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The Eurofever Project: towards better care for autoinflammatory diseases

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Abstract

Autoinflammatory diseases are a group of diseases characterized by inflammatory attacks. The monogenic forms of these diseases are also classified as the hereditary periodic fever syndromes. All are characterized by attacks of fever along with certain clinical features and high acute phase reactants. Most of these monogenic diseases are associated with hereditary disorders of the interleukin-1 pathway. The most common autoinflammatory disease is familial Mediterranean fever. The other rather common monogenic diseases are the tumor necrosis factor receptor-associated periodic syndrome, hyperimmunoglobulinemia D with periodic fever syndrome, and cryopyrin-associated periodic fever syndromes (CAPS). However, a number of multifactorial diseases such as Behçet disease are now also categorized under the topic of autoinflammatory diseases. The main features and management of these diseases will be reviewed. Finally, we introduce the “Eurofever” project, aimed to increase awareness and education for the aforementioned diseases. We conclude that the pediatrician should be aware of the features and management of autoinflammatory diseases since all present with fever—the most common symptom of pediatric practice.

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References

  1. Aksentijevich I, Masters SL, Ferguson PJ et al (2009) An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med 360:2426–2437

    Article  PubMed  CAS  Google Scholar 

  2. Bilginer Y, Ayaz NA, Ozen S (2010) Anti-IL-1 treatment for secondary amyloidosis in an adolescent with FMF and Behçet’s disease. Clin Rheumatol 29:209–210

    Article  PubMed  Google Scholar 

  3. Bodar EJ, van der Hilst JC, Drenth JP et al (2005) Effect of etanercept and anakinra on inflammatory attacks in the hyper-IgD syndrome: introducing a vaccination provocation model. Neth J Med 63:260–264

    PubMed  CAS  Google Scholar 

  4. Borghini S, Tassi S, Chiesa S et al (2010) Clinical presentation and pathogenesis of cold-induced autoinflammatory disease in a family with recurrence of a NLRP12 mutation. Arthritis Rheum (in press)

  5. Caorsi R, Pelagatti MA, Federici S et al (2010) Periodic fever, apthous stomatitis, pharyngitis and adenitis syndrome. Curr Opin Rheumatol 22:579–584

    Article  PubMed  Google Scholar 

  6. Chae JJ, Wood G, Masters SL et al (2006) The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1beta production. Proc Natl Acad Sci USA 103:9982–9987

    Article  PubMed  CAS  Google Scholar 

  7. Chae JJ, Wood G, Richard K et al (2008) The familial Mediterranean fever protein, pyrin, is cleaved by caspase-1 and activates NF-kappa B through its N-terminal fragment. Blood 112:1794–1803

    Article  PubMed  CAS  Google Scholar 

  8. Cortis E, de Benedetti F, Insalaco A et al (2004) Abnormal production of tumor necrosis factor (TNF)-alpha and clinical efficacy of the TNF inhibitor etanercept in a patient with PAPA syndrome [corrected]. J Pediatr 145:851–855

    Article  PubMed  Google Scholar 

  9. D’Osualdo A, Ferlito F, Prigione I et al (2006) Neutrophils from patients with TNFRSF1A mutations display resistance to tumor necrosis factor-induced apoptosis—pathogenetic and clinical implications. Arthritis Rheum 54:998–1008

    Article  PubMed  Google Scholar 

  10. Dierselhuis MP, Frenkel J, Wulffraat NM et al (2005) Anakinra for flares of pyogenic arthritis in PAPA syndrome. Rheumatology (Oxford) 44:406–408

    Article  CAS  Google Scholar 

  11. Drenth JP, Cuisset L, Grateau G et al (1999) Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group. Nat Genet 22:178–181

    Article  PubMed  CAS  Google Scholar 

  12. Drenth JP, Vonk AG, Simon A et al (2001) Limited efficacy of thalidomide in the treatment of febrile attacks of the hyper-IgD and periodic fever syndrome: a randomized, double-blind, placebo-controlled trial. J Pharmacol Exp Ther 298:1221–1226

    PubMed  CAS  Google Scholar 

  13. Drewe E, McDermott EM, Powell PT et al (2003) 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. Rheumatol 42:235–239

    Article  CAS  Google Scholar 

  14. Feldmann J, Prieur AM, Quartier P et al (2002) Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet 71:198–203

    Article  PubMed  CAS  Google Scholar 

  15. Frenkel J, Houten SM, Waterham HR et al (2001) Clinical and molecular variability in childhood periodic fever with hyperimmunoglobulinaemia D. Rheumatology (Oxford) 40:579–584

    Article  CAS  Google Scholar 

  16. Gattorno M, Caorsi R, Meini A et al (2009) Differentiating PFAPA syndrome from monogenic periodic fevers. Pediatrics 124:e721–e728

    Article  PubMed  Google Scholar 

  17. Gattorno M, Pelagatti MA, Meini A et al (2008) Persistent efficacy of anakinra in patients with tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum 58:1516–1520

    Article  PubMed  CAS  Google Scholar 

  18. Gattorno M, Sormani MP, D’Osualdo A et al (2008) A diagnostic score for molecular analysis of hereditary autoinflammatory syndromes with periodic fever in children. Arthritis Rheum 58:1823–1832

    Article  PubMed  CAS  Google Scholar 

  19. Girschick HJ, Zimmer C, Klaus G et al (2007) Chronic recurrent multifocal osteomyelitis: what is it and how should it be treated? Nat Clin Pract Rheumatol 3:733–738

    Article  PubMed  Google Scholar 

  20. Goldbach-Mansky R, Dailey NJ, Canna SW et al (2006) Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med 355:581–592

    Article  PubMed  CAS  Google Scholar 

  21. Hawkins PN, Lachmann HJ, McDermott MF (2003) Interleukin-1-receptor antagonist in the Muckle–Wells syndrome. N Engl J Med 348:2583–2584

    Article  PubMed  Google Scholar 

  22. Hofer M, Pillet P, Berg S et al (2008) PFAPA (periodic fever, aphtous stomatitis, pharyngitis and cervical adenitis) Syndrome registry: analysis of a cohort of 214 patients. Clin Exp Rheumatol 26:214

    Google Scholar 

  23. Hoffman HM, Mueller JL, Broide DH et al (2001) Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome. Nat Genet 29:301–305

    Article  PubMed  CAS  Google Scholar 

  24. Hoffman HM, Rosengren S, Boyle DL et al (2004) Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet 364:1779–1785

    Article  PubMed  CAS  Google Scholar 

  25. Hoffman HM, Throne ML, Amar NJ et al (2008) Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum 58:2443–2452

    Article  PubMed  CAS  Google Scholar 

  26. Houten SM, Romeijn GJ, Koster J et al (1999) Identification and characterization of three novel missense mutations in mevalonate kinase cDNA causing mevalonic aciduria, a disorder of isoprene biosynthesis. Hum Mol Genet 8:1523–1528

    Article  PubMed  CAS  Google Scholar 

  27. Hull KM, Shoham N, Chae JJ et al (2003) The expanding spectrum of systemic autoinflammatory disorders and their rheumatic manifestations. Curr Opin Rheumatol 15:61–69

    Article  PubMed  CAS  Google Scholar 

  28. International Study Group for Behcet’s Disease (1990) Criteria for diagnosis of Behcet’s disease. Lancet 335:1078–1080

    Google Scholar 

  29. Jacobelli S, Andre M, Alexandra JF et al (2007) Failure of anti-TNF therapy in TNF receptor 1-associated periodic syndrome (TRAPS). Rheumatology (Oxford) 46:1211–1212

    Article  CAS  Google Scholar 

  30. Jansson AF, Muller TH, Gliera L et al (2009) Clinical score for nonbacterial osteitis in children and adults. Arthritis Rheum 60:1152–1159

    Article  PubMed  Google Scholar 

  31. Jeru I, Duquesnoy P, Fernandes-Alnemri T et al (2008) Mutations in NALP12 cause hereditary periodic fever syndromes. Proc Natl Acad Sci USA 105:1614–1619

    Article  PubMed  CAS  Google Scholar 

  32. Kallinich T, Haffner D, Niehues T et al (2007) Colchicine use in children and adolescents with familial Mediterranean fever: literature review and consensus statement. Pediatrics 119:e474–e483

    Article  PubMed  Google Scholar 

  33. Kone-Paut I, Marce-Bello M, Shahram F et al (2011) Registries in rheumatological and musculoskeletal conditions. Paediatric Behcet’s disease: an international cohort study of 110 patients. One-year follow-up data. Rheumatology (Oxford) 50:184–188

    Article  Google Scholar 

  34. Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB et al (2009) Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med 360:2416–2425

    Article  PubMed  CAS  Google Scholar 

  35. Lindor NM, Arsenault TM, Solomon H et al (1997) A new autosomal dominant disorder of pyogenic sterile arthritis, pyoderma gangrenosum, and acne: PAPA syndrome. Mayo Clin Proc 72:611–615

    Article  PubMed  CAS  Google Scholar 

  36. Livneh A, Langevitz P, Zemer D et al (1997) Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 40:1879–1885

    Article  PubMed  CAS  Google Scholar 

  37. Majeed HA, Al-Tarawna M, El-Shanti H et al (2001) The syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia. Report of a new family and a review. Eur J Pediatr 160:705–710

    PubMed  CAS  Google Scholar 

  38. Marshall GS, Edwards KM, Lawton AR (1989) PFAPA syndrome. Pediatr Infect Dis J 8:658–659

    PubMed  CAS  Google Scholar 

  39. Masters SL, Simon A, Aksentijevich I et al (2009) Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease (*). Annu Rev Immunol 27:621–668

    Article  PubMed  CAS  Google Scholar 

  40. McDermott MF, Aksentijevich I, Galon J et al (1999) Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97:133–144

    Article  PubMed  CAS  Google Scholar 

  41. McGonagle D, McDermott MF (2006) A proposed classification of the immunological diseases. PLoS Med 3:e297

    Article  PubMed  Google Scholar 

  42. Miceli-Richard C, Lesage S, Rybojad M et al (2001) CARD15 mutations in Blau syndrome. Nat Genet 29:19–20

    Article  PubMed  CAS  Google Scholar 

  43. Miettunen PM, Wei X, Kaura D et al (2009) Dramatic pain relief and resolution of bone inflammation following pamidronate in 9 pediatric patients with persistent chronic recurrent multifocal osteomyelitis (CRMO). Pediatr Rheumatol Online J 7:2

    Article  PubMed  Google Scholar 

  44. Neven B, Callebaut I, Prieur AM et al (2004) Molecular basis of the spectral expression of CIAS1 mutations associated with phagocytic cell-mediated autoinflammatory disorders CINCA/NOMID, MWS, and FCU. Blood 103:2809–2815

    Article  PubMed  CAS  Google Scholar 

  45. Ozen S (2003) Familial Mediterranean fever: revisiting an ancient disease. Eur J Pediatr 162:449–454

    Article  PubMed  Google Scholar 

  46. Ozen S (2010) Pediatric onset Behcet disease. Curr Opin Rheumatol 22:585–589

    Article  PubMed  Google Scholar 

  47. Prieur AM, Griscelli C (1981) Arthropathy with rash, chronic meningitis, eye lesions, and mental retardation. J Pediatr 99:79–83

    Article  PubMed  CAS  Google Scholar 

  48. Rose CD, Wouters CH, Meiorin S et al (2006) Pediatric granulomatous arthritis: an international registry. Arthritis Rheum 54:3337–3344

    Article  PubMed  Google Scholar 

  49. Shoham NG, Centola M, Mansfield E et al (2003) Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway. Proc Natl Acad Sci USA 100:13501–13506

    Article  PubMed  CAS  Google Scholar 

  50. Simon A, Bodar EJ, van der Hilst JC et al (2004) Beneficial response to interleukin 1 receptor antagonist in traps. Am J Med 117:208–210

    Article  PubMed  CAS  Google Scholar 

  51. Simon A, Drewe E, van der Meer JW et al (2004) Simvastatin treatment for inflammatory attacks of the hyperimmunoglobulinemia D and periodic fever syndrome. Clin Pharmacol Ther 75:476–483

    Article  PubMed  CAS  Google Scholar 

  52. Takada K, Aksentijevich I, Mahadevan V et al (2003) Favorable preliminary experience with etanercept in two patients with the hyperimmunoglobulinemia D and periodic fever syndrome. Arthritis Rheum 48:2645–2651

    Article  PubMed  CAS  Google Scholar 

  53. The French FMF Consortium (1997) A candidate gene for familial Mediterranean fever. Nat Genet 17:25–31

    Article  Google Scholar 

  54. The International FMF Consortium (1997) Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 90:797–807

    Article  Google Scholar 

  55. Thomas KT, Feder HM, Lawton AR et al (1999) Periodic fever syndrome in children. J Pediatr 135:15–21

    Article  PubMed  CAS  Google Scholar 

  56. Tunca M, Akar S, Onen F et al (2005) Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine (Baltimore) 84:1–11

    Article  Google Scholar 

  57. van der Hilst JC, Bodar EJ, Barron KS et al (2008) Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome. Medicine (Baltimore) 87:301–310

    Article  Google Scholar 

  58. Veldhoen M, Hirota K, Christensen J et al (2009) Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells. J Exp Med 206:43–49

    Article  PubMed  CAS  Google Scholar 

  59. Yalcinkaya F, Ozen S, Ozcakar Z et al (2008) A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Clin Exp Rheumatol 26:178

    Google Scholar 

  60. Yasui K, Yashiro M, Tsuge M et al (2010) Thalidomide dramatically improves the symptoms of early-onset sarcoidosis/Blau syndrome: its possible action and mechanism. Arthritis Rheum 62:250–257

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This paper was supported by the Eurofever Project by the Executive Agency for Health and Consumers (EAHC, Project No. 2007332) and EUROTRAPS (FP7 project n. HEALTH-F2-2008-200923).

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Authors and Affiliations

  1. Department of Pediatrics, Faculty of Medicine, Hacettepe University, 06100, Ankara, Turkey

    Seza Ozen

  2. Department of Pediatrics, University of Utrecht, Utrecht, The Netherlands

    Joost Frenkel

  3. UO Pediatria II—Reumatologia, “G. Gaslini” Institute, Genoa, Italy

    Nicola Ruperto & Marco Gattorno

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  1. Seza Ozen
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  2. Joost Frenkel
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  3. Nicola Ruperto
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  4. Marco Gattorno
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Correspondence to Seza Ozen.

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Ozen, S., Frenkel, J., Ruperto, N. et al. The Eurofever Project: towards better care for autoinflammatory diseases. Eur J Pediatr 170, 445–452 (2011). https://doi.org/10.1007/s00431-011-1411-z

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  • DOI: https://doi.org/10.1007/s00431-011-1411-z

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