Current Rheumatology Reports

, Volume 13, Issue 5, pp 388–394 | Cite as

Familial Mediterranean Fever and Seronegative Arthritis



Familial Mediterranean fever (FMF) is characterized by recurrent, self-limited episodes of polyserositis, with articular involvement also being a common manifestation. The pattern and joint predilection of arthritis show many similarities to those of spondyloarthritis. Moreover, case series suggest an increased prevalence of ankylosing spondylitis or spondyloarthritis among FMF patients. FMF is caused by mutations in the MEFV gene encoding pyrin, which is believed to be involved in regulation of interelukin-1β activation. Recent studies conducted in populations with a high background carrier rate of MEFV variants have reported an increased frequency of M694V among AS patients with no personal or family history of FMF. These findings are of interest, as both candidate gene and genome-wide association studies suggest that the interleukin-1 cytokine pathway may be implicated in the pathogenesis of ankylosing spondylitis. Therefore, association of M694V with ankylosing spondylitis can be recognized as a geographic region–specific risk factor affecting a common inflammatory pathway in the disease pathogenesis.


Ankylosing spondylitis Spondyloarthritis Seronegative arthritis Familial Mediterranean fever MEFV Pyrin 



No potential conflicts of interest relevant to this article were reported.


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  1. 1.
    Onen F. Familial Mediterranean fever. Rheumatol Int. 2006;26:489–96.PubMedCrossRefGoogle Scholar
  2. 2.
    French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet. 1997;17:25–31.CrossRefGoogle Scholar
  3. 3.
    International FMF. Consortium: 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;90:797–807.CrossRefGoogle Scholar
  4. 4.
    •• Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol. 2009, 27:621–668. The authors in this review proposed an updated classification for hereditary and acquired forms of autoinflammatory disorders based on molecular pathophysiology. FMF and AS are both included but in different categories. PubMedCrossRefGoogle Scholar
  5. 5.
    Infevers: an online database for autoinflammatory mutations. Available at Accessed March 2, 2011.
  6. 6.
    Touitou I. The spectrum of familial Mediterranean fever (FMF) mutations. Eur J Hum Genet. 2001;9:473–83.PubMedCrossRefGoogle Scholar
  7. 7.
    • Marek-Yagel D, Bar-Joseph I, Pras E, Berkun Y. Is E148Q a benign polymorphism or a disease-causing mutation? The Journal of Rheumatology 2009, 36:2372. The authors extracted the data on E148Q from four published studies and found no difference between the Israeli controls and FMF patients. PubMedCrossRefGoogle Scholar
  8. 8.
    Heller H, Gafni J, Michaeli D, et al. The arthritis of familial Mediterranean fever (FMF). Arthritis Rheum. 1966;9:1–17.PubMedCrossRefGoogle Scholar
  9. 9.
    Garcia-Gonzalez A, Weisman MH. The arthritis of familial Mediterranean fever. Semin Arthritis Rheum. 1992;22:139–50.PubMedCrossRefGoogle Scholar
  10. 10.
    Majeed HA, Rawashdeh M. The clinical patterns of arthritis in children with familial Mediterranean fever. QJM. 1997;90:37–43.PubMedGoogle Scholar
  11. 11.
    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;44:1416–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Sneh E, Pras M, Michaeli D, et al. Protracted arthritis in familial Mediterranean fever. Rheumatol Rehabil. 1977;16:102–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Kaushansky K, Finerman GA, Schwabe AD. Chronic destructive arthritis in familial Mediterranean fever: the predominance of hip involvement and its management. Clin Orthop Relat Res. 1981:156–161.Google Scholar
  14. 14.
    Salai M, Langevitz P, Blankstein A, et al. Total hip replacement in familial Mediterranean fever. Bull Hosp Jt Dis. 1993;53:25–8.PubMedGoogle Scholar
  15. 15.
    Brik R, Shinawi M, Kepten I, et al. Familial Mediterranean fever: clinical and genetic characterization in a mixed pediatric population of Jewish and Arab patients. Pediatrics. 1999;103:e70.PubMedCrossRefGoogle Scholar
  16. 16.
    Tunca M, Akar S, Onen F, et al. Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine (Baltimore). 2005;84:1–11.CrossRefGoogle Scholar
  17. 17.
    Cefle A, Kamali S, Sayarlioglu M, et al. A comparison of clinical findings of familial Mediterranean fever patients with and without amyloidosis. Rheumatol Int. 2005;25:442–6.PubMedCrossRefGoogle Scholar
  18. 18.
    Dilsen N. [Familial Mediterranean fever (periodic disease) associated with ankylopoietic spondylitis. (Apropos of a case)]. Turk Tip Cemiy Mecm. 1963;29:160–7.PubMedGoogle Scholar
  19. 19.
    Dilsen NA. Ankylosing spondylitis in familial Mediterranean fever (periodic disease). Excerpta Medica Intern Congr ser. 1973;299:107.Google Scholar
  20. 20.
    Yazici H, Turunc M, Ozdogan H, et al. Observer variation in grading sacroiliac radiographs might be a cause of ‘sacroiliitis’ reported in certain disease states. Ann Rheum Dis. 1987;46:139–45.PubMedCrossRefGoogle Scholar
  21. 21.
    Brodey PA, Wolff SM. Radiographic changes in the sacroiliac joints in familial Mediterranean fever. Radiology. 1975;114:331–3.PubMedGoogle Scholar
  22. 22.
    Langevitz P, Livneh A, Zemer D, et al. Seronegative spondyloarthropathy in familial Mediterranean fever. Semin Arthritis Rheum. 1997;27:67–72.PubMedCrossRefGoogle Scholar
  23. 23.
    Baraliakos X, Listing J, von der Recke A, Braun J. The natural course of radiographic progression in ankylosing spondylitis—evidence for major individual variations in a large proportion of patients. Rheumatol. 2009, 36:997–1002. This study indicates that radiographic progression in AS is rather variable, and the authors propose to differentiate patients as fast, moderate, and slow radiographic progressors based on development of new syndesmophytes over time.PubMedCrossRefGoogle Scholar
  24. 24.
    Boonen A, vander Cruyssen B, de Vlam K, et al. Spinal radiographic changes in ankylosing spondylitis: association with clinical characteristics and functional outcome. J Rheumatol. 2009;36:1249–55.PubMedCrossRefGoogle Scholar
  25. 25.
    Nash P, Mease PJ, Braun J, van der Heijde D. Seronegative spondyloarthropathies: to lump or split? Ann Rheum Dis. 2005;64 Suppl 2:ii9–13.PubMedCrossRefGoogle Scholar
  26. 26.
    Younes M, Kahn MF, Meyer O. Hip involvement in patients with familial Mediterranean fever. A review of ten cases. Joint Bone Spine. 2002;69:560–5.PubMedCrossRefGoogle Scholar
  27. 27.
    •• Kasifoglu T, Calisir 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, 28:41–46. This study investigated the presence of sacroiliitis among FMF patients using MRI of the sacroiliac joints in addition to conventional radiography, and found a higher-than-expected prevalence of sacroiliitis. Almost all patients with FMF and sacroiliitis carried at least one allele of the M694V variant.PubMedCrossRefGoogle Scholar
  28. 28.
    Akar S, Soysal O, Yuksel F, et al. High prevalence of axial spondyloarthritis in patients with familial Mediteranean fever, and a greater allelic frequency of M694V in familial Mediteranean fever patients with radiograpic sacroiliitis. Arthritis Rheum. 2010;62:S278.Google Scholar
  29. 29.
    Knockaert DC, Malysse IG, Peetermans WE. Ankylosing spondylitis. An unusual manifestation of familial Mediterranean fever. Report of a case complicated by amyloidosis and polyneuropathy. Clin Rheumatol. 1989;8:408–12.PubMedCrossRefGoogle Scholar
  30. 30.
    Sari I, Simsek I, Guvenc I, et al. Osteopoikilosis coexistent with ankylosing spondylitis and familial Mediterranean fever. Rheumatol Int. 2009;29:321–3.PubMedCrossRefGoogle Scholar
  31. 31.
    Duman I, Balaban B, Tugcu I, Dincer K. Familial mediterranean fever unusually coexisted in an ankylosing spondylitis patient. MEFV mutation has any role? Rheumatol Int. 2007;27:689–90.PubMedCrossRefGoogle Scholar
  32. 32.
    Kaushik P, el-Sobkie NI, Shehab D, Malaviya AN. Familial Mediterranean fever with HLA B-27 positive ankylosing spondylitis in a young Armenian man. Clin Exp Rheumatol. 1999;17:387–8.PubMedGoogle Scholar
  33. 33.
    Keles I, Aydin G, Tosun A, et al. Familial Mediterranean fever and ankylosing spondylitis in a patient with juvenile idiopathic arthritis: a case report and review of the literature. Rheumatol Int. 2006;26:846–51.PubMedCrossRefGoogle Scholar
  34. 34.
    Akar S, Birlik M, Sari I, et al. M694V mutation may have a role in susceptibility to ankylosing spondylitis. Rheumatol Int. 2009;29:1259–60.PubMedCrossRefGoogle Scholar
  35. 35.
    •• Cosan F, Ustek D, Oku B, et al. Association of familial Mediterranean fever-related MEFV variations with ankylosing spondylitis. Arthritis Rheum. 2010, 62:3232–3236. This study reported a significantly higher frequency of M694V among AS patients with no personal or family history of FMF as compared with healthy controls.PubMedCrossRefGoogle Scholar
  36. 36.
    •• Akkoc N, Sari I, Akar S, et al. Increased prevalence of M694V in patients with ankylosing spondylitis: additional evidence for a link with familial Mediterranean fever. Arthritis Rheum. 2010, 62:3059–3063. This study reported a significantly higher frequency of M694V among AS patients than in healthy controls and patients with rheumatoid arthritis.PubMedCrossRefGoogle Scholar
  37. 37.
    Durmus D, Alayli G, Cengiz K, et al. Clinical significance of MEFV mutations in ankylosing spondylitis. Joint Bone Spine. 2009;76:260–4.PubMedCrossRefGoogle Scholar
  38. 38.
    Akkoc N, Gul A. Comment on the article by Durmus et al. “Clinical significance of MEFV mutations in ankylosing spondylitis”. Joint Bone Spine. 2010;77:281.PubMedCrossRefGoogle Scholar
  39. 39.
    Cinar M, Dinc A, Simsek I, et al. The rate and significance of Mediterranean fever gene mutations in patients with ankylosing spondylitis: a three-month, longitudinal clinical study. Rheumatol Int. 2008;29:37–42.PubMedCrossRefGoogle Scholar
  40. 40.
    Maras Y, Calguneri M, Akdogan A, et al. MEFV mutations frequency and effect on disease severity in ankyloing spondylitis EULAR Meeting Abstracts. 2007, 66:400.Google Scholar
  41. 41.
    •• Reveille JD. The genetic basis of spondyloarthritis. Ann Rheum Dis. 2011, 70 Suppl 1:i44-50. This is a very comprehensive review on the genetics of AS.PubMedCrossRefGoogle Scholar
  42. 42.
    Burton PR, Clayton DG, Cardon LR, et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet. 2007;39:1329–37.PubMedCrossRefGoogle Scholar
  43. 43.
    •• Reveille JD, Sims AM, Danoy P, et al. Genome-wide association study of ankylosing spondylitis identifies non-MHC susceptibility loci. Nat Genet. 2010, 42:123–127. This recent genome-wide association study confirmed the strong association of the HLA-B region and also revealed several non-HLA susceptibility genes for AS.PubMedCrossRefGoogle Scholar
  44. 44.
    Sims AM, Timms AE, Bruges-Armas J, et al. Prospective meta-analysis of interleukin 1 gene complex polymorphisms confirms associations with ankylosing spondylitis. Ann Rheum Dis. 2008;67:1305–9.PubMedCrossRefGoogle Scholar
  45. 45.
    Carter KW, Pluzhnikov A, Timms AE, et al. Combined analysis of three whole genome linkage scans for ankylosing spondylitis. Rheumatology (Oxford). 2007;46:763–71.CrossRefGoogle Scholar
  46. 46.
    •• Sims JE, Smith DE. The IL-1 family: regulators of immunity. Nat Rev Immunol. 2010, 10:89–102. This paper provided a very comprehensive review of the IL-1 family in health and disease.PubMedCrossRefGoogle Scholar
  47. 47.
    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;112:1794–803.PubMedCrossRefGoogle Scholar
  48. 48.
    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;13:236–49.PubMedCrossRefGoogle Scholar
  49. 49.
    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;14:1457–66.PubMedCrossRefGoogle Scholar
  50. 50.
    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;234:40–52.CrossRefGoogle Scholar
  51. 51.
    Shiohara M, Taniguchi S, Masumoto J, et al. ASC, which is composed of a PYD and a CARD, is up-regulated by inflammation and apoptosis in human neutrophils. Biochem Biophys Res Commun. 2002;293:1314–8.PubMedCrossRefGoogle Scholar
  52. 52.
    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.PubMedCrossRefGoogle Scholar
  53. 53.
    Dowds TA, Masumoto J, Chen FF, et al. Regulation of cryopyrin/Pypaf1 signaling by pyrin, the familial Mediterranean fever gene product. Biochem Biophys Res Commun. 2003;302:575–80.PubMedCrossRefGoogle Scholar
  54. 54.
    Stehlik C, Lee SH, Dorfleutner A, et al. Apoptosis-associated speck-like protein containing a caspase recruitment domain is a regulator of procaspase-1 activation. J Immunol. 2003;171:6154–63.PubMedGoogle Scholar
  55. 55.
    Lachmann HJ, Sengul B, Yavuzsen TU, et al. Clinical and subclinical inflammation in patients with familial Mediterranean fever and in heterozygous carriers of MEFV mutations. Rheumatology (Oxford). 2006;45:746–50.CrossRefGoogle Scholar
  56. 56.
    Booty MG, Chae JJ, Masters SL, et al. Familial Mediterranean fever with a single MEFV mutation: where is the second hit? Arthritis Rheum. 2009, 60:1851–1861. This study described patients with classical features of FMF despite a single MEFV mutation.PubMedCrossRefGoogle Scholar
  57. 57.
    Ustek D, Ekmekci C, Oku B, et al. MEFV gene 3′-UTR Alu repeat polymorphisms in patients with familial Mediterranean fever. Clin Exp Rheumatol. 2008;26:S72–6.PubMedGoogle Scholar
  58. 58.
    Ben-Chetrit E, Peleg H, Aamar S, Heyman SN. The spectrum of MEFV clinical presentations—is it familial Mediterranean fever only? Rheumatology (Oxford). 2009, 48:1455–1459. This study discusses the atypical autoinflammatory clinical features in patients carrying MEFV variations.CrossRefGoogle Scholar
  59. 59.
    Kone-Paut I, Hentgen V, Guillaume-Czitrom S, et al. The clinical spectrum of 94 patients carrying a single mutated MEFV allele. Rheumatology (Oxford). 2009;48:840–2.CrossRefGoogle Scholar
  60. 60.
    Touitou I, Magne X, Molinari N, et al. MEFV mutations in Behcet’s disease. Hum Mutat. 2000;16:271–2.PubMedCrossRefGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Division of Rheumatology and Immunology, Department of Internal MedicineDokuz Eylul University, Faculty of MedicineIzmirTurkey
  2. 2.Division of Rheumatology, Department of Internal Medicine, Istanbul Faculty of MedicineIstanbul UniversityIstanbulTurkey

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