Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS) Media Backgrounder

Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS)

An Extremely Rare Autoinflammatory Disease
Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS) is a rare
autoinflammatory disease that can affect both children and adults1-3. This genetically
inherited disease is characterized by long and intermittent attacks that can involve fever,
abdominal pain, conjunctivitis, severe skin rash, swelling around the eyes and severe
muscle and joint pain1-3. The condition is described as systemic because its symptoms can
affect the whole body.
TRAPS, formerly known as familial Hibernian fever, is one of three conditions that make up
the hereditary periodic fever syndromes (HPFSs); along with hyperimmunoglobulinemia D
and periodic fever syndrome (HIDS) and familial Mediterranean fever (FMF)1. The disease
onset of TRAPS usually occurs later in life compared with the other HPFSs, with most
patients developing the condition before the age of 201. Males are more than 30% more
likely to develop the disease than females but there is no gender specific difference in the
symptoms of the disease1,4.
TRAPS is a rare disease, so few data exist on its incidence and prevalence. The prevalence
of TRAPS in Germany in children under 16 years of age5 and also in the UK population6
has been estimated to be approximately one patient per one million individuals. There are
currently no global prevalence or incidence rates for TRAPS7.
The role of inflammation in TRAPS
Mutations in TNFRSF1A, the gene encoding Tumor Necrosis Factor (TNF) Receptor Type 1
(TNFR1), cause the signs and symptoms associated with TRAPS. Although the exact
mechanism by which these mutations lead to TRAPS symptoms is unknown, several have
been suggested8,9.
It has been suggested that, while mutated TNFR1 may still have the ability to bind strongly to
TNF, the receptor cannot stay bound to the cell surface. This results in the build up of
unbound TNFR1 within the cell which can result in the release of proinflammatory cytokines
(immune signalling molecules)8.
Recent evidence suggests that, aside from TNF, other cytokines, such as interleukin-1 beta
(IL-1 beta), may play an important role in the pathogenesis of TRAPS10. Patients with the
condition have been shown to have an increased activation of NF-kappa B, a signalling
molecule involved in the secretion of IL-1 beta and other proinflammatory cytokines8,10.
Unsuccessfully treated TRAPS can lead to severe complications
Amyloidosis is a serious complication of TRAPS and is estimated to occur in 25% of
patients11. This long-term complication involves the production of a protein called serum
amyloid A (SAA) during inflammation, and can lead to liver and/or kidney failure. In some
instances, amyloidosis can be fatal12.

Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS) Media Backgrounder

Diagnosis and treatment challenges

HPFSs, including TRAPS, often remain unrecognized and undiagnosed for many years and
diagnosis can involve extensive investigation, including exploratory surgery1. Misdiagnosis
can also be a problem, as the symptoms of TRAPS can appear to mimic other conditions13.
Currently, there are no approved treatments for TRAPS. Potential treatment options include
nonsteroidal anti-inflammatory drugs and corticosteroids1. While these have shown to relieve
some of the symptoms associated with TRAPS, there can be problems with limited and
intermittent efficacy14. In addition, long-term corticosteroid use in children is associated with
potentially serious adverse effects including growth suppression and delayed puberty15.
Research has also been undertaken into the use of anti-TNF compounds, although none
have been approved for use in TRAPS to date.
With limitations in currently available treatment options and varying success of anti-TNF
compounds4,16, there remains a strong unmet need for therapies that can address the
symptoms associated with TRAPS, including inflammation. The role of other cytokines in the
pathogenesis of TRAPS is a promising area of research which could yield potential new
treatments.
References
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Fietta P. Autoinflammatory diseases: the hereditary periodic fever syndromes. Acta Biomed 2004;
75(2):92-9.
Simon A, van der Meer JW. Pathogenesis of familial periodic fever syndromes or hereditary
autoinflammatory syndromes. Am J Physiol Regul Integr Comp Physiol 2007; 292(1):R86-98.
Borghini S, Fiore M, Di Duca M, et al. Candidate genes in patients with autoinflammatory syndrome
resembling tumor necrosis factor receptor-associated periodic syndrome without mutations in the
TNFRSF1A gene. J Rheumatol 2011; 38(7):1378-84.
Hull KM, Drewe E, Aksentijevich I, et al. The TNF receptor-associated periodic syndrome (TRAPS):
emerging concepts of an autoinflammatory disorder. Medicine (Baltimore) 2002; 81(5):349-68.
Lainka E, Neudorf U, Lohse P, et al. Incidence of TNFRSF1A mutations in German children:
epidemiological, clinical and genetic characteristics. Rheumatology 2009; 48:987-91.
Lachmann HJ, Hawkins PN. Developments in the scientific and clinical understanding of autoinflammatory
disorders. Arthritis Res Ther 2009; 11(1):212.
Lainka E, Neudorf U, Lohse P, et al. Incidence of TNFRSF1A mutations in German children:
epidemiological, clinical and genetic characteristics. Rheumatology (Oxford) 2009; 48(8):987-91.
Henderson C, Goldbach-Mansky R. Monogenic autoinflammatory diseases: new insights into clinical
aspects and pathogenesis. Curr Opin Rheumatol 2010; 22(5):567-78.
Glaser RL, Goldbach-Mansky R. The spectrum of monogenic autoinflammatory syndromes:
understanding disease mechanisms and use of targeted therapies. Curr Allergy Asthma Rep 2008;
8(4):288-98.
Nedjai B, Hitman GA, Quillinan N, et al. Proinflammatory action of the antiinflammatory drug infliximab in
tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum 2009; 60(2):619-25.
Dode C, Cuisset L, Delpech M, et al. TNFRSF1A-associated periodic syndrome (TRAPS), Muckle-Wells
syndrome (MWS) and renal amyloidosis. J Nephrol 2003; 16(3):435-7.
Aksentijevich I, Galon J, Soares M, et al. The tumor-necrosis-factor receptor-associated periodic
syndrome: new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for
further genetic heterogeneity of periodic fevers. Am J Hum Genet 2001; 69(2):301-14.
Manki A, Nishikomori R, Nakata-Hizume M, et al. Tumor necrosis factor receptor-associated periodic
syndrome mimicking systemic juvenile idiopathic arthritis. Allergol Int 2006; 55(3):337-41.
Jesus AA, Oliveira JB, Hilario MO, et al. Pediatric hereditary autoinflammatory syndromes. J Pediatr (Rio
J) 2010; 86(5):353-66.
Doull IJ, Campbell MJ, Holgate ST. Duration of growth suppressive effects of regular inhaled
corticosteroids. Arch Dis Child 1998; 78(2):172-3.
Gattorno M, Pelagatti MA, Meini A, et al. Persistent efficacy of anakinra in patients with tumor necrosis
factor receptor-associated periodic syndrome. Arthritis Rheum 2008; 58(5):1516-20.

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Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS) Media Backgrounder

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