases from the Eurofever/EUROTRAPS international registry. Ann Rheum Dis 73(12):2160–2167, 2014. doi: 10.1136/annrheumdis-2013-204184.

Diagnosis

  • Clinical evaluation

  • Genetic testing

Diagnosis of TRAPS is based on history, examination, and genetic testing.

Proposed diagnostic criteria include the presence of a positive family history, long-lasting fever episodes, periorbital edema, migratory rash, and myalgia and the absence of vomiting and aphthous ulcers. These criteria have a sensitivity of 59% and a specificity of 84% (1).

Nonspecific findings include neutrophilia, elevated acute-phase reactants, and polyclonal gammopathy during attacks. Patients should be screened regularly for proteinuria.

Diagnosis reference

  • 1. Federici S, Sormani MP, Ozen S, et al: Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers. Ann Rheum Dis 74(5):799–805, 2015. doi: 10.1136/annrheumdis-2014-206580.

Treatment

  • Corticosteroids

  • Anakinra and canakinumab

Short-term corticosteroids (prednisone at least 20 mg orally once a day), with or without nonsteroidal anti-inflammatory drugs, are effective for terminating inflammatory attacks. The dosage may need to be increased over time and this therapy may, over time, lead to more prolonged flare-ups.

Other options include anakinra 100 mg subcutaneously once a day (1, 2) and canakinumab 150 mg subcutaneously every 4 weeks (3, 4). Etanercept has proved to be only partially effective (5, 6).

Treatment references

  • 1. ter Haar NM, Oswald M, Jeyaratnam J, et al: Recommendations for the management of autoinflammatory diseases. Ann Rheum Dis 74(9):1636–1644, 2015. doi: 10.1136/annrheumdis-2015-207546.

  • 2. Gattorno M, Pelagatti MA, Meini A, et al: Persistent efficacy of anakinra in patients with tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum 58:1516–1520, 2008. doi: 10.1002/art.23475.

  • 3. Gattorno M, Obici L, Cattalini M, et al: Canakinumab treatment for patients with active recurrent or chronic TNF receptor-associated periodic syndrome (TRAPS): An open-label, phase II study. Ann Rheum Dis 76(1):173–178, 2016. doi: 10.1136/annrheumdis-2015-209031.

  • 4. De Benedetti F, Gattorno M, Anton J, et al: Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. N Engl J Med 378(20):1908–1919, 2018. doi: 10.1056/NEJMoa1706314.

  • 5. Drewe E, McDermott EM, Powell PT, et al: Prospective study of anti-tumour necrosis factor receptor superfamily 1B fusion protein, and case study of anti-tumour necrosis factor receptor superfamily 1A fusion protein, in tumour necrosis factor receptor associated periodic syndrome (TRAPS): Clinical and laboratory findings in a series of seven patients. Rheumatology 42:235–239, 2003. doi: 10.1093/rheumatology/keg070.

  • 6. Quillinan N, Mannion G, Mohammad A, et al: Failure of sustained response to etanercept and refractoriness to anakinra in patients with T50M TNF-receptor-associated periodic syndrome. Ann Rheum Dis 70(9):1692–1693, 2011. doi: 10.1136/ard.2010.144279.

Drugs Mentioned In This Article

Drug Name Select Trade
ILARIS
ENBREL
RAYOS
KINERET
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