Cryopyrin-Associated Periodic

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 1. Fietta P. Autoinflammatory diseases: the hereditary periodic fever syndromes. Acta Biomed 2004; 75(2):92-9. 2. 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. 3. 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. 4. 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. 5. 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. 6. Lachmann HJ, Hawkins PN. Developments in the scientific and clinical understanding of autoinflammatory disorders. Arthritis Res Ther 2009; 11(1):212. 7. 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. 8. Henderson C, Goldbach-Mansky R. Monogenic autoinflammatory diseases: new insights into clinical aspects and pathogenesis. Curr Opin Rheumatol 2010; 22(5):567-78. 9. 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. 10. 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. 11. 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. 12. 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. 13. 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. 14. Jesus AA, Oliveira JB, Hilario MO, et al. Pediatric hereditary autoinflammatory syndromes. J Pediatr (Rio J) 2010; 86(5):353-66. 15. Doull IJ, Campbell MJ, Holgate ST. Duration of growth suppressive effects of regular inhaled corticosteroids. Arch Dis Child 1998; 78(2):172-3. 16. 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