Familial Mediterranean Fever

  • Shai Padeh
  • Yelda Bilginer
  • Seza OzenEmail author


Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized by recurrent, sporadic, self-limited episodes of fever accompanied by peritonitis, pleuritis, arthritis, and/or erysipelas-like erythema. The disease is prevalent among populations surrounding the Mediterranean Sea, however, in recent years, more cases have been reported in countries not related or close to this region. The frequency of episodes varies from once every week to several times a year, and unlike the term “periodic disease”, the attacks are at random and not cyclic. A typical attack of FMF lasts 0.5–3 days, and between attacks patients are mostly asymptomatic. One of the devastating outcomes of FMF is the development of AA amyloidosis, which mostly affects the kidneys but may involve other organs. Since 1972, life-long prophylactic colchicine has been the treatment of choice for FMF, which reduces the number of acute attacks and prevents the development of amyloidosis. Several sets of diagnostic criteria and several severity scores have been proposed. The disease is caused by gain-of-function mutations in the MEFV gene, encoding pyrin, a protein which by binding to additional proteins form the pyrin inflammasome. Mutated pyrin is associated with activation of caspase-1 and the release of interleukin (IL)-1ß, resulting in inflammation. Unraveling the molecular mechanisms of FMF led to the understanding of the potential of IL1ß blockade as a novel treatment in patients with colchicine-resistant FMF. However, colchicine remains the main treatment of FMF.


Familial Mediterranean fever Pyrin Colchicine Interleukin 1 Treatment Canakinumab, anakinra, rilonacept Autoinflammatory disease 



Autoinflammatory Disease Damage Index


Autoinflammatory Disease Activity Index


Antineutrophil cytoplasmic antibodies


Apoptotic speck protein containing a caspase recruitment domain


Caspase recruitment domain


C-reactive protein


Erythrocyte sedimentation rate


European League Against Rheumatism


FMF Arthritis Vasculitis and Orphan Disease Research group


Familial Mediterranean fever




International Severity Score for FMF


Juvenile idiopathic arthritis




MEditerranean FeVer gene


Neutrophil extracellular traps


Pyrin-associated autoinflammation with neutrophilic dermatosis


Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis


Protracted febrile myalgia syndrome


Protein kinase N


Pediatric Rheumatology International Trials Organization


Pyrin domain


Serum amyloid A


Single Hub and Access point for paediatric Rheumatology in Europe


Tumor necrosis factor


Tumor necrosis factor receptor-associated periodic syndrome


Tripartite motif


  1. 1.
    Adwan MH. A brief history of familial Mediterranean fever. Saudi Med J. 2015;36:1126–7.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Siegal S. Benign paroxysmal peritonitis (benign paroxysmal peritonitis). Ann Intern Med. 1945;23:1–21.CrossRefGoogle Scholar
  3. 3.
    Reimann HA. Periodic disease; a probable syndrome including periodic fever, benign paroxysmal peritonitis, cyclic neutropenia and intermittent arthralgia. J Am Med Assoc. 1948;136:239–44.PubMedCrossRefGoogle Scholar
  4. 4.
    Reimann HA. Perplexities of a periodic entity. JAMA. 1964;190:241.PubMedGoogle Scholar
  5. 5.
    Cattan D. Familial Mediterranean fever: is low mortality from tuberculosis a specific advantage for MEFV mutations carriers? Mortality from tuberculosis among Muslims, Jewish, French, Italian and Maltese patients in Tunis (Tunisia) in the first half of the 20th century. Clin Exp Rheumatol. 2003;21(Suppl 30):S53–4; author reply S54.PubMedGoogle Scholar
  6. 6.
    Heller H, Sohar E, Sherf L. Familial Mediterranean fever. AMA Arch Intern Med. 1958;102:50–71.PubMedCrossRefGoogle Scholar
  7. 7.
    Munzer D. Periodic peritonitis. Analysis of 19 cases. Dis Colon Rectum. 1966;9:168–72.PubMedCrossRefGoogle Scholar
  8. 8.
    Sohar E, Gafni J, Pras M, Heller H. Familial Mediterranean fever. A survey of 470 cases and review of the literature. Am J Med. 1967;43(2):227–53.CrossRefGoogle Scholar
  9. 9.
    Goldfinger SE. Colchicine for familial Mediterranean fever. N Engl J Med. 1972;287(25):1302.PubMedGoogle Scholar
  10. 10.
    Aral O, Ozdogan H, Yazici H. The other physician behind the use of colchicine for the treatment of familial Mediterranean fever. Clin Exp Rheumatol. 2001;19(Suppl 24):S13–4.PubMedGoogle Scholar
  11. 11.
    Zemer D, Revach M, Pras M, et al. A controlled trial of colchicine in preventing attacks of familial mediterranean fever. N Engl J Med. 1974;291:932–4.PubMedCrossRefGoogle Scholar
  12. 12.
    Goldstein RC, Schwabe AD. Prophylactic colchicine therapy in familial Mediterranean fever. A controlled, double-blind study. Ann Intern Med. 1974;81:792–4.PubMedCrossRefGoogle Scholar
  13. 13.
    French FMFC. A candidate gene for familial Mediterranean fever. Nat Genet. 1997;17:25–31.CrossRefGoogle Scholar
  14. 14.
    The International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell. 1997;90:797–807.CrossRefGoogle Scholar
  15. 15.
    Milhavet F, Cuisset L, Hoffman HM, et al. The infevers autoinflammatory mutation online registry: update with new genes and functions. Hum Mutat. 2008;29(6):803–8.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Martinon F, Burns K, Tschopp J. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002;10:417–26.CrossRefGoogle Scholar
  17. 17.
    Papin S, Cuenin S, Agostini L, et al. The SPRY domain of Pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1beta processing. Cell Death Differ. 2007;14(8):1457–66.PubMedCrossRefGoogle Scholar
  18. 18.
    Gao W, Yang J, Liu W, Wang Y, Shao F. Site-specific phosphorylation and microtubule dynamics control Pyrin inflammasome activation. Proc Natl Acad Sci U S A. 2016;113(33):E4857–66.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Xu H, Yang J, Gao W, et al. Innate immune sensing of bacterial modifications of Rho GTPases by the Pyrin inflammasome. Nature. 2014;513(7517):237–41.CrossRefGoogle Scholar
  20. 20.
    Shohat M, Halpern GJ. Familial Mediterranean fever—a review. Genet Med. 2011;13:487–98.PubMedCrossRefGoogle Scholar
  21. 21.
    Shohat M. Familial Mediterranean fever. In: Adam MP, et al., editors. GeneReviews((R)). Seattle, WA: University of Washington, Seattle; 1993.Google Scholar
  22. 22.
    Camus D, Shinar Y, Aamar S, et al. ‘Silent’ carriage of two familial Mediterranean fever gene mutations in large families with only a single identified patient. Clin Genet. 2012;82(3):288–91.PubMedCrossRefGoogle Scholar
  23. 23.
    Hentgen V, Grateau G, Kone-Paut I, et al. Evidence-based recommendations for the practical management of Familial Mediterranean fever. Semin Arthritis Rheum. 2013;43:387–91.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    La Regina M, Nucera G, Diaco M, et al. Familial Mediterranean fever is no longer a rare disease in Italy. Eur J Hum Genet. 2003;11(1):50–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Balci B, Tinaztepe K, Yilmaz E, et al. MEFV gene mutations in familial Mediterranean fever phenotype II patients with renal amyloidosis in childhood: a retrospective clinicopathological and molecular study. Nephrol Dial Transplant. 2002;17(11):1921–3.PubMedCrossRefGoogle Scholar
  26. 26.
    Touitou I, Sarkisian T, Medlej-Hashim M, et al. Country as the primary risk factor for renal amyloidosis in familial Mediterranean fever. Arthritis Rheum. 2007;56(5):1706–12.PubMedCrossRefGoogle Scholar
  27. 27.
    Saatci U, Ozen S, Ozdemir S, et al. Familial Mediterranean fever in children: report of a large series and discussion of the risk and prognostic factors of amyloidosis. Eur J Pediatr. 1997;156(8):619–23.PubMedCrossRefGoogle Scholar
  28. 28.
    Lidar M, Livneh A. Familial Mediterranean fever: clinical, molecular and management advancements. Neth J Med. 2007;65:318–24.PubMedGoogle Scholar
  29. 29.
    Ben-Chetrit E, Touitou I. Familial mediterranean fever in the world. Arthritis Rheum. 2009;61:1447–53.PubMedCrossRefGoogle Scholar
  30. 30.
    Ozen S, Karaaslan Y, Ozdemir O, et al. Prevalence of juvenile chronic arthritis and familial Mediterranean fever in Turkey: a field study. J Rheumatol. 1998;25(12):2445–9.PubMedGoogle Scholar
  31. 31.
    Daniels M, Shohat T, Brenner-Ullman A, Shohat M. Familial Mediterranean fever: high gene frequency among the non-Ashkenazic and Ashkenazic Jewish populations in Israel. Am J Med Genet. 1995;55(3):311–4.PubMedCrossRefGoogle Scholar
  32. 32.
    Touitou I. The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet. 2001;9:473–83.PubMedCrossRefGoogle Scholar
  33. 33.
    Tunca M, Akar S, Onen F, et al. Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine (Baltimore). 2005;84(1):1–11.CrossRefGoogle Scholar
  34. 34.
    Cobankara V, Fidan G, Türk T, Zencir M, Colakoglu M, Ozen S. The prevalence of familial Mediterranean fever in the Turkish province of Denizli: a field study with a zero patient design. Clin Exp Rheumatol. 2004;22(4 Suppl 34):S27–30.PubMedGoogle Scholar
  35. 35.
    Sarkisian T, Ajrapetian H, Beglarian A, Shahsuvarian G, Egiazarian A. Familial Mediterranean fever in Armenian population. Georgian Med News. 2008;(156):105–11.Google Scholar
  36. 36.
    Gershoni-Baruch R, Shinawi M, Leah K, Badarnah K, Brik R. Familial Mediterranean fever: prevalence, penetrance and genetic drift. Eur J Hum Genet. 2001;9(8):634–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Buades J, Ben-Chetrit E, Levy M. Familial Mediterranean fever in the “Chuetas” of Mallorca—origin in inquisition? Isr J Med Sci. 1995;31(8):497–9.PubMedGoogle Scholar
  38. 38.
    Belmahi L, Sefiani A, Fouveau C, et al. Prevalence and distribution of MEFV mutations among Arabs from the Maghreb patients suffering from familial Mediterranean fever. C R Biol. 2006;329(2):71–4.PubMedCrossRefGoogle Scholar
  39. 39.
    Fragouli E, Eliopoulos E, Petraki E, et al. Familial Mediterranean fever in crete: a genetic and structural biological approach in a population of ‘intermediate risk. Clin Genet. 2008;73:152–9.PubMedCrossRefGoogle Scholar
  40. 40.
    Giaglis S, Papadopoulos V, Kambas K, et al. MEFV alterations and population genetics analysis in a large cohort of Greek patients with familial Mediterranean fever. Clin Genet. 2007;71(5):458–67.PubMedCrossRefGoogle Scholar
  41. 41.
    Migita K, Izumi Y, Jiuchi Y, et al. Familial Mediterranean fever is no longer a rare disease in Japan. Arthritis Res Ther. 2016;18:175.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Ghosh K. Familial Mediterranean fever: an unusual disease enlightening the inflammation biology. Indian J Hum Genet. 2014;20(1):1–3.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Chae JJ, Wood G, Richard K, et al. The familial Mediterranean fever protein, pyrin, is cleaved by caspase-1 and activates NF-kappaB through its N-terminal fragment. Blood. 2008;112(5):1794–803.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Touitou I, Lesage S, McDermott M, et al. Infevers: an evolving mutation database for auto-inflammatory syndromes. Hum Mutat. 2004;24(3):194–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Shinar Y, Livneh A, Langevitz P, et al. Genotype-phenotype assessment of common genotypes among patients with familial Mediterranean fever. J Rheumatol. 2000;27(7):1703–7.PubMedGoogle Scholar
  46. 46.
    Papadopoulos VP, Giaglis S, Mitroulis I, Ritis K. The population genetics of familial mediterranean fever: a meta-analysis study. Ann Hum Genet. 2008;72:752–61.PubMedCrossRefGoogle Scholar
  47. 47.
    Zaks N, Shinar Y, Padeh S, et al. Analysis of the three most common MEFV mutations in 412 patients with familial Mediterranean fever. Isr Med Assoc J. 2003;5(8):585–8.PubMedGoogle Scholar
  48. 48.
    Tchernitchko D, Legendre M, Cazeneuve C, Delahaye A, Niel F, Amselem S. The E148Q MEFV allele is not implicated in the development of familial Mediterranean fever. Hum Mutat. 2003;22(4):339–40.PubMedCrossRefGoogle Scholar
  49. 49.
    Chaabouni HB, Ksantini M, M’rad R, et al. MEFV mutations in Tunisian patients suffering from familial Mediterranean fever. Semin Arthritis Rheum. 2007;36(6):397–401.PubMedCrossRefGoogle Scholar
  50. 50.
    Booth DR, Gillmore JD, Lachmann HJ, et al. The genetic basis of autosomal dominant familial Mediterranean fever. QJM. 2000;93(4):217–21.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Makiko Tajika MA, Kobayashi K, Fujimaki K, Agematsu K, Umeda Y. Familial Mediterranean fever E148Q/P369S/R408Q exon 3 variant with severe abdominal pain and PFAPA-like symptoms. J Clin Case Rep. 2016;6:790.Google Scholar
  52. 52.
    Ryan JG, Masters SL, Booty MG, et al. Clinical features and functional significance of the P369S/R408Q variant in pyrin, the familial Mediterranean fever protein. Ann Rheum Dis. 2010;69(7):1383–8.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Moghaddas F, Llamas R, De Nardo D, et al. A novel pyrin-associated autoinflammation with neutrophilic dermatosis mutation further defines 14-3-3 binding of pyrin and distinction to familial Mediterranean fever. Ann Rheum Dis. 2017;76:2085–94.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Portincasa P, Scaccianoce G, Palasciano G. Familial mediterranean fever: a fascinating model of inherited autoinflammatory disorder. Eur J Clin Investig. 2013;43:1314–27.CrossRefGoogle Scholar
  55. 55.
    Bar-Eli M, Ehrenfeld M, Levy M, Gallily R, Eliakim M. Leukocyte chemotaxis in recurrent polyserositis (familial Mediterranean fever). Am J Med Sci. 1981;281(1):15–8.PubMedCrossRefGoogle Scholar
  56. 56.
    Apostolidou E, Skendros P, Kambas K, et al. Neutrophil extracellular traps regulate IL-1β-mediated inflammation in familial Mediterranean fever. Ann Rheum Dis. 2016;75:269–77.PubMedCrossRefGoogle Scholar
  57. 57.
    Manukyan G, Aminov R, Hakobyan G, Davtyan T. Accelerated apoptosis of neutrophils in familial Mediterranean Fever. Front Immunol. 2015;6:239.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Omenetti A, Carta S, Delfino L, Martini A, Gattorno M, Rubartelli A. Increased NLRP3-dependent interleukin 1β secretion in patients with familial Mediterranean fever: correlation with MEFV genotype. Ann Rheum Dis. 2014;73:462–9.PubMedCrossRefGoogle Scholar
  59. 59.
    Gang N, Drenth JP, Langevitz P, et al. Activation of the cytokine network in familial Mediterranean fever. J Rheumatol. 1999;26(4):890–7.PubMedGoogle Scholar
  60. 60.
    Yildirim K, Uzkeser H, Keles M, et al. Relationship between serum interleukin-1beta levels and acute phase response proteins in patients with familial Mediterranean fever. Biochem Med (Zagreb). 2012;22(1):109–13.CrossRefGoogle Scholar
  61. 61.
    Gohar F, Orak B, Kallinich T, et al. Correlation of secretory activity of neutrophils with genotype in patients with familial Mediterranean fever. Arthritis Rheumatol. 2016;68:3010–22.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Koga T, Migita K, Sato S, et al. Multiple serum cytokine profiling to identify combinational diagnostic biomarkers in attacks of familial Mediterranean fever. Medicine (Baltimore). 2016;95:e3449.CrossRefGoogle Scholar
  63. 63.
    Weinert C, Morger D, Djekic A, Grütter MG, Mittl PR. Crystal structure of TRIM20 C-terminal coiled-coil/B30.2 fragment: implications for the recognition of higher order oligomers. Sci Rep. 2015;5:10819.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Martinon F, Hofmann K, Tschopp J. The pyrin domain: a possible member of the death domain-fold family implicated in apoptosis and inflammation. Curr Biol. 2001;11:R118–20.CrossRefGoogle Scholar
  65. 65.
    Gumucio DL, Diaz A, Schaner P, et al. Fire and ICE: the role of pyrin domain-containing proteins in inflammation and apoptosis. Clin Exp Rheumatol. 2002;20(4 Suppl 26):S45–53.Google Scholar
  66. 66.
    Kohl A, Grutter MG. Fire and death: the pyrin domain joins the death-domain superfamily. C R Biol. 2004;327:1077–86.PubMedCrossRefGoogle Scholar
  67. 67.
    Richards N, Schaner P, Diaz A, et al. Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis. J Biol Chem. 2001;276(42):39320–9.CrossRefGoogle Scholar
  68. 68.
    Yu JW, Wu J, Zhang Z, et al. Cryopyrin and pyrin activate caspase-1, but not NF-kappaB, via ASC oligomerization. Cell Death Differ. 2006;13(2):236–49.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Yu JW, Fernandes-Alnemri T, Datta P, et al. Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants. Mol Cell. 2007;28(2):214–27.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Seshadri S, Duncan MD, Hart JM, Gavrilin MA, Wewers MD. Pyrin levels in human monocytes and monocyte-derived macrophages regulate IL-1beta processing and release. J Immunol. 2007;179(2):1274–81.PubMedCrossRefGoogle Scholar
  71. 71.
    Gavrilin MA, Abdelaziz DH, Mostafa M, et al. Activation of the pyrin inflammasome by intracellular Burkholderia cenocepacia. J Immunol. 2012;188(7):3469–77.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Chae JJ, Wood G, Masters SL, et al. 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 U S A. 2006;103(26):9982–7.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Hesker PR, Nguyen M, Kovarova M, Ting JP, Koller BH. Genetic loss of murine pyrin, the familial Mediterranean fever protein, increases interleukin-1β levels. PLoS One. 2012;7:e51105.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Chae JJ, Cho YH, Lee GS, et al. Gain-of-function Pyrin mutations induce NLRP3 protein-independent interleukin-1β activation and severe autoinflammation in mice. Immunity. 2011;34:755–68.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Aubert DF, Xu H, Yang J, et al. A burkholderia Type VI effector deamidates Rho GTPases to activate the pyrin inflammasome and trigger inflammation. Cell Host Microbe. 2016;19(5):664–74.PubMedCrossRefGoogle Scholar
  77. 77.
    Mansfield E, Chae JJ, Komarow HD, et al. The familial Mediterranean fever protein, pyrin, associates with microtubules and colocalizes with actin filaments. Blood. 2001;98(3):851–9.PubMedCrossRefGoogle Scholar
  78. 78.
    Waite AL, Schaner P, Hu C, et al. Pyrin and ASC co-localize to cellular sites that are rich in polymerizing actin. Exp Biol Med (Maywood). 2009;234(1):40–52.CrossRefGoogle Scholar
  79. 79.
    Booty MG, Chae JJ, Masters SL, et al. Familial Mediterranean fever with a single MEFV mutation: where is the second hit? Arthritis Rheum. 2009;60(6):1851–61.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Marek-Yagel D, Berkun Y, Padeh S, et al. Clinical disease among patients heterozygous for familial Mediterranean fever. Arthritis Rheum. 2009;60(6):1862–6.PubMedCrossRefGoogle Scholar
  81. 81.
    Ozen S. Changing concepts in familial Mediterranean fever: is it possible to have an autosomal-recessive disease with only one mutation? Arthritis Rheum. 2009;60(6):1575–7.PubMedCrossRefGoogle Scholar
  82. 82.
    Aldea A, Campistol JM, Arostegui JI, et al. A severe autosomal-dominant periodic inflammatory disorder with renal AA amyloidosis and colchicine resistance associated to the MEFV H478Y variant in a Spanish kindred: an unusual familial Mediterranean fever phenotype or another MEFV-associated periodic inflammatory disorder? Am J Med Genet A. 2004;124A(1):67–73.PubMedCrossRefGoogle Scholar
  83. 83.
    Moradian MM, Sarkisian T, Ajrapetyan H, Avanesian N. Genotype-phenotype studies in a large cohort of Armenian patients with familial Mediterranean fever suggest clinical disease with heterozygous MEFV mutations. J Hum Genet. 2010;55(6):389–93.PubMedCrossRefGoogle Scholar
  84. 84.
    Rowczenio DM, Iancu DS, Trojer H, et al. Autosomal dominant familial Mediterranean fever in Northern European Caucasians associated with deletion of p.M694 residue-a case series and genetic exploration. Rheumatology (Oxford). 2017;56(2):209–13.CrossRefGoogle Scholar
  85. 85.
    Stoffels M, Szperl A, Simon A, et al. MEFV mutations affecting pyrin amino acid 577 cause autosomal dominant autoinflammatory disease. Ann Rheum Dis. 2014;73(2):455–61.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Ross JJ. Goats, germs, and fever: are the pyrin mutations responsible for familial Mediterranean fever protective against Brucellosis? Med Hypotheses. 2007;68:499–501.PubMedCrossRefGoogle Scholar
  87. 87.
    Kalyoncu M, Acar BC, Cakar N, et al. Are carriers for MEFV mutations “healthy”? Clin Exp Rheumatol. 2006;24(5 Suppl 42):S120–2.PubMedGoogle Scholar
  88. 88.
    Ben-Chetrit E, Levy M. Familial Mediterranean fever. Lancet. 1998;351:659–64.PubMedCrossRefGoogle Scholar
  89. 89.
    Padeh S, Berkun Y. Familial Mediterranean fever. Curr Opin Rheumatol. 2016;28:523–9.PubMedCrossRefGoogle Scholar
  90. 90.
    Padeh S, Livneh A, Pras E, et al. Familial Mediterranean fever in the first two years of life: a unique phenotype of disease in evolution. J Pediatr. 2010;156:985–9.PubMedCrossRefGoogle Scholar
  91. 91.
    Federici S, Sormani MP, Ozen S, et al. Evidence-based provisional clinical classification criteria for autoinflammatory periodic fevers. Ann Rheum Dis. 2015;74(5):799–805.CrossRefGoogle Scholar
  92. 92.
    Langevitz P, Livneh A, Zemer D, Shemer J, Pras M. Seronegative spondyloarthropathy in familial Mediterranean fever. Semin Arthritis Rheum. 1997;27(2):67–72.PubMedCrossRefGoogle Scholar
  93. 93.
    Kasifoglu T, Calişir C, Cansu DU, Korkmaz C. The frequency of sacroiliitis in familial Mediterranean fever and the role of HLA-B27 and MEFV mutations in the development of sacroiliitis. Clin Rheumatol. 2009;28(1):41–6.PubMedCrossRefGoogle Scholar
  94. 94.
    Langevitz P, Zemer D, Livneh A, Shemer J, Pras M. Protracted febrile myalgia in patients with familial Mediterranean fever. J Rheumatol. 1994;21(9):1708–9.PubMedGoogle Scholar
  95. 95.
    Ozen S, Demirkaya E, Erer B, et al. EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis. 2016;75(4):644–51.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Alayli G, Durmus D, Ozkaya O, Sen HE, Genc G, Kuru O. Frequency of juvenile fibromyalgia syndrome in children with familial Mediterranean fever: effects on depression and quality of life. Clin Exp Rheumatol. 2011;29(6 Suppl 69):S127–32.PubMedPubMedCentralGoogle Scholar
  97. 97.
    Ben-Zvi I, Livneh A. Chronic inflammation in FMF: markers, risk factors, outcomes and therapy. Nat Rev Rheumatol. 2011;7:105–12.PubMedCrossRefGoogle Scholar
  98. 98.
    Duzova A, Ozaltin F, Ozon A, et al. Bone mineral density in children with familial Mediterranean fever. Clin Rheumatol. 2004;23(3):230–4.PubMedCrossRefGoogle Scholar
  99. 99.
    Livneh A, Madgar I, Langevitz P, Zemer D. Recurrent episodes of acute scrotum with ischemic testicular necrosis in a patient with familial Mediterranean fever. J Urol. 1994;151(2):431–2.PubMedCrossRefGoogle Scholar
  100. 100.
    Gedalia A, Zamir S. Neurologic manifestations in familial Mediterranean fever. Pediatr Neurol. 1993;9:301–2.PubMedCrossRefGoogle Scholar
  101. 101.
    Gok F, Sari E, Erdogan O, Altun D, Babacan O. Familial Mediterranean fever and IgA nephropathy: case report and review of the literature. Clin Nephrol. 2008;70(1):62–4.PubMedCrossRefGoogle Scholar
  102. 102.
    Yalcinkaya F, Ozçakar ZB, Kasapçopur O, et al. Prevalence of the MEFV gene mutations in childhood polyarteritis nodosa. J Pediatr. 2007;151(6):675–8.PubMedCrossRefGoogle Scholar
  103. 103.
    Ozdogan H, Arisoy N, Kasapçapur O, et al. Vasculitis in familial Mediterranean fever. J Rheumatol. 1997;24(2):323–7.PubMedGoogle Scholar
  104. 104.
    Touitou I, Magne X, Molinari N, et al. MEFV mutations in Behcet’s disease. Hum Mutat. 2000;16(3):271–2.PubMedCrossRefGoogle Scholar
  105. 105.
    Ayaz NA, Ozen S, Bilginer Y, et al. MEFV mutations in systemic onset juvenile idiopathic arthritis. Rheumatology (Oxford). 2009;48(1):23–5.CrossRefGoogle Scholar
  106. 106.
    Batu ED, Kara Eroğlu F, Tsoukas P, et al. Periodic fever, aphthosis, pharyngitis, and adenitis syndrome: analysis of patients from two geographic areas. Arthritis Care Res (Hoboken). 2016;68(12):1859–65.CrossRefGoogle Scholar
  107. 107.
    van der Hilst JC, Simon A, Drenth JP. Hereditary periodic fever and reactive amyloidosis. Clin Exp Med. 2005;5:87–98.PubMedCrossRefGoogle Scholar
  108. 108.
    Atoyan S, Hayrapetyan H, Sarkisian T, Ben-Chetrit E. MEFV and SAA1 genotype associations with clinical features of familial Mediterranean fever and amyloidosis in Armenia. Clin Exp Rheumatol. 2016;34(6 Suppl 102):72–6.PubMedGoogle Scholar
  109. 109.
    Migita K, Agematsu K, Masumoto J, et al. The contribution of SAA1 polymorphisms to Familial Mediterranean fever susceptibility in the Japanese population. PLoS One. 2013;8:e55227.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Niemi K, Teirilä L, Lappalainen J, et al. Serum amyloid A activates the NLRP3 inflammasome via P2X7 receptor and a cathepsin B-sensitive pathway. J Immunol. 2011;186(11):6119–28.PubMedCrossRefGoogle Scholar
  111. 111.
    Lachmann HJ, Sengül B, Yavuzşen TU, et al. Clinical and subclinical inflammation in patients with familial Mediterranean fever and in heterozygous carriers of MEFV mutations. Rheumatology (Oxford). 2006;45(6):746–50.CrossRefGoogle Scholar
  112. 112.
    Duzova A, Bakkaloglu A, Besbas N, et al. Role of A-SAA in monitoring subclinical inflammation and in colchicine dosage in familial Mediterranean fever. Clin Exp Rheumatol. 2003;21(4):509–14.PubMedGoogle Scholar
  113. 113.
    Stankovic Stojanovic K, Hentgen V, Fellahi S, et al. Concordance between CRP and SAA in familial Mediterranean fever during attack-free period: a study of 218 patients. Clin Biochem. 2017;50(4–5):206–9.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Kallinich T, Wittkowski H, Keitzer R, Roth J, Foell D. Neutrophil-derived S100A12 as novel biomarker of inflammation in familial Mediterranean fever. Ann Rheum Dis. 2010;69(4):677–82.PubMedCrossRefGoogle Scholar
  115. 115.
    Livneh A, Langevitz P, Zemer D, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. 1997;40(10):1879–85.CrossRefGoogle Scholar
  116. 116.
    Yalcinkaya F, Ozen S, Ozçakar ZB, et al. A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology (Oxford). 2009;48(4):395–8.CrossRefGoogle Scholar
  117. 117.
    Demirkaya E, Saglam C, Turker T, et al. Performance of different diagnostic criteria for familial Mediterranean fever in children with periodic fevers: results from a Multicenter International Registry. J Rheumatol. 2016;43(1):154–60.CrossRefGoogle Scholar
  118. 118.
    Shinar Y, Obici L, Aksentijevich I, et al. Guidelines for the genetic diagnosis of hereditary recurrent fevers. Ann Rheum Dis. 2012;71(10):1599–605.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Ozen S, Bilginer Y. A clinical guide to autoinflammatory diseases: familial Mediterranean fever and next-of-kin. Nat Rev Rheumatol. 2014;10:135–47.PubMedCrossRefGoogle Scholar
  120. 120.
    Giancane G, Ter Haar NM, Wulffraat N, et al. Evidence-based recommendations for genetic diagnosis of familial Mediterranean fever. Ann Rheum Dis. 2015;74(4):635–41.PubMedPubMedCentralCrossRefGoogle Scholar
  121. 121.
    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.CrossRefGoogle Scholar
  122. 122.
    Chappey ON, Niel E, Wautier JL, et al. Colchicine disposition in human leukocytes after single and multiple oral administration. Clin Pharmacol Ther. 1993;54(4):360–7.PubMedCrossRefGoogle Scholar
  123. 123.
    Klimecki WT, Futscher BW, Grogan TM, Dalton WS. P-glycoprotein expression and function in circulating blood cells from normal volunteers. Blood. 1994;83(9):2451–8.PubMedGoogle Scholar
  124. 124.
    Ben-Chetrit E, Levy M. Does the lack of the P-glycoprotein efflux pump in neutrophils explain the efficacy of colchicine in familial Mediterranean fever and other inflammatory diseases? Med Hypotheses. 1998;51:377–80.PubMedCrossRefGoogle Scholar
  125. 125.
    Dinarello CA. Novel targets for interleukin 18 binding protein. Ann Rheum Dis. 2001;60(Suppl 3):iii18–24.PubMedPubMedCentralGoogle Scholar
  126. 126.
    Ben-Chetrit E, Bergmann S, Sood R. Mechanism of the anti-inflammatory effect of colchicine in rheumatic diseases: a possible new outlook through microarray analysis. Rheumatology (Oxford). 2006;45:274–82.CrossRefGoogle Scholar
  127. 127.
    Leung YY, Yao Hui LL, Kraus VB. Colchicine—update on mechanisms of action and therapeutic uses. Semin Arthritis Rheum. 2015;45:341–50.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Ozen S, Kone-Paut I, Gul A. Colchicine resistance and intolerance in familial mediterranean fever: definition, causes, and alternative treatments. Semin Arthritis Rheum. 2017;47:115–20.PubMedCrossRefGoogle Scholar
  129. 129.
    Misawa T, Takahama M, Kozaki T, et al. Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat Immunol. 2013;14(5):454–60.PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Van Gorp H, Saavedra PH, de Vasconcelos NM, et al. Familial Mediterranean fever mutations lift the obligatory requirement for microtubules in Pyrin inflammasome activation. Proc Natl Acad Sci U S A. 2016;113(50):14384–9.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Krendel M, Zenke FT, Bokoch GM. Nucleotide exchange factor GEF-H1 mediates cross-talk between microtubules and the actin cytoskeleton. Nat Cell Biol. 2002;4:294–301.PubMedCrossRefGoogle Scholar
  132. 132.
    Berkun Y, Wason S, Brik R, et al. Pharmacokinetics of colchicine in pediatric and adult patients with familial Mediterranean fever. Int J Immunopathol Pharmacol. 2012;25(4):1121–30.PubMedCrossRefGoogle Scholar
  133. 133.
    Polat A, Acikel C, Sozeri B, et al. Comparison of the efficacy of once- and twice-daily colchicine dosage in pediatric patients with familial Mediterranean fever—a randomized controlled noninferiority trial. Arthritis Res Ther. 2016;18:85.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Sonmez HE, Batu ED, Bilginer Y, Özen S. Discontinuing colchicine in symptomatic carriers for MEFV (Mediterranean FeVer) variants. Clin Rheumatol. 2017;36(2):421–5.PubMedCrossRefGoogle Scholar
  135. 135.
    Yesilkaya S, Acikel C, Fidanci BE, et al. Development of a medication adherence scale for familial Mediterranean fever (MASIF) in a cohort of Turkish children. Clin Exp Rheumatol. 2015;33(6 Suppl 94):S156–62.PubMedGoogle Scholar
  136. 136.
    Fradkin A, Yahav J, Zemer D, Jonas A. Colchicine-induced lactose malabsorption in patients with familial Mediterranean fever. Isr J Med Sci. 1995;31(10):616–20.PubMedGoogle Scholar
  137. 137.
    Padeh S, Gerstein M, Berkun Y. Colchicine is a safe drug in children with familial Mediterranean fever. J Pediatr. 2012;161(6):1142.PubMedCrossRefGoogle Scholar
  138. 138.
    Ben-Chetrit E, Navon P. Colchicine-induced leukopenia in a patient with familial Mediterranean fever: the cause and a possible approach. Clin Exp Rheumatol. 2003;21(Suppl 30):S38–40.PubMedGoogle Scholar
  139. 139.
    Choi SS, Chan KF, Ng HK, Mak WP. Colchicine-induced myopathy and neuropathy. Hong Kong Med J. 1999;5(2):204–7.PubMedGoogle Scholar
  140. 140.
    Finkelstein Y, Aks SE, Hutson JR, et al. Colchicine poisoning: the dark side of an ancient drug. Clin Toxicol (Phila). 2010;48(5):407–14.CrossRefGoogle Scholar
  141. 141.
    Hung IF, Wu AK, Cheng VC, et al. Fatal interaction between clarithromycin and colchicine in patients with renal insufficiency: a retrospective study. Clin Infect Dis. 2005;41(3):291–300.PubMedCrossRefGoogle Scholar
  142. 142.
    Terkeltaub RA, Furst DE, Digiacinto JL, Kook KA, Davis MW. Novel evidence-based colchicine dose-reduction algorithm to predict and prevent colchicine toxicity in the presence of cytochrome P450 3A4/P-glycoprotein inhibitors. Arthritis Rheum. 2011;63(8):2226–37.PubMedCrossRefGoogle Scholar
  143. 143.
    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.PubMedCrossRefGoogle Scholar
  144. 144.
    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.PubMedCrossRefGoogle Scholar
  145. 145.
    Belkhir R, Moulonguet-Doleris L, Hachulla E, Prinseau J, Baglin A, Hanslik T. Treatment of familial Mediterranean fever with anakinra. Ann Intern Med. 2007;146(11):825–6.PubMedCrossRefGoogle Scholar
  146. 146.
    Bilginer Y, Ayaz NA, Ozen S. Anti-IL-1 treatment for secondary amyloidosis in an adolescent with FMF and Behcet’s disease. Clin Rheumatol. 2010;29:209–10.PubMedCrossRefGoogle Scholar
  147. 147.
    Cetin P, Sari I, Sozeri B, et al. Efficacy of interleukin-1 targeting treatments in patients with familial Mediterranean fever. Inflammation. 2015;38(1):27–31.PubMedCrossRefGoogle Scholar
  148. 148.
    Moser C, Pohl G, Haslinger I, et al. Successful treatment of familial Mediterranean fever with Anakinra and outcome after renal transplantation. Nephrol Dial Transplant. 2009;24:676–8.PubMedCrossRefGoogle Scholar
  149. 149.
    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.PubMedPubMedCentralGoogle Scholar
  150. 150.
    Pras M. Familial Mediterranean fever: from the clinical syndrome to the cloning of the pyrin gene. Scand J Rheumatol. 1998;27:92–7.PubMedCrossRefGoogle Scholar
  151. 151.
    Ben-Zvi I, Kukuy O, Giat E, et al. Anakinra for colchicine-resistant familial mediterranean fever: a randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 2017;69:854–62.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Hashkes PJ, Spalding SJ, Giannini EH, et al. Rilonacept for colchicine-resistant or -intolerant familial Mediterranean fever: a randomized trial. Ann Intern Med. 2012;157(8):533–41.PubMedCrossRefPubMedCentralGoogle Scholar
  153. 153.
    Eroglu FK, Beşbaş N, Topaloglu R, Ozen S. Treatment of colchicine-resistant Familial Mediterranean fever in children and adolescents. Rheumatol Int. 2015;35:1733–7.PubMedCrossRefGoogle Scholar
  154. 154.
    Sozeri B, Gulez N, Ergin M, Serdaroglu E. The experience of canakinumab in renal amyloidosis secondary to Familial Mediterranean fever. Mol Cell Pediatr. 2016;3:33.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Brik R, Butbul-Aviel Y, Lubin S, et al. Canakinumab for the treatment of children with colchicine-resistant familial Mediterranean fever: a 6-month open-label, single-arm pilot study. Arthritis Rheumatol. 2014;66(11):3241–3.PubMedCrossRefGoogle Scholar
  156. 156.
    Gul A, Ozdogan H, Erer B, et al. Efficacy and safety of canakinumab in adolescents and adults with colchicine-resistant familial Mediterranean fever. Arthritis Res Ther. 2015;17:243.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Ozdogan H, Ugurlu S. Canakinumab for the treatment of familial Mediterranean fever. Expert Rev Clin Immunol. 2017;13:393–404.PubMedCrossRefGoogle Scholar
  158. 158.
    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
  159. 159.
    Bilgen SA, Kilic L, Akdogan A, 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;17:358–62.PubMedCrossRefGoogle Scholar
  160. 160.
    Kaplan E, Mukamel M, Barash J, et al. Protracted febrile myalgia in children and young adults with familial Mediterranean fever: analysis of 15 patients and suggested criteria for working diagnosis. Clin Exp Rheumatol. 2007;25(4 Suppl 45):S114–7.PubMedGoogle Scholar
  161. 161.
    Majeed HA, Al-Qudah AK, Qubain H, Shahin HM. The clinical patterns of myalgia in children with familial Mediterranean fever. Semin Arthritis Rheum. 2000;30(2):138–43.PubMedCrossRefGoogle Scholar
  162. 162.
    Mercan R, Turan A, Bitik B, Tufan A, Haznedaroglu S, Goker B. Rapid resolution of protracted febrile myalgia syndrome with anakinra: report of two cases. Mod Rheumatol. 2016;26(3):458–9.PubMedGoogle Scholar
  163. 163.
    Ugurlu S, Hacioglu A, Adibnia Y, Hamuryudan V, Ozdogan H. Tocilizumab in the treatment of twelve cases with aa amyloidosis secondary to familial mediterranean fever. Orphanet J Rare Dis. 2017;12:105.PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Piram M, Frenkel J, Gattorno M, et al. A preliminary score for the assessment of disease activity in hereditary recurrent fevers: results from the AIDAI (Auto-Inflammatory Diseases Activity Index) Consensus Conference. Ann Rheum Dis. 2011;70(2):309–14.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Piram M, Koné-Paut I, Lachmann HJ, et al. Validation of the auto-inflammatory diseases activity index (AIDAI) for hereditary recurrent fever syndromes. Ann Rheum Dis. 2014;73(12):2168–73.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Mor A, Shinar Y, Zaks N, et al. Evaluation of disease severity in familial Mediterranean fever. Semin Arthritis Rheum. 2005;35(1):57–64.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Pras E, Livneh A, Balow JE Jr, et al. Clinical differences between North African and Iraqi Jews with familial Mediterranean fever. Am J Med Genet. 1998;75(2):216–9.PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Demirkaya E, Acikel C, Hashkes P, et al. Development and initial validation of international severity scoring system for familial Mediterranean fever (ISSF). Ann Rheum Dis. 2016;75(6):1051–6.PubMedPubMedCentralCrossRefGoogle Scholar
  169. 169.
    Ter Haar NM, Annink KV, Al-Mayouf SM, et al. Development of the autoinflammatory disease damage index (ADDI). Ann Rheum Dis. 2017;76(5):821–30.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Ozen S, Demirkaya E, Duzova A, et al. FMF50: a score for assessing outcome in familial Mediterranean fever. Ann Rheum Dis. 2014;73(5):897–901.PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Akse-Onal V, Sağ E, Ozen S, et al. Decrease in the rate of secondary amyloidosis in Turkish children with FMF: are we doing better? Eur J Pediatr. 2010;169(8):971–4.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Pediatrics AEdmond and Lily Safra Children’s Hospital, Sheba Medical CenterTel HashomerIsrael
  2. 2.Department of Pediatric RheumatologyHacettepe UniversityAnkaraTurkey

Personalised recommendations