Familial Mediterranean Fever

Updated: Sep 30, 2016
  • Author: John O Meyerhoff, MD; Chief Editor: Herbert S Diamond, MD  more...
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Overview

Practice Essentials

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. See Presentation. As the name indicates, FMF occurs within families and is much more common in individuals of Mediterranean descent than in persons of any other ethnicity. [1]

Genetic testing is now available for FMF. Testing for a limited number of genes may be appropriate in patients with a known ethnic background. See Workup.

Colchicine is extremely effective in preventing attacks of FMF and preventing the development of amyloidosis. Biologic agents (eg, anakinra, rilonacept, canakinumab) are used for second-line therapy. See Treatment and Medication.

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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); the protein is also called marenostrin (derived from the phrase "our sea," because of the Mediterranean heritage of most patients).

Pyrin is expressed mostly in neutrophils. To date, its main functions have been determined to involve the innate immune response, such as inflammasome assemblage and, as a part of the inflammasome, sensing intracellular danger signals, activating mediators of inflammation, and resolving inflammation by the autophagy of regulators of innate immunity. [2] In patients with FMF, uninhibited pyrin activity results in uncontrolled production of interleukin-1 (IL-1), leading to episodes of inflammation (with accompanying fever) in the peritoneum, pleura, and joints; persistent subclinical inflammation is also common. [3, 4]

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. [5]

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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. [6] 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. [7]

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. [8, 9]

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. [10]

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- and Age-relate Demographics

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

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. In a retrospective review, 5 of 18 heterozygous children with onset below age 6 years went into remission at puberty and were able to stop colchicine. [11]

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