Familial Mediterranean Fever 

  • Author: John O Meyerhoff, MD; Chief Editor: Herbert S Diamond, MD   more...
 
Updated: Jan 19, 2012
 

Background

Familial Mediterranean fever (FMF) is also called recurrent polyserositis. The salient features of FMF include brief recurrent episodes of peritonitis, pleuritis, and arthritis, usually with accompanying fever. FMF occurs within families and is much more common in individuals of Mediterranean descent than in persons of any other ethnicity.

Next

Pathophysiology

Nonsense or missense mutations in the MEFV (Mediterranean fever) gene appear to cause the disease in many cases. MEFV produces a protein called pyrin (derived from the association with predominant fever) or marenostrin (derived from the phrase "our sea," because of the Mediterranean heritage of most patients).

The protein is expressed mostly in neutrophils. Its exact function is unknown, but it may function as an inhibitor of chemotactic factor (C5a) or perhaps of interleukin (IL)–8.[1] Individuals with normal pyrin/marenostrin levels may have the ability to deactivate the target chemotactic factor when it is produced in response to an inflammatory stimulus. However, patients with FMF lack this ability, resulting in uninhibited activity of the chemotactic factor and episodes of inflammation (with accompanying fever) in the peritoneum, pleura, and joints. Presumably, these inflammatory episodes lead to the excess production of amyloid A protein from the acute phase and reactant serum amyloid A with subsequent deposition in the kidneys; however, only patients with specific MEFV haplotypes develop amyloidosis.

Previous
Next

Epidemiology

Frequency

International

The frequency of FMF in any location depends on the ethnic background of the population. To survive ethnic and religious persecution, many Mediterranean families converted to other religions or intermarried members of other ethnic groups, thus carrying the MEFV gene with them.

  • In Ashkenazi Jewish people (descended from Eastern European Jewish people and including most European and American Jewish people), the prevalence of FMF is 1 case per 73,000 population, with a MEFV gene frequency now estimated at perhaps 1 per 5, in contrast to previous estimates of 1 per 135.[2] This suggests that not all mutations have equal penetrance.
  • In Sephardic Jewish people (descended from Jewish people who were expelled from Spain, largely to North Africa, and including other Middle Eastern Jewish populations), the prevalence of FMF is 1 case per 250-1000 population, with a gene frequency of 1 per 8-16.
  • In Armenian persons (based on epidemiology among Armenian populations in Lebanon and southern California), the estimated prevalence of FMF is 1 case per 500 population, with a gene frequency of 1 per 7.
  • Turkish people (from one study) may have a prevalence of approximately 1 case per 1000 population.
  • Arabic people (from one study) may have a prevalence of 1 case per 2600 population in children and a gene frequency of 1 per 50.
  • Since the development of gene testing, which allows confirmation of FMF in some cases, the disease has been reported in unexpected locations, including by two Japanese groups.[3, 4]
  • Migrations of guest workers around the world have highlighted the need for physicians to think about formerly uncommon illnesses in their home countries and the need for review articles in national journals.[5]

Mortality/Morbidity

  • Nephrotic syndrome: Before the institution of colchicine therapy, mortality due to nephrotic syndrome was almost universal by age 50 years in North African Sephardic Jewish patients. Among other Sephardic Jewish, Ashkenazi Jewish, and Armenian patients, amyloidosis was extremely rare. The mortality rate among Turkish patients was high, but this high rate may have represented selection bias. No pre–colchicine-therapy data are available from Arabic patients.
  • Appendectomies: Many patients with undiagnosed FMF have undergone appendectomy because the severity of the peritoneal episodes seemed to indicate appendicitis.
  • Chronic arthritis: Approximately 5% of patients with FMF develop chronic arthritis that sometimes leads to destructive arthritis of hips or knees and may necessitate joint replacements. Approximately 10% of patients with chronic arthritis develop seronegative spondyloarthropathy.
  • Fertility and pregnancy: Approximately one third of female patients with FMF are infertile, and 20-30% of pregnancies result in fetal loss.

Sex

  • In adults, FMF is more prevalent in men than in women, with a male-to-female ratio of 1.5-2:1.

Age

  • Of all persons with FMF, 50-60% are younger than 10 years, 80-95% are younger than 20 years, and 5-10% are older than 20 years at onset. Onset in persons older than 40 years is rare.
Previous
 
 
Contributor Information and Disclosures
Author

John O Meyerhoff, MD  Assistant Professor, Department of Internal Medicine, Johns Hopkins University School of Medicine; Clinical Scholar in Rheumatology, Department of Medicine, Sinai Hospital of Baltimore

John O Meyerhoff, MD is a member of the following medical societies: American College of Physicians and American College of Rheumatology

Disclosure: Nothing to disclose.

Specialty Editor Board

Carlos J Lozada, MD  Director of Rheumatology Fellowship Program, Professor, Department of Medicine, Division of Rheumatology and Immunology, University of Miami, Leonard M Miller School of Medicine

Carlos J Lozada, MD is a member of the following medical societies: American College of Physicians and American College of Rheumatology

Disclosure: Pfizer Honoraria Speaking and teaching; Amgen Honoraria Speaking and teaching

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Elliot Goldberg, MD  Dean of the Western Pennsylvania Clinical Campus, Professor, Department of Medicine, Temple University School of Medicine

Elliot Goldberg, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, and American College of Rheumatology

Disclosure: Nothing to disclose.

Alex J Mechaber, MD, FACP  Senior Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine

Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine

Disclosure: Nothing to disclose.

Chief Editor

Herbert S Diamond, MD  Adjunct Professor of Medicine, Division of Rheumatology, University of Pittsburgh School of Medicine; Chairman Emeritus, Department of Internal Medicine, Western Pennsylvania Hospital

Herbert S Diamond, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American College of Rheumatology, American Medical Association, and Phi Beta Kappa

Disclosure: Merck Ownership interest Other; Smith Kline Ownership interest Other; Zimmer Ownership interest Other

References
  1. Apostolidou E, Kambas K, Chrysanthopoulou A, Kourtzelis I, Speletas M, Ritis K, et al. Genetic analysis of C5a receptors in neutrophils from patients with familial Mediterranean fever. Mol Biol Rep. Dec 21 2011;[Medline].

  2. Gershoni-Baruch R, Brik R, Shinawi M, Livneh A. The differential contribution of MEFV mutant alleles to the clinical profile of familial Mediterranean fever. Eur J Hum Genet. Feb 2002;10(2):145-9. [Medline]. [Full Text].

  3. Tomiyama N, Higashiuesato Y, Oda T, et al. MEFV mutation analysis of familial Mediterranean fever in Japan. Clin Exp Rheumatol. Jan-Feb 2008;26(1):13-7. [Medline].

  4. Kim S, Ikusaka M, Mikasa G, et al. Clinical study of 7 cases of familial Mediterranean fever with MEFV gene mutation. Intern Med. 2007;46(5):221-5. [Medline]. [Full Text].

  5. Lidar M, Livneh A. Familial Mediterranean fever: clinical, molecular and management advancements. Neth J Med. Oct 2007;65(9):318-24. [Medline]. [Full Text].

  6. Lidar M, Kedem R, Langevitz P, et al. Intravenous colchicine for treatment of patients with familial Mediterranean fever unresponsive to oral colchicine. J Rheumatol. Dec 2003;30(12):2620-3. [Medline].

  7. Mor A, Pillinger MH, Kishimoto M, et al. Familial Mediterranean fever successfully treated with etanercept. J Clin Rheumatol. Feb 2007;13(1):38-40. [Medline].

  8. Roldan R, Ruiz AM, Miranda MD, et al. Anakinra: new therapeutic approach in children with Familial Mediterranean Fever resistant to colchicine. Joint Bone Spine. Jul 2008;75(4):504-5. [Medline].

  9. Tunca M, Akar S, Soyturk M, et al. The effect of interferon alpha administration on acute attacks of familial Mediterranean fever: A double-blind, placebo-controlled trial. Clin Exp Rheumatol. Jul-Aug 2004;22(4 Suppl 34):S37-40. [Medline].

  10. Tweezer-Zaks N, Rabinovich E, Lidar M, et al. Interferon-alpha as a treatment modality for colchicine- resistant familial Mediterranean fever. J Rheumatol. Jul 2008;35(7):1362-5. [Medline].

  11. Calguneri M, Apras S, Ozbalkan Z, et al. The efficacy of continuous interferon alpha administration as an adjunctive agent to colchicine-resistant familial Mediterranean fever patients. Clin Exp Rheumatol. Jul-Aug 2004;22(4 Suppl 34):S41-4. [Medline].

  12. Ben-Chetrit E, Berkun Y, Ben-Chetrit E, et al. The outcome of pregnancy in the wives of men with familial mediterranean fever treated with colchicine. Semin Arthritis Rheum. Oct 2004;34(2):549-52. [Medline].

  13. Ben-Chetrit E, Levy M. Familial Mediterranean fever. Lancet. Feb 28 1998;351(9103):659-64. [Medline].

  14. Lidar M, Kedem R, Mor A, et al. Arthritis as the sole episodic manifestation of familial Mediterranean fever. J Rheumatol. May 2005;32(5):859-62. [Medline].

  15. Livneh A, Langevitz P, Zemer D, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum. Oct 1997;40(10):1879-85. [Medline].

  16. Livneh A, Langevitz P, Zemer D, et al. The changing face of familial Mediterranean fever. Semin Arthritis Rheum. Dec 1996;26:612-27. [Medline].

  17. Majeed HA, El-Khateeb M, El-Shanti H, et al. The spectrum of familial Mediterranean fever gene mutations in Arabs: report of a large series. Semin Arthritis Rheum. Jun 2005;34(6):813-8. [Medline].

  18. Meyerhoff J. Familial Mediterranean fever: report of a large family, review of the literature, and discussion of the frequency of amyloidosis. Medicine (Baltimore). Jan 1980;59(1):66-77. [Medline].

  19. 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). Jul 1998;77:268-97. [Medline].

  20. Sohar E, Gafni J, Pras M, et al. Familial Mediterranean fever. A survey of 470 cases and review of the literature. Am J Med. Aug 1967;43(2):227-53. [Medline].

  21. Tunca M, Akar S, Onen F, et al. Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine (Baltimore). Jan 2005;84(1):1-11. [Medline].

Previous
Next
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2012 by WebMD LLC.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.