Tumor Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome (TRAPS)

  • Sinisa SavicEmail author
  • Michael F. McDermott


Tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) is an autosomal dominant hereditary disease, caused by heterozygous mutations in TNFRSF1A, which encodes for TNF-receptor 1 (TNFR1). Most of the pathogenic mutations are single-nucleotide missense variants localized in extracellular, cysteine rich domains of the receptor. The pathogenesis of TRAPS is complex and likely involves several mutually non-exclusive molecular mechanisms, however, co-expression of the mutated and wild type of the receptor is required in all cases. The proposed mechanisms include abnormal TNFR1 cleavage; increased activation of nuclear factor kappa B (NF-κB)/mitogen-activated protein kinase; ligand-independent activation of mutant TNFR1; generation of mitochondrial reactive oxygen species (ROS) leading to enhanced activation of the NLRP3 inflammasome; TNFR1 misfolding and retention within the endoplasmic reticulum (ER) leading to activation of ER-associated endonuclease, inositol-requiring enzyme 1 (IRE-1) and resulting in hyper-responsiveness to lipopolysaccharide via selective degradation of microRNAs (miRs).

The majority of patients with TRAPS are symptomatic from childhood, with the median age of symptom onset reported to be about 4 years. Most patients report episodic attacks of fever, with serositis manifesting as abdominal and/or chest pain, myalgia with or without typical overlying migratory rash, arthralgia and arthritis. The minority of patients will have continuous symptoms, and many will have biochemical evidence of systemic inflammatory response even in the absence of symptoms. Prior to effective therapies, systemic amyloidosis was found in up to 15% of patients. The diagnosis of TRAPS still depends on molecular genetic analysis for conformation since formal diagnostic criteria have yet to be developed. Anti-interleukin (IL)-1 biological agents are currently the first choice of treatment for patients who require ongoing therapy.


TNF-receptor 1 (TNFR1) Endoplasmic reticulum (ER) stress Mitochondrial reactive oxygen species (ROS) Inositol-requiring enzyme 1 (IRE1) Anakinra, canakinumab 





A disintegrin and metalloproteinase


Cryopyrin-associated periodic syndrome


Cysteine-rich domains


C-reactive protein.


Dermal fibroblasts


Disease-modifying anti-rheumatic drugs


Endoplasmic reticulum


Familial Hibernian fever


Familial Mediterranean fever


I kappa beta


I kappa B kinase




Inositol-requiring enzyme 1


c-Jun N-terminal kinase




Mitogen-activated protein kinase




Mevalonate kinase deficiency


Mitochondrial ROS


Nicotinamide adenine dinucleotide phosphate


Nuclear factor-κB


NACHT, LRR and PYD domains-containing protein 3


NADPH oxidases


Nonsteroidal anti-inflammatory drugs


Oxidative phosphorylation


Polymerase chain reaction


Protein kinase (PKR)-like endoplasmic reticulum kinase


Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis


Physician global assessment


Receptor-interacting protein


Reactive oxygen species


Serum amyloid A


TNF-alpha converting enzyme


Toll-like receptor


Tumor necrosis factor


TNF receptor 1


Unfolded protein response


X-box binding protein 1


  1. 1.
    Williamson LM, Hull D, Mehta R, et al. Familial Hibernian fever. Q J Med. 1982;51:469–80.PubMedPubMedCentralGoogle Scholar
  2. 2.
    McDermott MF, Ogunkolade BW, McDermott EM, et al. Linkage of familial Hibernian fever to chromosome 12p13. Am J Hum Genet. 1998;62:1446–51.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Mulley J, Saar K, Hewitt G, et al. Gene localization for an autosomal dominant familial periodic fever to 12p13. Am J Hum Genet. 1998;62:884–9.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    McDermott MF, Aksentijevich I, Galon J, et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell. 1999;97:133–44.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Lachmann HJ. Clinical immunology review series: an approach to the patient with a periodic fever syndrome. Clin Exp Immunol. 2011;165:301–9.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    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;69:301–14.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Dode C, Andre M, Bienvenu T, et al. The enlarging clinical, genetic, and population spectrum of tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum. 2002;46:2181–8.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Ravet N, Rouaghe S, Dode C, et al. Clinical significance of P46L and R92Q substitutions in the tumour necrosis factor superfamily 1A gene. Ann Rheum Dis. 2006;65:1158–62.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Wajant H, Scheurich P. TNFR1-induced activation of the classical NF-kappaB pathway. FEBS J. 2011;278:862–76.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell. 2003;114:181–90.PubMedCrossRefPubMedCentralGoogle Scholar
  11. 11.
    Xanthoulea S, Pasparakis M, Kousteni S, et al. Tumor necrosis factor (TNF) receptor shedding controls thresholds of innate immune activation that balance opposing TNF functions in infectious and inflammatory diseases. J Exp Med. 2004;200:367–76.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Chan FK. Three is better than one: pre-ligand receptor assembly in the regulation of TNF receptor signaling. Cytokine. 2007;37:101–7.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Black RA. Tumor necrosis factor-alpha converting enzyme. Int J Biochem Cell Biol. 2002;34:1–5.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Aganna E, Hammond L, Hawkins PN, et al. Heterogeneity among patients with tumor necrosis factor receptor-associated periodic syndrome phenotypes. Arthritis Rheum. 2003;48:2632–44.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Drewe E, Huggins ML, Morgan AG, Cassidy MJ, Powell RJ. Treatment of renal amyloidosis with etanercept in tumour necrosis factor receptor-associated periodic syndrome. Rheumatology (Oxford). 2004;43:1405–8.CrossRefGoogle Scholar
  16. 16.
    Nowlan ML, Drewe E, Bulsara H, et al. Systemic cytokine levels and the effects of etanercept in TNF receptor-associated periodic syndrome (TRAPS) involving a C33Y mutation in TNFRSF1A. Rheumatology (Oxford). 2006;45:31–7.CrossRefGoogle Scholar
  17. 17.
    Simon A, Park H, Maddipati R, et al. Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome. Proc Natl Acad Sci U S A. 2010;107:9801–6.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Nedjai B, Hitman GA, Yousaf N, et al. Abnormal tumor necrosis factor receptor I cell surface expression and NF-kappaB activation in tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum. 2008;58:273–83.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Todd I, Radford PM, Draper-Morgan KA, et al. Mutant forms of tumour necrosis factor receptor I that occur in TNF-receptor-associated periodic syndrome retain signalling functions but show abnormal behaviour. Immunology. 2004;113:65–79.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Lobito AA, Kimberley FC, Muppidi JR, et al. Abnormal disulfide-linked oligomerization results in ER retention and altered signaling by TNFR1 mutants in TNFR1-associated periodic fever syndrome (TRAPS). Blood. 2006;108:1320–7.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    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. 2012;71:2035–43.CrossRefGoogle Scholar
  22. 22.
    Martinon F, Chen X, Lee AH, Glimcher LH. TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nat Immunol. 2010;11:411–8.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Tirasophon W, Lee K, Callaghan B, Welihinda A, Kaufman RJ. The endoribonuclease activity of mammalian IRE1 autoregulates its mRNA and is required for the unfolded protein response. Genes Dev. 2000;14:2725–36.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Maurel M, Chevet E, Tavernier J, Gerlo S. Getting RIDD of RNA: IRE1 in cell fate regulation. Trends Biochem Sci. 2014;39:245–54.PubMedCrossRefGoogle Scholar
  25. 25.
    Schulte LN, Westermann AJ, Vogel J. Differential activation and functional specialization of miR-146 and miR-155 in innate immune sensing. Nucleic Acids Res. 2013;41:542–53.PubMedCrossRefGoogle Scholar
  26. 26.
    Harrison SR, Scambler T, Oubussad L, et al. Inositol-requiring enzyme 1-mediated downregulation of MicroRNA (miR)-146a and miR-155 in primary dermal fibroblasts across three TNFRSF1A mutations results in hyperresponsiveness to lipopolysaccharide. Front Immunol. 2018;9:173.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Pearce EL, Pearce EJ. Metabolic pathways in immune cell activation and quiescence. Immunity. 2013;38:633–43.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    O’Neill LA. Glycolytic reprogramming by TLRs in dendritic cells. Nat Immunol. 2014;15:314–5.PubMedCrossRefGoogle Scholar
  29. 29.
    O’Neill LA, Kishton RJ, Rathmell J. A guide to immunometabolism for immunologists. Nat Rev Immunol. 2016;16:553–65.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Pearce EL, Poffenberger MC, Chang CH, Jones RG. Fueling immunity: insights into metabolism and lymphocyte function. Science. 2013;342:1242454.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Bulua AC, Simon A, Maddipati R, et al. Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J Exp Med. 2011;208:519–33.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Kamata H, Honda S, Maeda S, Chang L, Hirata H, Karin M. Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell. 2005;120:649–61.PubMedCrossRefGoogle Scholar
  33. 33.
    Bachetti T, Chiesa S, Castagnola P, et al. Autophagy contributes to inflammation in patients with TNFR-associated periodic syndrome (TRAPS). Ann Rheum Dis. 2013;72:1044–52.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Bachetti T, Ceccherini I. Tumor necrosis factor receptor-associated periodic syndrome as a model linking autophagy and inflammation in protein aggregation diseases. J Mol Med (Berl). 2014;92:583–94.CrossRefGoogle Scholar
  35. 35.
    Moscat J, Diaz-Meco MT. p62 at the crossroads of autophagy, apoptosis, and cancer. Cell. 2009;137:1001–4.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Schmaltz R, Vogt T, Reichrath J. Skin manifestations in tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Dermatoendocrinol. 2010;2:26–9.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Toro JR, Aksentijevich I, Hull K, Dean J, Kastner DL. Tumor necrosis factor receptor-associated periodic syndrome: a novel syndrome with cutaneous manifestations. Arch Dermatol. 2000;136:1487–94.PubMedGoogle Scholar
  38. 38.
    Rigante D, Cantarini L. Monogenic autoinflammatory syndromes at a dermatological level. Arch Dermatol Res. 2011;303:375–80.PubMedCrossRefGoogle Scholar
  39. 39.
    Hull KM, Wong K, Wood GM, Chu WS, Kastner DL. Monocytic fasciitis: a newly recognized clinical feature of tumor necrosis factor receptor dysfunction. Arthritis Rheum. 2002;46:2189–94.PubMedCrossRefGoogle Scholar
  40. 40.
    Quillinan N, Mohammad A, Mannion G, et al. Imaging evidence for persistent subclinical fasciitis and arthritis in tumour necrosis factor receptor-associated periodic syndrome (TRAPS) between febrile attacks. Ann Rheum Dis. 2010;69:1408–9.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Cantarini L, Lucherini OM, Cimaz R, Brizi MG, Galeazzi M. Serosal involvement in adult-onset autoinflammatory disorders. Respiration. 2010;80:260–1; author reply 262.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Cantarini L, Lucherini OM, Baldari CT, Laghi Pasini F, Galeazzi M. Familial clustering of recurrent pericarditis may disclose tumour necrosis factor receptor-associated periodic syndrome. Clin Exp Rheumatol. 2010;28:405–7.PubMedPubMedCentralGoogle Scholar
  43. 43.
    Cantarini L, Lucherini OM, Cimaz R, Baldari CT, Laghi Pasini F, Galeazzi M. Sacroileitis and pericarditis: atypical presentation of tumor necrosis factor receptor-associated periodic syndrome and response to etanercept therapy. Clin Exp Rheumatol. 2010;28:290–1.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Minden K, Aganna E, McDermott MF, Zink A. Tumour necrosis factor receptor associated periodic syndrome (TRAPS) with central nervous system involvement. Ann Rheum Dis. 2004;63:1356–7.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Wildemann B, Rudofsky G Jr, Kress B, Jarius S, Konig F, Schwenger V. The tumor-necrosis-factor-associated periodic syndrome, the brain, and tumor-necrosis-factor-alpha antagonists. Neurology. 2007;68:1742–4.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    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. 2014;73:2160–7.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Cantarini L, Rigante D, Merlini G, et al. The expanding spectrum of low-penetrance TNFRSF1A gene variants in adults presenting with recurrent inflammatory attacks: clinical manifestations and long-term follow-up. Semin Arthritis Rheum. 2014;43:818–23.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Hernandez-Rodriguez J, Ruiz-Ortiz E, Tome A, et al. Clinical and genetic characterization of the autoinflammatory diseases diagnosed in an adult reference center. Autoimmun Rev. 2016;15:9–15.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Ruiz-Ortiz E, Iglesias E, Soriano A, et al. Disease phenotype and outcome depending on the age at disease onset in patients carrying the R92Q low-penetrance variant in TNFRSF1A gene. Front Immunol. 2017;8:299.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Pelagatti MA, Meini A, Caorsi R, et al. Long-term clinical profile of children with the low-penetrance R92Q mutation of the TNFRSF1A gene. Arthritis Rheum. 2011;63:1141–50.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Jawaheer D, Seldin MF, Amos CI, et al. A genomewide screen in multiplex rheumatoid arthritis families suggests genetic overlap with other autoimmune diseases. Am J Hum Genet. 2001;68:927–36.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Amoura Z, Dode C, Hue S, et al. Association of the R92Q TNFRSF1A mutation and extracranial deep vein thrombosis in patients with Behcet’s disease. Arthritis Rheum. 2005;52:608–11.CrossRefGoogle Scholar
  53. 53.
    Touitou I, Kone-Paut I. Autoinflammatory diseases. Best Pract Res Clin Rheumatol. 2008;22:811–29.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Federici S, Sormani MP, Ozen S, et al. Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers. Ann Rheum Dis. 2015;74:799–805.CrossRefGoogle Scholar
  55. 55.
    Gattorno M, Sormani MP, D’Osualdo A, et al. A diagnostic score for molecular analysis of hereditary autoinflammatory syndromes with periodic fever in children. Arthritis Rheum. 2008;58:1823–32.CrossRefGoogle Scholar
  56. 56.
    Tanaka N, Izawa K, Saito MK, et al. High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study. Arthritis Rheum. 2011;63:3625–32.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Nakagawa K, Gonzalez-Roca E, Souto A, et al. Somatic NLRP3 mosaicism in Muckle-Wells syndrome. A genetic mechanism shared by different phenotypes of cryopyrin-associated periodic syndromes. Ann Rheum Dis. 2015;74:603–10.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Zhou Q, Aksentijevich I, Wood GM, et al. Brief report: cryopyrin-associated periodic syndrome caused by a myeloid-restricted somatic NLRP3 mutation. Arthritis Rheumatol. 2015;67:2482–6.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Rowczenio DM, Gomes SM, Arostegui JI, et al. Late-onset cryopyrin-associated periodic syndromes caused by somatic NLRP3 mosaicism-UK single center experience. Front Immunol. 2017;8:1410.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Rowczenio DM, Trojer H, Omoyinmi E, et al. Brief report: association of tumor necrosis factor receptor-associated periodic syndrome with gonosomal mosaicism of a novel 24-nucleotide TNFRSF1A deletion. Arthritis Rheumatol. 2016;68:2044–9.CrossRefGoogle Scholar
  61. 61.
    ter Haar NM, Oswald M, Jeyaratnam J, et al. Recommendations for the management of autoinflammatory diseases. Ann Rheum Dis. 2015;74:1636–44.CrossRefGoogle Scholar
  62. 62.
    Ter Haar N, Lachmann H, Ozen S, et al. Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review. Ann Rheum Dis. 2013;72:678–85.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Bulua AC, Mogul DB, Aksentijevich I, et al. Efficacy of etanercept in the tumor necrosis factor receptor-associated periodic syndrome: a prospective, open-label, dose-escalation study. Arthritis Rheum. 2012;64:908–13.PubMedCrossRefGoogle Scholar
  64. 64.
    Simsek I, Kaya A, Erdem H, Pay S, Yenicesu M, Dinc A. No regression of renal amyloid mass despite remission of nephrotic syndrome in a patient with TRAPS following etanercept therapy. J Nephrol. 2010;23:119–23.PubMedGoogle Scholar
  65. 65.
    Ozen S, Kuemmerle-Deschner JB, Cimaz R, et al. International retrospective chart review of treatment patterns in severe familial mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, and mevalonate kinase deficiency/hyperimmunoglobulinemia D syndrome. Arthritis Care Res (Hoboken). 2017;69:578–86.CrossRefGoogle Scholar
  66. 66.
    Nedjai B, Quillinan N, Coughlan RJ, et al. Lessons from anti-TNF biologics: infliximab failure in a TRAPS family with the T50M mutation in TNFRSF1A. Adv Exp Med Biol. 2011;691:409–19.PubMedCrossRefGoogle Scholar
  67. 67.
    Church LD, Churchman SM, Hawkins PN, McDermott MF. Hereditary auto-inflammatory disorders and biologics. Springer Semin Immunopathol. 2006;27:494–508.PubMedCrossRefGoogle Scholar
  68. 68.
    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;60:619–25.PubMedCrossRefGoogle Scholar
  69. 69.
    Simon A, Bodar EJ, van der Hilst JC, et al. Beneficial response to interleukin 1 receptor antagonist in traps. Am J Med. 2004;117:208–10.PubMedCrossRefGoogle Scholar
  70. 70.
    Sacre K, Brihaye B, Lidove O, et al. Dramatic improvement following interleukin 1beta blockade in tumor necrosis factor receptor-1-associated syndrome (TRAPS) resistant to anti-TNF-alpha therapy. J Rheumatol. 2008;35:357–8.PubMedPubMedCentralGoogle Scholar
  71. 71.
    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;58:1516–20.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Obici L, Meini A, Cattalini M, et al. Favourable and sustained response to anakinra in tumour necrosis factor receptor-associated periodic syndrome (TRAPS) with or without AA amyloidosis. Ann Rheum Dis. 2011;70:1511–2.PubMedCrossRefGoogle Scholar
  73. 73.
    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. 2017;76:173–8.PubMedCrossRefGoogle Scholar
  74. 74.
    De Benedetti F, Gattorno M, Anton J, et al. Canakinumab for the treatment of autoinflammatory recurrent fever syndromes. N Engl J Med. 2018;378:1908–19.CrossRefGoogle Scholar
  75. 75.
    La Torre F, Muratore M, Vitale A, Moramarco F, Quarta L, Cantarini L. Canakinumab efficacy and long-term tocilizumab administration in tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Rheumatol Int. 2015;35:1943–7.PubMedCrossRefGoogle Scholar
  76. 76.
    Savic S, Ouboussad L, Dickie LJ, et al. The role of IL-6 and LPS in pathogenesis of TRAPS. Pediatr Rheumatol. 2013;11:A153.CrossRefGoogle Scholar
  77. 77.
    Akasbi N, Soyfoo MS. Successful treatment of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) with tocilizumab: a case report. Eur J Rheumatol. 2015;2:35–6.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Vaitla PM, Radford PM, Tighe PJ, et al. Role of interleukin-6 in a patient with tumor necrosis factor receptor-associated periodic syndrome: assessment of outcomes following treatment with the anti-interleukin-6 receptor monoclonal antibody tocilizumab. Arthritis Rheum. 2011;63:1151–5.PubMedCrossRefGoogle Scholar
  79. 79.
    Coll RC, Robertson AA, Chae JJ, et al. A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases. Nat Med. 2015;21:248–55.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Youm YH, Nguyen KY, Grant RW, et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015;21:263–9.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Panayi GS, Corrigall VM. Immunoglobulin heavy-chain-binding protein (BiP): a stress protein that has the potential to be a novel therapy for rheumatoid arthritis. Biochem Soc Trans. 2014;42:1752–5.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Kirkham B, Chaabo K, Hall C, et al. Safety and patient response as indicated by biomarker changes to binding immunoglobulin protein in the phase I/IIA RAGULA clinical trial in rheumatoid arthritis. Rheumatology (Oxford). 2016;55:1993–2000.CrossRefGoogle Scholar
  83. 83.
    Qiu Q, Zheng Z, Chang L, et al. Toll-like receptor-mediated IRE1alpha activation as a therapeutic target for inflammatory arthritis. EMBO J. 2013;32:2477–90.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Izumi S, Nakasa T, Miyaki S, Ochi M. STF-083010, the inhibitor of ER stress transducer IRE-1, suppresses rheumatoid synovitis. Arthritis Rheum. 2015;67(Suppl 10).Google Scholar
  85. 85.
    Savic S, Ouboussad L, Dickie LJ, et al. TLR dependent XBP-1 activation induces an autocrine loop in rheumatoid arthritis synoviocytes. J Autoimmun. 2014;50:59–66.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    McDermott EM, Smillie DM, Powell RJ. Clinical spectrum of familial Hibernian fever: a 14-year follow-up study of the index case and extended family. Mayo Clin Proc. 1997;72:806–17.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Obici L, Merlini G. Amyloidosis in autoinflammatory syndromes. Autoimmun Rev. 2012;12:14–7.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Clinical Immunology and AllergySt James’s University HospitalLeedsUK
  2. 2.Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM)St James’s University HospitalLeedsUK

Personalised recommendations