Familial Mediterranean Fever

Author: John O Meyerhoff, MD; Chief Editor: Herbert S Diamond, MD

Updated: Nov 6, 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.

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.

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 precolchicine-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, 8095% are younger than 20 years, a History
The preeminent feature of familial Mediterranean fever (FMF) is the paroxysm, the
classic onset of which occurs without warning, although some patients may be able to
detect premonitory symptoms. The paroxysms usually last 48-96 hours, with peak
intensity occurring within the first 12 hours. A plateau with resolution follows, usually
occurring more slowly than the onset of symptoms.

Fever
Temperatures rise rapidly to 38-40C (100.4-104F). Temperature
increases may occur before other manifestations.
o In mild attacks, fever may be the only manifestation.
Peritoneal symptoms
o Almost all patients with FMF experience abdominal episodes. Patients
develop abdominal pain that may progress to peritonitis, resembling a
surgical abdomen.
o Patients with FMF frequently have symptoms consistent with appendicitis
or cholecystitis and commonly undergo appendectomies and
cholecystectomies because the abdominal episodes of FMF are not
recognized as such.
o The symptoms may also mimic renal colic.
o In many cases, patients develop constipation during the attack and
diarrhea after the attack resolves.
o Even with recurrent attacks, adhesions are rare.
Pleural and pericardial symptoms
o The frequency of pleural and pericardial attacks varies among ethnic
groups, with 25-80% of patients reporting pleuritic episodes.
o Effusions occasionally occur. Pericarditis may develop, but tamponade
and constrictive pericarditis are rare.
Synovial symptoms
o The rate of synovial symptoms varies from 25-75% in reported series. The
episodes may resemble gout in their acute onset and intensity. Knees,
ankles, and wrists are the joints most commonly affected. An arthritis that
resembles seronegative spondyloarthritis may also occur.
o The joints are normal between attacks, and permanent damage is unusual.
o Arthritic symptoms tend to last several days longer than abdominal
symptoms. Episodes can be protracted.
o

Arthritis may be the only manifestation. FMF should be considered in

patients with a family history of FMF or who live in an endemic area.
Dermatologic manifestations
o As many as 50% of patients with FMF report erysipelaslike rashes on the
lower extremities, particularly below the knees.
o Rash and fever may be the only manifestations of attacks.
Muscle symptoms
o Recent descriptions more often include reports of severe myalgia lasting
3-6 weeks. These episodes do not respond to colchicine therapy.
o Symptoms are consistent with fibromyalgia.
Pelvic symptoms: Female patients with FMF may have episodes of pelvic
inflammatory disease.
Scrotal attacks: In males, inflammation of the tunica vaginalis testis may mimic
episodes of testicular torsion.
Vasculitis: An increased frequency of Henoch-Schnlein purpura and polyarteritis
nodosa is reported in persons with FMF, even in children. Behet disease is also
more common.
Amyloidosis
o In a patient of the appropriate ethnic group, the typical progression is
proteinuria, followed by nephrotic syndrome, and, inevitably, death from
renal failure.
o One third of patients with amyloidosis develop renal vein thrombosis.
Nephrotic syndrome is reported in patients as young as 14 years. Despite
the frequency and extent of amyloid deposits in the renal system, deposits
in other organs are only rarely reported as significant.
o Prolonged survival resulting from colchicine therapy, dialysis, and renal
transplantation allows additional manifestations of amyloidosis to develop.
Some patients have intestinal involvement, which may lead to
malabsorption and death.
o Some patients with a family history of FMF present with amyloid
nephropathy without ever having experienced an amyloid attack.
Furthermore, some patients with otherwise typical FMF may develop renal
failure without previous proteinuria.
o

Physical
Physical findings of FMF depend mostly on the serosal surface involved.

Temperatures can reach as high as 40C (104F), but, in most cases, rapid
defervescence occurs within 12 hours.
A boardlike or surgical abdomen is present with typical findings of peritonitis (ie,
abdominal tenderness, decreased bowel sounds). Splenomegaly is common in
response to the inflammation. Patients with pleural involvement may have
shallow breathing and chest-wall tenderness, but friction rubs are rare.
Joints show typical inflammatory changes, with warmth, erythema, or swelling.

A well-demarcated, erythematous, warm rash, particularly below the knee,

ranging from 15-50 cm2 may develop and may be accompanied by swelling.
Patients with painful myalgia syndrome may have tender muscles.
Female patients with symptoms mimicking pelvic inflammatory syndrome may
experience pain upon cervical motion and may develop tender enlarged ovaries.
Unilateral, erythematous, and tender swelling of the scrotum occurs in scrotal
attacks. The typical manifestations of Behet disease and Henoch-Schnlein
purpura may be observed.
Amyloidosis is usually asymptomatic, with hypertension reported in 35% of
patients late in the disease. Renal vein thrombosis may develop and manifests as
loin pain.

Causes
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.

Multiple mutations are located on the MEFV gene. Most of the 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.[2]
Other genes may be involved in FMF. This 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.

Differential Diagnoses

Acute Rheumatic Fever

Appendicitis
Calcium Pyrophosphate Deposition Disease
Gout
Lyme Disease
Nephrolithiasis
Pericarditis, Acute
Pleurodynia
Systemic Lupus Erythematosus

Laboratory Studies
Results of routine blood tests performed during the acute attacks of familial
Mediterranean fever (FMF) are nonspecific. Levels of acute-phase reactants (ie, Creactive protein, amyloid A protein, fibrinogen) are elevated, as is the erythrocyte
sedimentation rate. The WBC count is usually elevated during an attack. The elevated
levels rapidly return to the reference range as the attack abates.
Proteinuria should raise a concern about possible amyloidosis. For unknown reasons,
hematuria occurs in 5% of patients.
Synovial fluid is inflammatory, with cell counts as high as 100,000/L.
Genetic testing is now available for FMF. Testing for a limited number of genes may be
appropriate in patients with a known ethnic background. Complete gene sequencing may
be more helpful in patients of mixed or unknown ethnicity. Symptomatic patients with at
least one MEFV mutation should be considered to have FMF. Patients with no gene
mutations who meet criteria for FMF should be offered a trial of colchicine. Given the
high gene frequency and low penetrance in certain populations (eg, Ashkenazi Jews,
Armenians), gene testing should be closely correlated to clinical findings to avoid falsepositive results.

Imaging Studies
Findings during an acute attack in patients with peritonitis, pleuritis, and arthritis are as
expected and include air-fluid levels, pleural effusions, and synovial effusions.

Procedures
Amyloidosis can be presumed in patients with FMF, particularly those of North African
descent who have proteinuria. Renal biopsy or, alternatively, submucosal rectal biopsy, is
indicated in these patients.

Histologic Findings
Massive amyloid infiltration of the blood vessels and of the endothelial side of the
glomerular basement membrane occurs in the kidneys. In the rectal submucosa, the
amyloid is found near the blood vessels.

Medical Care
Colchicine is so effective in preventing attacks of familial Mediterranean fever (FMF)
and preventing the development of amyloidosis that the most important aspects of
medical care are to make the correct diagnosis and to institute therapy.

Administer colchicine therapy daily (0.6 mg bid or 0.5 mg bid, depending on the dosage
form available) in patients at risk of developing amyloidosis (eg, North African Jewish
people, Turkish people, Armenian people living in Armenia). Other Sephardic Jewish
people and Arabic people are at lower risk but also probably require daily colchicine
therapy.
Ashkenazi Jewish people and Armenian people living in America seem to be at extremely
low risk of amyloidosis and may need treatment only to prevent attacks. If attacks are
rare and patients can determine when they are beginning, treatment with intermittent
colchicine therapy at the onset of attacks may be sufficient.
The regimen for acute attacks in patients not taking daily colchicine is 0.6 mg every hour
for 4 doses, then 0.6 mg every 2 hours for 2 doses and then 0.6 mg every 12 hours for 4
doses. Colchicine should be started as soon as the patient recognizes that an attack is
occurring. If the initial doses are effective, patients may be able to do without the later
doses, but this varies from patient to patient.
In patients who do not respond to twice-a-day dosing, administer colchicine 3, or even 4,
times a day. In patients who have difficulty tolerating colchicine, start therapy at once-aday dosing and gradually increase the dose. In patients whose conditions were not
responsive to oral colchicine, the addition of 1 mg IV once a week reduced the number of
attacks in 10 of 13 patients and the severity of attacks in 6 of 13 patients.[6]
Some patients develop lactose intolerance and may respond to a lactose-free diet.
In patients whose conditions do not respond to colchicine, the use of interferon-alpha, the
tumor necrosis factorblocking drug etanercept,[7] and the IL-1 receptor antagonist
anakinra[8] may be effective. Rilonacept, a once-weekly subcutaneous injection IL-1
decoy receptor, has been shown, in combination with continuation of colchicine, to
reduce the number of attacks in patients who did not respond optimally.[9] Interferon-alpha
has been used in an intermittent fashion and as prophylaxis, with varying results.[10, 11, 12]
Colchicine also stabilizes the amount of proteinuria in patients with amyloid nephropathy.
Renal disease may resolve in patients with a creatinine level of less than 1.5 mg/dL who
are treated with more than 1.5 mg/d of colchicine.
Hemodialysis can be used for patients who develop renal failure. Peritoneal dialysis tends
to increase the number of abdominal attacks.
Patients who experience episodes of prolonged myalgia with fever and severe pain may
need treatment with prednisone (1 mg/kg) for as long as 6 weeks.
Patients with exertional lower extremity muscle pain respond to rest.
Treat patients with fibromyalgia with the usual agents for this condition.

Patients who develop seronegative spondyloarthropathy are treated with nonsteroidal

anti-inflammatory drugs. Some of these patients require remission-type drugs (as used in
rheumatoid arthritis) and receive follow-up care by a rheumatologist.

Surgical Care
Before the advent of colchicine therapy, renal transplantation was performed in patients
with end-stage renal disease due to amyloid nephropathy. Now, renal failure develops
only in patients who are not compliant with therapy or those who cannot tolerate
adequate doses of colchicine.

Consultations
Since the advent of colchicine therapy, most treated patients are asymptomatic and do not
need consultation with a specialist.
Consider consultation with a nephrologist for patients with proteinuria that is not
responsive to colchicine.
Consultation with a rheumatologist is indicated in patients with the following conditions:

Seronegative spondyloarthropathy not responsive to nonsteroidal antiinflammatory drugs

Fibromyalgia not responsive to the usual treatments
Coexistent Henoch-Schnlein purpura, polyarteritis nodosa, or Behet disease

Medication Summary
The goals of therapy are to reduce morbidity and to prevent complications.

Anti-inflammatory agents
Class Summary
Colchicine is the drug of choice for familial Mediterranean fever (FMF).
View full drug information

Colchicine (Colcrys)
Decreases leukocyte motility and phagocytosis in inflammatory responses.

Further Outpatient Care

Patients with familial Mediterranean fever (FMF) should be seen regularly to ensure
compliance with therapy. Only 2% of 906 patients who were at high risk and compliant
developed amyloidosis, compared with 49% of 54 patients who admitted noncompliance.
Teenagers are typically a noncompliant group and need long-term daily therapy to
prevent chronic complications. For many of these patients, noncompliance is associated
with severe symptoms, which may reinforce the need for therapy. Communicating with
patients' pharmacies to determine how often they are obtaining refills may be the best
way to assess compliance.
Perform a urinalysis at every visit, particularly in patients at risk of developing
amyloidosis. If proteinuria is present, assess patients carefully for compliance. Exclude
other causes of proteinuria (eg, heavy sports activity). If proteinuria is confirmed,
increase the daily dose of colchicine.
For unknown reasons, hematuria occurs in approximately 5% of patients. Its presence,
along with prolonged abdominal or muscle pain, suggests the development of
polyarteritis nodosa.

Complications
Patients with amyloidosis may develop an acute onset of renal failure if they are stressed
by dehydration, infection, or both.
Renal vein thrombosis may occur in nephrotic patients. This condition may manifest as
abdominal or flank pain, increasing proteinuria, and worsening renal function. Acute
anticoagulation may stabilize or improve renal function.

Prognosis
Patients who are compliant with daily colchicine can probably expect to have a normal
lifespan if colchicine is started before proteinuria develops.
Even with amyloidosis, the use of colchicine, dialysis, and renal transplantation should
extend a patient's life beyond age 50 years.

Patient Education
Patients with FMF need to understand the importance of strict compliance with daily
colchicine therapy.