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 General reference Tumor necrosis factor receptor–associated periodic syndrome is an autosomal dominant disorder causing recurrent fever and painful, migratory myalgias with tender overlying erythema. Diagnosis... read more ).
With treatment, the prognosis is good, but it is more guarded in patients with renal amyloidosis Amyloidosis Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more 
.
General reference
1. Cudrici C, Deuitch N, Aksentijevich I: Revisiting TNF receptor-associated periodic syndrome (TRAPS): Current perspectives. Int J Mol Sci 21(9):3263, 2020. doi: 10.3390/ijms21093263
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 General reference Tumor necrosis factor receptor–associated periodic syndrome is an autosomal dominant disorder causing recurrent fever and painful, migratory myalgias with tender overlying erythema. Diagnosis... read more ).
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 Amyloidosis Amyloidosis is any of a group of disparate conditions characterized by extracellular deposition of insoluble fibrils composed of misaggregated proteins. These proteins may accumulate locally... read more involving the kidneys has been reported in 10% of patients; the median age of presentation is 43 years.
Autoinflammatory periodic fever disorders
 CAPS = cryopyrin-associated periodic syndromes; FMF = familial Mediterranean fever; NOMID = neonatal-onset multisystem inflammatory disease; PFAPA = periodic fevers with aphthous stomatitis, pharyngitis, and adenitis; TRAPS = tumor necrosis factor receptor–associated periodic syndrome. Adapted from Sag E, Bilginer Y, Ozen S: Autoinflammatory diseases with periodic fevers. Curr Rheumatol Rep 19(7):41, 2017. doi: 10.1007/s11926-017-0670-8 |
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 Diagnosis reference Tumor necrosis factor receptor–associated periodic syndrome is an autosomal dominant disorder causing recurrent fever and painful, migratory myalgias with tender overlying erythema. Diagnosis... read more ).
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 Treatment references Tumor necrosis factor receptor–associated periodic syndrome is an autosomal dominant disorder causing recurrent fever and painful, migratory myalgias with tender overlying erythema. Diagnosis... read more , 2 Treatment references Tumor necrosis factor receptor–associated periodic syndrome is an autosomal dominant disorder causing recurrent fever and painful, migratory myalgias with tender overlying erythema. Diagnosis... read more ) and canakinumab 150 mg subcutaneously every 4 weeks (3 Treatment references Tumor necrosis factor receptor–associated periodic syndrome is an autosomal dominant disorder causing recurrent fever and painful, migratory myalgias with tender overlying erythema. Diagnosis... read more , 4 Treatment references Tumor necrosis factor receptor–associated periodic syndrome is an autosomal dominant disorder causing recurrent fever and painful, migratory myalgias with tender overlying erythema. Diagnosis... read more ). Etanercept has proved to be only partially effective (5 Treatment references Tumor necrosis factor receptor–associated periodic syndrome is an autosomal dominant disorder causing recurrent fever and painful, migratory myalgias with tender overlying erythema. Diagnosis... read more , 6 Treatment references Tumor necrosis factor receptor–associated periodic syndrome is an autosomal dominant disorder causing recurrent fever and painful, migratory myalgias with tender overlying erythema. Diagnosis... read more ).
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 |
|---|---|
etanercept |
Enbrel |
anakinra |
Kineret |
canakinumab |
Ilaris |
prednisone |
Deltasone, Predone, RAYOS, Sterapred, Sterapred DS |
