Practice Essentials
Familial Mediterranean fever (FMF), also known as recurrent polyserositis, is a hereditary autoinflammatory disorder characterized mainly by brief recurrent episodes of peritonitis, pleuritis, and arthritis, usually with accompanying fever. Attacks often begin in childhood; in approximately 90% of cases, clinical onset is before age 20 years. [1] See Presentation. As the name indicates, FMF occurs within families and is most common in individuals of Mediterranean descent. [2]
FMF is a clinical diagnosis, but it can be supported by genetic testing. In select patients with the appropriate ethnic background, testing for a limited number of genes may be used. See Workup.
Colchicine is extremely effective in preventing attacks of FMF and preventing the development of amyloidosis. Colchicine is typically administered daily, but if attacks are rare and patients can determine when they are beginning, intermittent treatment at the onset of attacks may be sufficient. An important benefit of treatment is the prevention of secondary amyloidosis, which otherwise could result in kidney failure. [3] Biologic agents (eg, anakinra, rilonacept, canakinumab) are used for second-line therapy. See Treatment and Medication.
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 (because of 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. [4]
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. [2, 5]
FMF attacks are also characterized by the release of neutrophil extracellular traps (NET), which are chromatin filaments ‘decorated’ with neutrophil granular and cytoplasmic proteins, including active IL-1β. NETs restrict their own generation by a negative feedback mechanism, which may help explain the self-limited nature of FMF attacks. [6, 7]
Presumably, the inflammatory episodes in persons with FMF lead to the excess production of amyloid A protein in the acute phase and reactant serum amyloid A with subsequent deposition in the kidneys. However, only patients with specific MEFV haplotypes develop amyloidosis. [8]
Etiology
FMF is a recessive genetic disease associated with missense and nonsense mutations in the MEFV gene, which is located on the short arm of chromosome 16. This gene codes for the protein known as pyrin or marenostrin.
More than 310 sequence variants in the MEFV gene have been identified, although not all not associated with a disease phenotype. [7] Most of the pathogenic mutations are in exon 10 of the gene between amino acids 680 and 761. One mutation, in exon 1 at amino acid 148, may represent as many as one quarter of the known mutations. Although certain mutations are more common in particular ethnic groups, patients usually inherit different mutations from each parent.
Homozygotes for M694V (valine for methionine at position 694) may experience more severe disease and may be more likely to develop amyloidosis. Patients with V726A (alanine for valine at position 726) may be at a lower risk of developing amyloidosis, although one study suggests that the combination of V726A and E148Q may be particularly amyloidogenic. [9]
Other genes may be involved in FMF. This possibility is supported by patients who meet criteria for FMF without identifiable mutations in MEFV and who have clinical manifestations that are indistinguishable from patients with MEFV mutations.
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. [9] 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. [10]
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. [11, 12]
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. [13]
Sex- and age-related demographics
In adults, FMF is more prevalent in men than in women, with a male-to-female ratio of 1.5-2:1.
At onset of symptoms, 50-60% of persons with FMF are younger than 10 years, 80-95% are younger than 20 years, and 5-10% are older than 20 years. Onset in persons older than 40 years is rare, and these individuals tend to experience milder disease. [1] In a retrospective review, 5 of 18 heterozygous children with onset before age 6 years went into remission at puberty and were able to stop colchicine. [14]
Prognosis
Patients who are compliant with daily colchicine can probably expect to have a normal lifespan if colchicine is started before proteinuria develops. Patients with amyloidosis may develop an acute onset of kidney failure if they are stressed by dehydration, infection, or both. Even with amyloidosis, the use of colchicine, dialysis, and kidney transplantation should extend a patient's life beyond age 50 years.
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.
Complications
Renal vein thrombosis may occur in nephrotic patients. This condition may manifest as abdominal or flank pain, increasing proteinuria, and worsening kidney function. Acute anticoagulation may stabilize or improve kidney function.
Many patients with undiagnosed FMF have undergone appendectomy because the severity of the peritoneal episodes seemed to indicate appendicitis.
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.
Approximately one third of female patients with FMF are infertile, and 20-30% of pregnancies result in fetal loss.
Patient Education
Patients with FMF need to understand the importance of strict compliance with daily colchicine therapy. Patient education information on FMF is available through the American College of Rheumatology.
