Free Online CME

How to Obtain AMA PRA
Category 1 Credit

  1. Read the CME monograph.
  2. Complete the CME post-test (each question must be answered correctly).
  3. Log into your myCME account.
  4. Complete the credit and evaluation form.
  5. Print your personalized CME certificate.

Technical Requirements

Familial Mediterranean Fever

Rula Hajj-Ali, MD

The clinical presentation of familiar Mediterranean fever (FMF) is characterized by sporadic, paroxysmal attacks of fever and serosal inflammation, which usually includes severe abdominal pain. It is inherited as an autosomal recessive trait. The gene responsible for FMF has been identified — a significant breakthrough that enhanced the medical understanding of the sequence of events in FMF.

Prevalence data show FMF primarily occurs in several ethnic groups originating in the Mediterranean area. In the US, FMF is frequently encountered in people of Ashkenazi Jew ancestry. However, FMF cases have been diagnosed in a wide variety of ethnic groups; thus, ancestry should not be used to rule out the diagnosis if other clinical characteristics are present.

Clinically, patients with FMF usually present with recurrent attacks of severe abdominal pain (in 95% of patients) and fever lasting 1 to 3 days that usually resolves spontaneously.1 More than 50% of patients experience a stereotypic prodrome before their attacks.2 The frequency of attacks varies, and there are no consistent triggering events, although some links have been observed with emotional stress, exposure to cold, vigorous exercise, and menstruation. Attacks tend to occur during the second half of pregnancy, indicating the probability of hormonal changes that affect the frequency of the attacks.

Most patients with FMF experience their first attack in early childhood. By age 10, 65% have experienced their initial attack. By age 20, 90% have experienced an attack.3 Because of this, it is important for clinicians to take the patient’s medical history back to infancy and childhood if FMF is suspected.


As noted, nearly all patients with FMF present with painful attacks localized to the abdomen.1 Pain and tenderness initially may be focal but then progress to become more generalized. The symptoms may closely resemble those of an acute surgical abdomen accompanied by guarding, rebound tenderness, rigidity, and a dynamic ileus. Exploratory laparotomy is sometimes unnecessarily performed. Recurrent attack of peritonitis may lead to adhesions, with the potential for causing small bowel obstructions or infertility in female patients.


Painful FMF attacks also can be localized to the chest. It is defined as direct inflammation in the pleura, but in some cases, it is referred pain from subdiaphragmatic inflammation. Pleural inflammation typically manifests as unilateral pleuritic chest pain with transient pleural effusions. Episodes typically resolve within 3 days but may last up to 1 week.


Arthritis is a common manifestation of FMF. North Africans are more prone to severe recurrent attacks of arthritis than Armenians and Ashkenazi Jews, who have relatively low prevalence rates. It is usually monoarticular or oligoarticular, and it usually affects large joints such as the knees, ankles, hips, and elbows. Joint effusions are common during synovitis attacks and can be inflammatory or noninflammatory. Inflammatory effusions are typically neutrophilic predominant.

Arthritis often occurs independently of other FMF manifestations and can last for weeks or months. Synovitis usually resolves without joint erosions; however, rare cases of deformity, functional limitation, osteoporosis, or aseptic necrosis have been reported. As noted, these reports are rare, so the effects cannot be generalized. Sacroiliitis occurs in up to 7% of FMF cases.

Erysipelas-like skin lesion

Approximately 7% to 40% of FMF patients experience an erysipelas-like skin lesion, most commonly those from the eastern Mediterranean region. These are tender, raised, erythematous lesions that mimic acute infectious cellulitis and usually occur unilaterally on the lower leg, ankle, or foot. Lesions are often the presenting feature of FMF in children. Recovery is mostly spontaneous and usually does not require antibiotics.

Other acute manifestations include the following:

  • Pericarditis, described in less than 1% of patients;
  • Self-limited orchitis and recurrent aseptic meningitis;
  • Rare protracted bouts of febrile myalgia lasting for a month or more;
  • Increased incidence of polyarthritis nodosa and Henoch-Schonlein purpura, both of which increase the risk of kidney involvement.4,5

Serum markers

During an acute attack, elevations occur in many serum markers of systemic inflammation: erythrocyte sedimentation rate, C-reactive protein, serum amyloid protein, fibrinogen, and beta-2 microglobulin. Leukocytosis with a predominance of neutrophils is common. Urine analysis is usually normal during an attack except if renal amyloidosis exists, in which case unexplained proteinuria may be seen between attacks.

Long-term complications

The primary long-term complication of FMF — secondary amyloidosis— is the major source of mortality in this disease. Before the advent of colchicine therapy, approximately 30% to 60% of patients with FMF died from amyloidosis.1,6 With the appropriate use of colchicine, 80% of patients have their proteinuria stabilize or regress.7

The prevalence of amyloidosis is much less common in Ashkenazi Jews and patients with FMF living in America, raising the question of whether there is a genetic predisposition to amyloidosis. At present, there is no definitive answer, although some evidence suggests a link. For example, the literature shows that some patients develop amyloidosis without any clinically apparent inflammatory attacks (ie, FMF type II). Also, there is a poor correlation between the severity or frequency of FMF attacks and the extent of amyloidosis. Furthermore, amyloidosis and severe arthritis are much more frequently observed with the V726A and the M694V mutation. It has been shown that beta and gamma alleles of type 1 serum amyloid are protective against the development of amyloidosis. These suggest that there is some genetic variability for the predisposition to amyloidosis.


The major criteria for the clinical diagnosis of FMF are the following:

  • Intermittent episodes of fever with robust interim health,
  • Concomitant serositis with abdominal pain and tenderness or pleuritis,
  • Absence of an alternative cause,
  • Responsiveness to colchicine,
  • Monoarthritis.

There are supportive criteria, such as a positive family history of Mediterranean ancestry, and amyloidosis may be present. Some patients will have had these symptoms since early childhood.

The most important feature is the episodic nature of attacks. Fever and FMF often comes up on the internet. It is important to differentiate the symptoms of FMS from other conditions that may present as abdominal pain and fever. The episodic nature of the pain along with high-grade fever (although not consistently through all the episodes) should provide clues for the diagnosis. Furthermore, the duration of the abdominal attack of FMF does not last more than 1 to 3 days.

Additionally, many other diseases and medical conditions closely resemble FMF. They need to be ruled out during the differential diagnosis (see table 1).

Table 1. Differential diagnosis of FMF: Medical conditions to rule out.
Appendicitis, intussusception, perforated peptic ulcer
Hereditary angioedema
Acute intermittent porphyria
Relapsing pancreatitis
Systemic lupus erythematosus and vasculitis
Abdominal epilepsy and abdominal migraine
Tumor necrosis factor receptor-1-associated periodic syndrome (TRAPS)
Hyper-IgD syndrome
Muckle-Wells syndrome
Familial cold autoinflammatory syndrome

Acutely, the most important symptom is the surgical abdomen. If the patient presents multiple times with these attacks, the diagnosis becomes clearer. There is some overlap with the other inflammatory disease, but not as much as the others. Fever and abdominal pain is more phenotypical than other autoinflammatory diseases.

When diagnosing a patient with recurrent febrile attacks, the first step is to exclude infection, autoimmune disease, and malignancies. The most important aspect is the family history as well as fever lasting just 1 to 3 days, which makes it a little bit different than the other autoinflammatory diseases.


The gene responsible for FMF, designated as MEFV, was identified on chromosome 16p13AE3 in 1997.8 The MEFV gene locus is composed of 10 exons encoding 781 amino acids, and the protein product has been named pyrin. Since then, more than 60 mutations have been detected for FMF. There are people who can carry the FMF gene but do not have symptoms. The carrier frequencies of mutant alleles are extremely high. Some people who have one allele have the clinical syndrome. Thus, having one allele is sufficient in the right clinical setting.

The initial segregation analyses indicated a recessive mode of inheritance for FMF. Mutations have not been identified in as many as 45% in the US and 28% in Jewish and Arab children in Israel. Up to 30% of FMF have only a single MEFV mutation within the coding sequence.

Several cases of apparently dominantly inherited FMF have been reported. At the molecular level, there have been other findings suggesting that FMF-associated pyrin mutation might lead to a gain of function, with gene-dosage effect, rather than a loss of function.


The most effective therapy for FMF is daily oral treatment with colchicine. Some patients require a high dose, up to 2 mg/day, which requires two or three doses every day. In turn, this creates an adherence problem that reduces outcomes. Most colchicine failures are actually caused by patients not taking the medication.

Clinically, colchicine prevents acute attacks and serum amyloid A amyloidosis. It is thought that a major effect is in modulating microtubules in neutrophils. It prevents inflammation by inhibiting neutrophil chemotaxis and reducing serum inflammatory cytokine levels. Reductions in inflammatory cytokine levels by colchicine can be explained by the finding that colchicine suppresses NF-kappa beta.

There may be a role for interleukin-1 blockade in FMF. Interleukin-1 beta is thought to be the major cytokine that actually propagates inflammation in this disease, and they may be abnormally induced by mutations in the C-terminal of the pyrin. Thus, the blockade of IL-1 beta could be a very important adjunctive therapy for FMF.

Rilonacept, an IL-1 beta blocker, has been shown to reduce the frequency of FMF attacks in patients with colchicine-resistant or colchicine-intolerant FMF.9 The design of this randomized, double-blind, single-participant trial was two 3-month courses of rilonacept and two 3-month courses on placebo. The outcome measures were differences in the frequency of FMF attacks and adverse effects. Overall, rilonacept reduced the frequency of FMF attacks and seemed to be a treatment option for patients with colchicine-resistant or -intolerant FMF. The study was limited by a small sample size, heterogeneity in the mutation, large age range, and patient indication (colchicine resistant or intolerance).


The following conclusions about FMF can be made:

  • It is defined as the sporadic, paroxysmal attacks of fever and serosal inflammation.
  • The cloning of the FMF gene (MEFV) enhanced the scientific understanding of the sequence of events.
  • Ethnic ancestry should not be used to rule out the diagnosis if other clinical characteristics are present.
  • Pyrin is composed of multiple domains with various roles in regulation of the innate immune response.
  • The major role of pyrin is the regulation of caspase-1 activation.
  • The inflammatory phenotypes of FMF are induced by IL-1 beta and NF-kappa beta, which are abnormally activated by FMF-associated mutations in the C-terminal domain of pyrin.
  • Blockade of IL-1 beta signaling or NF-kappa beta activation are intriguing targets for the treatment of FMF.

<< Previous

Next >>