Familial Mediterranean Fever: Current Approaches to Diagnosis and Treatment
Mikhail M. Kostik, 
Olga V. Zhogova,
Natalia V. Lagunova,
Sergey V. Ivanovskiy,
Oksana L. Kolobova,
Larisa N. Melnikova
Olga V. Zhogova,
Natalia V. Lagunova,
Sergey V. Ivanovskiy,
Oksana L. Kolobova,
Larisa N. Melnikova https://doi.org/10.15690/vsp.v17i5.1953
Abstract
Familial Mediterranean fever is a typical monogenic disease with an autosomal recessive inheritance pattern; caused by mutations in the MEFV gene, which encodes the pyrin protein. It is a relatively rare pathology in the practice of paediatricians and rheumatologists of the Russian Federation. The article provides up-to-date data on the disease prevalence, presents a complete clinical picture of the auto-inflammatory syndrome, discusses diagnostic criteria and methods for treating patients with familial Mediterranean fever.
Keywords
familial Mediterranean fever,
periodic fever,
fever of unknown origin,
interleukin 1,
colchicine,
anakinra,
canakinumab
Supporting agencies: Novartis
About the Authors
Mikhail M. Kostik
St. Petersburg State Pediatric Medical University
Russian Federation
Disclosure of interest:
Russian Federation
Disclosure of interest:
Receiving fees for lecturing from Pfaizer, AbbVie, Novartis
Olga V. Zhogova
V.I. Vernadskiy Crimean Federal University; Republican Pediatric Clinical Hospital
Russian Federation
Simferopol.
Disclosure of interest: Not declared
Russian Federation
Simferopol.
Disclosure of interest: Not declared
Natalia V. Lagunova
V.I. Vernadskiy Crimean Federal University
Russian Federation
Simferopol.
Disclosure of interest: Not declared
Russian Federation
Simferopol.
Disclosure of interest: Not declared
Sergey V. Ivanovskiy
V.I. Vernadskiy Crimean Federal University; Republican Pediatric Clinical Hospital
Russian Federation
Simferopol.
Disclosure of interest: Not declared
Russian Federation
Simferopol.
Disclosure of interest: Not declared
Oksana L. Kolobova
St. Petersburg State Pediatric Medical University
Russian Federation
Disclosure of interest: Not declared
Russian Federation
Disclosure of interest: Not declared
Larisa N. Melnikova
St. Petersburg State Pediatric Medical University
Russian Federation
Disclosure of interest: Not declared
Russian Federation
Disclosure of interest: Not declared
References
1. 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(1):133–144. doi: 10.1016/s0092-8674(00)80721-7.
2. 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(4):797–807. doi: 10.1016/s0092-8674(00)80539-5.
3. French FMFC. A candidate gene for familial Mediterranean fever. Nat Genet. 1997;17(1):25–31. doi: 10.1038/ng0997-25.
4. igh.cnrs.fr [Internet]. Institut de genetique humaine. Infevers: an online database for autoinflammatory mutations [cited 2018 Aug 14]. Available from: http://fmf.igh.cnrs.fr/ISSAID/infevers/.
5. Park H, Bourla AB, Kastner DL, et al. Lighting the fires within: the cell biology of autoinflammatory diseases. Nat Rev Immunol. 2012;12(8):570–580. doi: 10.1038/nri3261.
6. Simon A, van der Meer JW. Pathogenesis of familial periodic fever syndromes or hereditary autoinflammatory syndromes. Am J Physiol Regul Integr Comp Physiol. 2007;292(1):R86–98. doi: 10.1152/ajpregu.00504.2006.
7. 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):9982–9987. doi: 10.1073/pnas.0602081103.
8. Aksentijevich I, Kastner DL. Genetics of monogenic autoinflammatory diseases: past successes, future challenges. Nat Rev Rheumatol. 2011;7(8):469–478. doi: 10.1038/nrrheum.2011.94.
9. 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):227–253. doi: 10.1016/0002-9343(67)90167-2.
10. Kastner DL, Aksentijevich I. Intermittent and periodic arthritis syndromes. In: Koopman WJ, Moreland LW, editors. Arthritis and allied conditions: a textbook of rheumatology. 15th ed. Philadelphia, USA: Lippincott Williams and Wilkins; 2005. pp. 1411–1461.
11. Salugina SO, Kuz’mina NN, Fedorov ES. Autovospalitel’nye sindromy — «novaya» mul’tidistsiplinarnaya problema pediatrii i revmatologii. Pediatria. 2012;91(5):120–132. (In Russ).
12. Yilmaz E, Ozen S, Balci B, et al. Mutation frequency of Familial Mediterranean Fever and evidence for a high carrier rate in the Turkish population. Eur J Hum Genet. 2001;9(7):553–555. doi: 10.1038/sj.ejhg.5200674.
13. Touitou I. Standardized testing for mutations in familial Mediterranean fever. Clin Chem. 2003;49(11):1781–1782. doi: 10.1373/clinchem.2003.025791.
14. Jarjour RA, Al-Berrawi S. Familial Mediterranean fever in Syrian children: phenotype-genotype correlation. Rheumatol Int. 2015;35(4):629–634. doi: 10.1007/s00296-014-3116-x.
15. Touitou I. The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet. 2001;9(7):473–483. doi: 10.1038/sj.ejhg.5200658.
16. Yigit S, Bagci H, Ozkaya O, et al. MEFV mutations in patients with familial Mediterranean fever in the Black Sea region of Turkey: Samsun experience [corrected]. J Rheumatol. 2008;35(1):106–113.
17. Yalcinkaya F, Ozen S, Ozcakar ZB, et al. A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology (Oxford). 2009;48(4):395–398. doi: 10.1093/rheumatology/ken509.
18. Barut K, Sahin S, Adrovic A, et al. Familial Mediterranean fever in childhood: a single-center experience. Rheumatol Int. 2018;38(1):67–74. doi: 10.1007/s00296-017-3796-0.
19. Ece A, Cakmak E, Uluca U, et al. The MEFV mutations and their clinical correlations in children with familial Mediterranean fever in southeast Turkey. Rheumatol Int. 2014;34(2):207–212. doi: 10.1007/s00296-013-2858-1.
20. Yalcinkaya F, Cakar N, Misirlioglu M, et al. Genotype-phenotype correlation in a large group of Turkish patients with familial mediterranean fever: evidence for mutation-independent amyloidosis. Rheumatology (Oxford). 2000;39(1):67–72. doi: 10.1093/rheumatology/39.1.67.
21. Samuels J, Aksentijevich I, Torosyan Y, et al. Familial Mediterranean fever at the millennium. Clinical spectrum, ancient mutations, and a survey of 100 American referrals to the National Institutes of Health. Medicine (Baltimore). 1998;77(4):268–297. doi: 10.1097/00005792-199807000-00005.
22. Ben-Chetrit E, Touitou I. Familial mediterranean Fever in the world. Arthritis Rheum. 2009;61(10):1447–1453. doi: 10.1002/art.24458.
23. Zadeh N, Getzug T, Grody WW. Diagnosis and management of familial Mediterranean fever: integrating medical genetics in a dedicated interdisciplinary clinic. Genet Med. 2011;13(3):263–269. doi: 10.1097/GIM.0b013e31820e27b1.
24. Kone-Paut I, Hentgen V, Touitou I. Current data on familial Mediterranean fever. Joint Bone Spine. 2011;78(2):111–114. doi: 10.1016/j.jbspin.2010.09.021.
25. 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. doi: 10.1186/s13075-015-0765-4.
26. Berkun Y, Ben-Chetrit E, Klar A, Ben-Chetrit E. Peritoneal adhesions and intestinal obstructions in patients with familial Mediterranean fever are they more frequent? Semin Arthritis Rheum. 2007;36(5):316–321. doi: 10.1016/j.semarthrit.2006.11.002.
27. Kasifoglu T, Cansu DU, Korkmaz C. Frequency of abdominal surgery in patients with familial Mediterranean fever. Intern Med. 2009;48(7):523–526. doi: 10.2169/internalmedicine.48.1602.
28. Rawashdeh MO, Majeed HA. Familial Mediterranean fever in Arab children: the high prevalence and gene frequency. Eur J Pediatr. 1996;155(7):540–544. doi: 10.1007/bf01957901.
29. 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. doi: 10.1097/01.md.0000152370.84628.0c.
30. Brik R, Shinawi M, Kasinetz L, Gershoni-Baruch R. The musculoskeletal manifestations of familial Mediterranean fever in children genetically diagnosed with the disease. Arthritis Rheum. 2001;44(6):1416–1419. doi: 10.1002/1529-0131(200106)44:6<1416::aid-art236>3.0.co;2-6.
31. Ozen S, Bakkaloglu A, Yilmaz E, et al. Mutations in the gene for familial Mediterranean fever: do they predispose to inflammation? J Rheumatol. 2003;30(9):2014–2018.
32. Borman P, Gokoglu F, Tasbas O, et al. Familial Mediterranean fever-related spondyloarthropathy. Singapore Med J. 2009;50(3): e116–119.
33. Eshed I, Rosman Y, Livneh A, et al. Exertional leg pain in familial Mediterranean fever: a manifestation of an underlying enthesopathy and a marker of more severe disease. Arthritis Rheumatol. 2014;66(11):3221–3226. doi: 10.1002/art.38797.
34. Langevitz P, Livneh A, Zemer D, et al. Seronegative spondyloarthropathy in familial Mediterranean fever. Semin Arthritis Rheum. 1997;27(2):67–72. doi: 10.1016/s0049-0172(97)80007-8.
35. Padeh S, Shinar Y, Pras E, et al. Clinical and diagnostic value of genetic testing in 216 Israeli children with Familial Mediterranean fever. J Rheumatol. 2003;30(1):185–190.
36. Korkmaz C, Ozdogan H, Kasapcopur O, Yazici H. Acute phase response in familial Mediterranean fever. Ann Rheum Dis. 2002;61(1):79–81. doi: 10.1136/ard.61.1.79.
37. Bayram MT, Cankaya T, Bora E, et al. Risk factors for subclinical inflammation in children with Familial Mediterranean fever. Rheumatol Int. 2015;35(8):1393–1398. doi: 10.1007/s00296-015-3227-z.
38. Kilic A, Varkal MA, Durmus MS, et al. Relationship between clinical findings and genetic mutations in patients with familial Mediterranean fever. Pediatr Rheumatol Online J. 2015;13:59. doi: 10.1186/s12969-015-0057-1.
39. Lachmann HJ, Goodman HJ, Gilbertson JA, et al. Natural history and outcome in systemic AA amyloidosis. N Engl J Med. 2007;356(23):2361–2371. doi: 10.1056/NEJMoa070265.
40. 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(3):387–391. doi: 10.1016/j.semarthrit.2013.04.011.
41. 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):635–641. doi: 10.1136/annrheumdis-2014-206844.
42. Livneh A, Langevitz P, Zemer D, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. 1997;40(10): 1879–1885. doi: 10.1002/art.1780401023.
43. Pras M. Familial Mediterranean fever: from the clinical syndrome to the cloning of the pyrin gene. Scand J Rheumatol. 1998;27(2): 92–97. doi: 10.1080/030097498440949.
44. Ozcakar ZB, Yalcinkaya F, Cakar N, et al. Application of the new pediatric criteria and Tel Hashomer criteria in heterozygous patients with clinical features of FMF. Eur J Pediatr. 2011;170(8): 1055–1057. doi: 10.1007/s00431-011-1404-y.
45. Kondi A, Hentgen V, Piram M, et al. Validation of the new paediatric criteria for the diagnosis of familial Mediterranean fever: data from a mixed population of 100 children from the French reference centre for auto-inflammatory disorders. Rheumatology (Oxford). 2010;49(11):2200–2203. doi: 10.1093/rheumatology/keq252.
46. Berkun Y, Eisenstein EM. Diagnostic criteria of familial Mediterranean fever. Autoimmun Rev. 2014;13(4–5):388–390. doi: 10.1016/j.autrev.2014.01.045.
47. Ben-Zvi I, Livneh A. Chronic inflammation in FMF: markers, risk factors, outcomes and therapy. Nat Rev Rheumatol. 2011;7(2): 105–112. doi: 10.1038/nrrheum.2010.181.
48. Celkan T, Celik M, Kasapcopur O, et al. The anemia of familial Mediterranean fever disease. Pediatr Hematol Onco. 2005;22(8): 657–665. doi: 10.1080/08880010500278681.
49. Aharoni D, Hiller N, Hadas-Halpern I. Familial Mediterranean fever: abdominal imaging findings in 139 patients and review of the literature. Abdom Imaging. 2000;25(3):297–300. doi: 10.1007/s002610000006.
50. Livneh A, Langevitz P, Zemer D, et al. The changing face of familial Mediterranean fever. Semin Arthritis Rheum. 1996;26(3):612–627. doi: 10.1016/S0049-0172(96)80012-6.
51. Salah S, El-Masry SA, Sheba HF, et al. Bone Mineral Density in Egyptian Children with Familial Mediterranean Fever. Iran J Med Sci. 2016;41(1):2–8.
52. Ben-Chetrit E, Berkun Y, Ben-Chetrit E, Ben-Chetrit A. The outcome of pregnancy in the wives of men with familial mediterranean fever treated with colchicine. Semin Arthritis Rheum. 2004;34(2):549–552. doi: 10.1016/j.semarthrit.2004.07.004.
53. Ben-Chetrit E, Ben-Chetrit A, Berkun Y, Ben-Chetrit E. Pregnancy outcomes in women with familial Mediterranean fever receiving colchicine: is amniocentesis justified? Arthritis Care Res (Hoboken). 2010;62(2):143–148. doi: 10.1002/acr.20061.
54. Marek-Yagel D, Berkun Y, Padeh S, et al. Clinical disease among patients heterozygous for familial Mediterranean fever. Arthritis Rheum. 2009;60(6):1862–1866. doi: 10.1002/art.24570.
55. 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):1851–1861. doi: 10.1002/art.24569.
56. 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(5):678–685. doi: 10.1136/annrheumdis-2011-201268.
57. Erken E, Ozer HT, Bozkurt B, et al. Early suppression of familial Mediterranean fever attacks by single medium dose methyl-prednisolone infusion. Joint Bone Spine. 2008;75(3):370–372. doi: 10.1016/j.jbspin.2007.10.004.
58. Ozen S, Demirkaya E, Erer B, et al. EULAR recommendations for the management of familial Mediterranean fever. Ann Rheum Dis. 2016;75(4):644–651. doi: 10.1136/annrheumdis-2015-208690.
59. Goldfinger SE. Colchicine for familial Mediterranean fever. N Engl J Med. 1972;287(25):1302. doi: 10.1056/NEJM197212212872514.
60. Dinarello CA, Wolff SM, Goldfinger SE, et al. Colchicine therapy for familial mediterranean fever. A double-blind trial. N Engl J Med. 1974;291(18):934–937. doi: 10.1056/NEJM197410312911804.
61. Kallinich T, Haffner D, Niehues T, et al. Colchicine use in children and adolescents with familial Mediterranean fever: literature review and consensus statement. Pediatrics. 2007;119:e474–483. doi: 10.1542/peds.2006-1434.
62. Ozturk MA, Kanbay M, Kasapoglu B, et al. Therapeutic approach to familial Mediterranean fever: a review update. Clin Exp Rheumatol. 2011;29(4 Suppl 67):S77–86.
63. Manna R, Cerquaglia C, Curigliano V, et al. Clinical features of familial Mediterranean fever: an Italian overview. Eur Rev Med Pharmacol Sci. 2009;13 Suppl 1:51–53.
64. Ben-Chetrit E, Levy M. Colchicine: 1998 update. Semin Arthritis Rheum. 1998;28(1):48–59. doi: 10.1016/s0049-0172(98)80028-0.
65. Padeh S, Gerstein M, Berkun Y. Colchicine is a safe drug in children with Familial Mediterranean Fever. J Pediatr. 2012;161(6): 1142–1146. doi: 10.1016/j.jpeds.2012.05.047.
66. 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):1121–1130. doi: 10.1177/039463201202500429.
67. 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):516–518. doi: 10.3899/jrheum.100718.
68. Meinzer U, Quartier P, Alexandra JF, et al. Interleukin-1 targeting drugs in familial Mediterranean fever: a case series and a review of the literature. Semin Arthritis Rheum. 2011;41(2):265–271. doi: 10.1016/j.semarthrit.2010.11.003.
69. Sakallioglu O, Duzova A, Ozen S. Etanercept in the treatment of arthritis in a patient with familial Mediterranean fever. Clin Exp Rheumatol. 2006;24(4):435–437.
70. Hashkes P, Spalding SJ, Giannini EH, et al. Rilonacept for colchicines-resistant or –intolerant familial Mediterranean fever: a randomized trial. Ann Intern Med. 2012;157(8):533–541. doi: 10.7326/0003-4819-157-8-201210160-00003.
71. De Benedetti F, Anton J, Ben-Chetrit E, et al. Efficacy and safety of canakinumab in patients with periodic fever syndromes (colchicine-resistant FMF, HIDS/MKD and TRAPS): results from a Phase 3, Pivotal, Umbrella Trial. Arthritis Rheumatol. 2016;68 (Suppl 10):3205.
72. Akar S, Cetin P, Kalyoncu U, et al. Nationwide experience with off-label use of interleukin-1 targeting treatment in Familial Mediterranean Fever patients. Arthritis Care Res (Hoboken). 2018;70(7):1090–1094. doi: 10.1002/acr.23446.
73. Varan O, Kucuk H, Babaoglu H, et al. Efficacy and safety of interleukin-1 inhibitors in familial Mediterranean fever patients complicated with amyloidosis. Mod Rheumatol. 2018:1–4. doi: 10.1080/14397595.2018.1457469.
74. Laskari K, Boura P, Dalekos GN, et al. Longterm beneficial effect of canakinumab in colchicine-resistant Familial Mediterranean Fever. J Rheumatol. 2017;44(1):102–109. doi: 10.3899/jrheum.160518.
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Kostik M.M., Zhogova O.V., Lagunova N.V., Ivanovskiy S.V., Kolobova O.L., Melnikova L.N. Familial Mediterranean Fever: Current Approaches to Diagnosis and Treatment. Current Pediatrics. 2018;17(5):371-380. (In Russ.) https://doi.org/10.15690/vsp.v17i5.1953
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