Skip to main content
SpringerLink
Log in

Monogenic Periodic Fever Syndromes: Treatment Options for the Pediatric Patient

  • Review Article
  • Published:
Pediatric Drugs Aims and scope Submit manuscript

Abstract

Autoinflammatory diseases are disorders of the innate immune system characterized by uncontrolled inflammation. The most commonly encountered autoinflammatory diseases are the hereditary periodic fever syndromes, which present with fever and other features of the skin, serosal membranes, and musculoskeletal system. The main inherited (monogenic) periodic fever syndromes are familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), and hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD). Recent advances in our understanding of the molecular and pathophysiological basis of autoinflammatory diseases have provided new treatment strategies. Patients with periodic fever syndromes have clearly benefited from anti-interleukin (IL)-1 treatment. Colchicine is still the mainstay of FMF therapy, but IL-1 blockade is also effective if colchicine fails. Early diagnosis and effective treatment can prevent irreversible organ damage. The scope of pathogenic mutations and more targeted therapy for better management of these rare diseases remains to be defined.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease (*). Annu Rev Immunol. 2009;27:621–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. French FMFC. A candidate gene for familial Mediterranean fever. Nat Genet. 1997;17(1):25–31.

    Article  Google Scholar 

  3. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium. Cell. 1997;90(4):797–807.

  4. Berkun Y, Padeh S, Reichman B, Zaks N, Rabinovich E, Lidar M, et al. A single testing of serum amyloid a levels as a tool for diagnosis and treatment dilemmas in familial Mediterranean fever. Semin Arthritis Rheum. 2007;37(3):182–8.

    Article  CAS  PubMed  Google Scholar 

  5. Heller H, Sohar E, Gafni J, Heller J. Amyloidosis in familial Mediterranean fever. An independent genetically determined character. Arch Intern Med. 1961;107:539–50.

    Article  CAS  PubMed  Google Scholar 

  6. Meinzer U, Quartier P, Alexandra JF, Hentgen V, Retornaz F, Kone-Paut I. Interleukin-1 targeting drugs in familial Mediterranean fever: a case series and a review of the literature. Semin Arthritis Rheum. 2011;41(2):265–71.

    Article  CAS  PubMed  Google Scholar 

  7. Ozen S, Bilginer Y, Aktay Ayaz N, Calguneri M. Anti-interleukin 1 treatment for patients with familial Mediterranean fever resistant to colchicine. J Rheumatol. 2011;38(3):516–8.

    Article  PubMed  Google Scholar 

  8. Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle–Wells syndrome. Nat Genet. 2001;29(3):301–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Aksentijevich I, Putnam CD, Remmers EF, Mueller JL, Le J, Kolodner RD, et al. The clinical continuum of cryopyrinopathies: novel CIAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum. 2007;56(4):1273–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kuemmerle-Deschner JB, Ozen S, Kone-Paut I, Goldbach-Mansky R, Lachmann H, Blank N, et al. Diagnostic criteria for cryopyrin-associated periodic syndrome (CAPS). Ann Rheum Dis. 2016. doi:10.1136/annrheumdis-2016-209686.

    Google Scholar 

  11. McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW, Centola M, 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(1):133–44.

    Article  CAS  PubMed  Google Scholar 

  12. Aksentijevich I, Galon J, Soares M, Mansfield E, Hull K, Oh HH, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Feldmann J, Prieur AM, Quartier P, Berquin P, Certain S, Cortis E, et al. 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. 2002;71(1):198–203.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Park YH, Wood G, Kastner DL, Chae JJ. Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat Immunol 2016;17(8):914-21.

    Article  CAS  PubMed  Google Scholar 

  15. van der Hilst JC, Bodar EJ, Barron KS, Frenkel J, Drenth JP, van der Meer JW, et al. Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome. Medicine (Baltimore). 2008;87(6):301–10.

    Article  PubMed  Google Scholar 

  16. ter Haar NM, Oswald M, Jeyaratnam J, Anton J, Barron KS, Brogan PA, et al. Recommendations for the management of autoinflammatory diseases. Ann Rheum Dis. 2015;74(9):1636–44.

    Article  PubMed  Google Scholar 

  17. Ozen S, Demirkaya E, Erer B, Livneh A, Ben-Chetrit E, Giancane G, et al. EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis. 2016;75(4):644–51.

    Article  CAS  PubMed  Google Scholar 

  18. Jesus AA, Goldbach-Mansky R. IL-1 blockade in autoinflammatory syndromes. Annu Rev Med. 2014;65:223–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Goldfinger SE. Colchicine for familial Mediterranean fever. N Engl J Med. 1972;287(25):1302.

    CAS  PubMed  Google Scholar 

  20. Padeh S, Gerstein M, Berkun Y. Colchicine is a safe drug in children with familial Mediterranean fever. J Pediatr. 2012;161(6):1142–6.

    Article  CAS  PubMed  Google Scholar 

  21. Livneh A, Langevitz P. Diagnostic and treatment concerns in familial Mediterranean fever. Baillieres Best Pract Res Clin Rheumatol. 2000;14(3):477–98.

    Article  CAS  PubMed  Google Scholar 

  22. Majeed HA, Rawashdeh M, El-Shanti H, Qubain H, Khuri-Bulos N, Shahin HM. Familial Mediterranean fever in children: the expanded clinical profile. QJM. 1999;92(6):309–18.

    Article  CAS  PubMed  Google Scholar 

  23. Zemer D, Livneh A, Danon YL, Pras M, Sohar E. Long-term colchicine treatment in children with familial Mediterranean fever. Arthritis Rheum. 1991;34(8):973–7.

    Article  CAS  PubMed  Google Scholar 

  24. Zemer D, Pras M, Sohar E, Modan M, Cabili S, Gafni J. Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever. N Engl J Med. 1986;314(16):1001–5.

    Article  CAS  PubMed  Google Scholar 

  25. Shinar Y, Obici L, Aksentijevich I, Bennetts B, Austrup F, Ceccherini I, et al. Guidelines for the genetic diagnosis of hereditary recurrent fevers. Ann Rheum Dis. 2012;71(10):1599–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ben-Chetrit E, Backenroth R. Amyloidosis induced, end stage renal disease in patients with familial Mediterranean fever is highly associated with point mutations in the MEFV gene. Ann Rheum Dis. 2001;60(2):146–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cerquaglia C, Diaco M, Nucera G, La Regina M, Montalto M, Manna R. Pharmacological and clinical basis of treatment of Familial Mediterranean Fever (FMF) with colchicine or analogues: an update. Curr Drug Targets Inflamm Allergy. 2005;4(1):117–24.

    Article  CAS  PubMed  Google Scholar 

  28. Park H, Bourla AB, Kastner DL, Colbert RA, Siegel RM. Lighting the fires within: the cell biology of autoinflammatory diseases. Nat Rev Immunol. 2012;12(8):570–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Grattagliano I, Bonfrate L, Ruggiero V, Scaccianoce G, Palasciano G, Portincasa P. Novel therapeutics for the treatment of familial Mediterranean fever: from colchicine to biologics. Clin Pharmacol Ther. 2014;95(1):89–97.

    Article  CAS  PubMed  Google Scholar 

  30. van der Hilst J, Moutschen M, Messiaen PE, Lauwerys BR, Vanderschueren S. Efficacy of anti-IL-1 treatment in familial Mediterranean fever: a systematic review of the literature. Biologics. 2016;10:75–80.

    PubMed  PubMed Central  Google Scholar 

  31. Hashkes PJ, Spalding SJ, Giannini EH, Huang B, Johnson A, Park G, et al. Rilonacept for colchicine-resistant or -intolerant familial Mediterranean fever: a randomized trial. Ann Intern Med. 2012;157(8):533–41.

    Article  PubMed  Google Scholar 

  32. Topaloglu R, Batu ED, Orhan D, Ozen S, Besbas N. Anti-interleukin 1 treatment in secondary amyloidosis associated with autoinflammatory diseases. Pediatr Nephrol. 2016;31(4):633–40.

    Article  PubMed  Google Scholar 

  33. Benedetti FD, Anton J, Gattorno M, Lachmann H, Kone-Paut I, Ozen S. A phase III pivotal umbrella trial of canakinumab in patients with autoinflammatory periodic fever syndromes (colchicine resistant FMF, HIDS/MKD and TRAPS). Ann Rheum Dis. 2016;75(suppl 2):615–6.

    Google Scholar 

  34. Seyahi E, Ozdogan H, Celik S, Ugurlu S, Yazici H. Treatment options in colchicine resistant familial Mediterranean fever patients: thalidomide and etanercept as adjunctive agents. Clin Exp Rheumatol. 2006;24(5 Suppl 42):S99–103.

    CAS  PubMed  Google Scholar 

  35. Bilgen SA, Kilic L, Akdogan A, Kiraz S, Kalyoncu U, Karadag O, et al. Effects of anti-tumor necrosis factor agents for familial mediterranean fever patients with chronic arthritis and/or sacroiliitis who were resistant to colchicine treatment. J Clin Rheumatol. 2011;17(7):358–62.

    Article  PubMed  Google Scholar 

  36. Ter Haar N, Lachmann H, Ozen S, Woo P, Uziel Y, Modesto C, et al. Treatment of autoinflammatory diseases: results from the Eurofever Registry and a literature review. Ann Rheum Dis. 2013;72(5):678–85.

    Article  PubMed  Google Scholar 

  37. Koitschev A, Gramlich K, Hansmann S, Benseler S, Plontke SK, Koitschev C, et al. Progressive familial hearing loss in Muckle–Wells syndrome. Acta Otolaryngol. 2012;132(7):756–62.

    Article  CAS  PubMed  Google Scholar 

  38. Kuemmerle-Deschner JB, Koitschev A, Ummenhofer K, Hansmann S, Plontke SK, Koitschev C, et al. Hearing loss in Muckle–Wells syndrome. Arthritis Rheum. 2013;65(3):824–31.

    Article  CAS  PubMed  Google Scholar 

  39. Neven B, Marvillet I, Terrada C, Ferster A, Boddaert N, Couloignier V, et al. Long-term efficacy of the interleukin-1 receptor antagonist anakinra in ten patients with neonatal-onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome. Arthritis Rheum. 2010;62(1):258–67.

    Article  CAS  PubMed  Google Scholar 

  40. Sibley CH, Plass N, Snow J, Wiggs EA, Brewer CC, King KA, et al. Sustained response and prevention of damage progression in patients with neonatal-onset multisystem inflammatory disease treated with anakinra: a cohort study to determine three- and five-year outcomes. Arthritis Rheum. 2012;64(7):2375–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J, Rubin BI, et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med. 2006;355(6):581–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ross JB, Finlayson LA, Klotz PJ, Langley RG, Gaudet R, Thompson K, et al. Use of anakinra (Kineret) in the treatment of familial cold autoinflammatory syndrome with a 16-month follow-up. J Cutan Med Surg. 2008;12(1):8–16.

    CAS  PubMed  Google Scholar 

  43. Sibley CH, Chioato A, Felix S, Colin L, Chakraborty A, Plass N, et al. A 24-month open-label study of canakinumab in neonatal-onset multisystem inflammatory disease. Ann Rheum Dis. 2015;74(9):1714–9.

    Article  CAS  PubMed  Google Scholar 

  44. Rodriguez-Smith J, Lin YC, Li Tsai W, Kim H, Montealegre-Sanchez G, Chapelle D, et al. CSF cytokines correlate with aseptic meningitis and blood brain barrier function in neonatal-onset multisystem inflammatory disease (NOMID). Arthritis Rheumatol. 2017. doi:10.1002/art.40055.

    PubMed  Google Scholar 

  45. Kone-Paut I, Lachmann HJ, Kuemmerle-Deschner JB, Hachulla E, Leslie KS, Mouy R, et al. Sustained remission of symptoms and improved health-related quality of life in patients with cryopyrin-associated periodic syndrome treated with canakinumab: results of a double-blind placebo-controlled randomized withdrawal study. Arthritis Res Ther. 2011;13(6):R202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, Leslie KS, Hachulla E, Quartier P, et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med. 2009;360(23):2416–25.

    Article  CAS  PubMed  Google Scholar 

  47. Kuemmerle-Deschner JB, Hachulla E, Cartwright R, Hawkins PN, Tran TA, Bader-Meunier B, et al. Two-year results from an open-label, multicentre, phase III study evaluating the safety and efficacy of canakinumab in patients with cryopyrin-associated periodic syndrome across different severity phenotypes. Ann Rheum Dis. 2011;70(12):2095–102.

    Article  CAS  PubMed  Google Scholar 

  48. Kuemmerle-Deschner JB, Ramos E, Blank N, Roesler J, Felix SD, Jung T, et al. Canakinumab (ACZ885, a fully human IgG1 anti-IL-1beta mAb) induces sustained remission in pediatric patients with cryopyrin-associated periodic syndrome (CAPS). Arthritis Res Ther. 2011;13(1):R34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kuemmerle-Deschner JB, Hofer F, Endres T, Kortus-Goetze B, Blank N, Weissbarth-Riedel E, et al. Real-life effectiveness of canakinumab in cryopyrin-associated periodic syndrome. Rheumatology (Oxford). 2016;55(4):689–96.

    Article  PubMed  Google Scholar 

  50. Yokota S, Imagawa T, Nishikomori R, Takada H, Abrams K, Lheritier K, et al. Long-term safety and efficacy of canakinumab in cryopyrin-associated periodic syndrome: results from an open-label, phase III pivotal study in Japanese patients. Clin Exp Rheumatol. 2016 [Epub ahead of print, PMID 27974104].

  51. Hoffman HM, Throne ML, Amar NJ, Sebai M, Kivitz AJ, Kavanaugh A, et al. Efficacy and safety of rilonacept (interleukin-1 Trap) in patients with cryopyrin-associated periodic syndromes: results from two sequential placebo-controlled studies. Arthritis Rheum. 2008;58(8):2443–52.

    Article  CAS  PubMed  Google Scholar 

  52. Hoffman HM, Throne ML, Amar NJ, Cartwright RC, Kivitz AJ, Soo Y, et al. Long-term efficacy and safety profile of rilonacept in the treatment of cryopryin-associated periodic syndromes: results of a 72-week open-label extension study. Clin Ther. 2012;34(10):2091–103.

    Article  CAS  PubMed  Google Scholar 

  53. Ozen S, Bilginer Y. A clinical guide to autoinflammatory diseases: familial Mediterranean fever and next-of-kin. Nat Rev Rheumatol. 2014;10(3):135–47.

    Article  CAS  PubMed  Google Scholar 

  54. Bulua AC, Mogul DB, Aksentijevich I, Singh H, He DY, Muenz LR, 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(3):908–13.

    Article  CAS  PubMed  Google Scholar 

  55. Nedjai B, Hitman GA, Quillinan N, Coughlan RJ, Church L, McDermott MF, et al. Proinflammatory action of the antiinflammatory drug infliximab in tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum. 2009;60(2):619–25.

    Article  CAS  PubMed  Google Scholar 

  56. Gattorno M, Pelagatti MA, Meini A, Obici L, Barcellona R, Federici S, et al. Persistent efficacy of anakinra in patients with tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheum. 2008;58(5):1516–20.

    Article  CAS  PubMed  Google Scholar 

  57. Gattorno M, Obici L, Cattalini M, Tormey V, Abrams K, Davis N, 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(1):173–8.

    Article  PubMed  Google Scholar 

  58. Quillinan N, Mannion G, Mohammad A, Coughlan R, Dickie LJ, McDermott MF, et al. Failure of sustained response to etanercept and refractoriness to anakinra in patients with T50M TNF-receptor-associated periodic syndrome. Ann Rheum Dis. 2011;70(9):1692–3.

    Article  CAS  PubMed  Google Scholar 

  59. Torene R, Nirmala N, Obici L, Cattalini M, Tormey V, Caorsi R, et al. Canakinumab reverses overexpression of inflammatory response genes in tumour necrosis factor receptor-associated periodic syndrome. Ann Rheum Dis. 2017;76(1):303–9.

    Article  PubMed  Google Scholar 

  60. Vaitla PM, Radford PM, Tighe PJ, Powell RJ, McDermott EM, Todd I, 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(4):1151–5.

    Article  PubMed  Google Scholar 

  61. 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(1):35–6.

    Article  PubMed  PubMed Central  Google Scholar 

  62. Hosoya T, Mizoguchi F, Hasegawa H, Miura K, Koike R, Kubota T, et al. A case presenting with the clinical characteristics of tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) without TNFRSF1A mutations successfully treated with tocilizumab. Intern Med. 2015;54(16):2069–72.

    Article  CAS  PubMed  Google Scholar 

  63. Simon A, Drewe E, van der Meer JW, Powell RJ, Kelley RI, Stalenhoef AF, et al. Simvastatin treatment for inflammatory attacks of the hyperimmunoglobulinemia D and periodic fever syndrome. Clin Pharmacol Ther. 2004;75(5):476–83.

    Article  CAS  PubMed  Google Scholar 

  64. Vitale A, Rigante D, Lucherini OM, Caso F, Muscari I, Magnotti F, et al. Biological treatments: new weapons in the management of monogenic autoinflammatory disorders. Mediators Inflamm. 2013;2013:939847.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Bodar EJ, van der Hilst JC, Drenth JP, van der Meer JW, Simon A. Effect of etanercept and anakinra on inflammatory attacks in the hyper-IgD syndrome: introducing a vaccination provocation model. Neth J Med. 2005;63(7):260–4.

    CAS  PubMed  Google Scholar 

  66. Kostjukovits S, Kalliokoski L, Antila K, Korppi M. Treatment of hyperimmunoglobulinemia D syndrome with biologics in children: review of the literature and Finnish experience. Eur J Pediatr. 2015;174(6):707–14.

    Article  PubMed  Google Scholar 

  67. Galeotti C, Meinzer U, Quartier P, Rossi-Semerano L, Bader-Meunier B, Pillet P, et al. Efficacy of interleukin-1-targeting drugs in mevalonate kinase deficiency. Rheumatology (Oxford). 2012;51(10):1855–9.

    Article  CAS  PubMed  Google Scholar 

  68. Shendi HM, Devlin LA, Edgar JD. Interleukin 6 blockade for hyperimmunoglobulin D and periodic fever syndrome. J Clin Rheumatol. 2014;20(2):103–5.

    Article  PubMed  Google Scholar 

  69. Arkwright PD, Abinun M, Cant AJ. Mevalonic aciduria cured by bone marrow transplantation. N Engl J Med. 2007;357(13):1350.

    Article  CAS  PubMed  Google Scholar 

  70. Neven B, Valayannopoulos V, Quartier P, Blanche S, Prieur AM, Debre M, et al. Allogeneic bone marrow transplantation in mevalonic aciduria. N Engl J Med. 2007;356(26):2700–3.

    Article  CAS  PubMed  Google Scholar 

  71. Chaudhury S, Hormaza L, Mohammad S, Lokar J, Ekong U, Alonso EM, et al. Liver transplantation followed by allogeneic hematopoietic stem cell transplantation for atypical mevalonic aciduria. Am J Transplant. 2012;12(6):1627–31.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

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

    Seza Ozen & Selcan Demir

Authors
  1. Seza Ozen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Selcan Demir
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Seza Ozen.

Ethics declarations

Conflict of interest

Seza Ozen has previously received consultancy and speaker fees from Novartis, Sobi, and R-Pharma. Selcan Demir has no conflicts of interest.

Funding

No sources of funding were used to conduct this study or prepare this manuscript.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ozen, S., Demir, S. Monogenic Periodic Fever Syndromes: Treatment Options for the Pediatric Patient. Pediatr Drugs 19, 303–311 (2017). https://doi.org/10.1007/s40272-017-0232-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40272-017-0232-6

Keywords

Search

Navigation