MEDITERRANAEN SEA FEVER

By Dr.Sally Zeinatie




SYNONYMS:

periodic disease,
recurrent polyserositis,
familial Mediterranean fever

DEFINITION:

Familial Mediterranean fever (FMF) is an inherited disorder of the inflammatory response characterized by recurring attacks of fever, accompanied by intense pain in the abdomen, chest, or joints. Attacks usually last 12-72 hours, and can occasionally involve a skin rash.

Kidney disease is a serious concern if the disorder is not treated. FMF is most prevalent in people of Armenian, Sephardic-Jewish, Arabic, and Turkish ancestry.

PATHOPHYSIOLOGY:

Nonsense or missense mutations in the MEFV (Mediterranean fever) gene appear to cause the disease. This gene 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).

Mutations occur in exons 2, 3, 5 and 10.
The function of pyrin has not been completely elucidated, but it appears to be a suppressor of the activation of caspase 1, the enzyme that stimulates production of interleukin 1β, a cytokine central to the process of inflammation.

It is not conclusively known what exactly sets off the attacks, and why overproduction of IL-1 would lead to particular symptoms in particular organs (e.g. joints or the peritoneal cavity).

GENETICS:

The MEFV gene is located on the short arm of chromosome 16 (16p13). The disease inherits in an autosomal recessive fashion. Therefore, two asymptomatic carrier parents have a 25% chance of a child with the disorder. FMF patients who marry a carrier or another FMF patient have a 50% and 100% chance, respectively, in having a child with FMF.

CLINICAL SYMPTOMS:

Fever:
An FMF attack is nearly always accompanied by a fever, but it may not be noticed in every case. Fevers are typically 100-104°F (38-40°C). Some people experience chills prior to the onset of fever.

Abdominal pain:
Nearly all people with FMF experience abdominal pain at one point or another, and for most it is the most common complaint. The pain can range from mild to severe, and can be diffuse or localized. It can mimic appendicitis, and many people with undiagnosed FMF have had appendectomies or exploratory surgery of the abdomen done, only to have the fever and abdominal pain return.

Chest pain:
Pleuritis, also called pleurisy, occurs in up to half of the affected individuals in certain ethnic groups. The pain is usually on one side of the chest. Pericarditis would also be felt as chest pain.

Joint pain:
About 50% of people with FMF experience joint pain during attacks. The pain is usually confined to one joint at a time, and often involves the hip, knee, or ankle. For some people, however, the recurrent joint pain becomes chronic arthritis.

Myalgia:
Up to 20% of individuals report muscle pain. These episodes typically last less than two days, and tend to occur in the evening or after physical exertion. Rare cases of muscle pain and fever lasting up to one month have been reported

Skin rash:
A rash, described as erysipelas-like erythema, accompanies attacks in a minority of people, and most often occurs on the front of the lower leg or top of the foot. The rash appears as a red, warm, swollen area about 4-6 in (10-15 cm) in diameter.

Amyloidosis:
FMF is associated with high levels in the blood of a protein called serum amyloid A (SAA). Over time, excess SAA tends to be deposited in tissues and organs throughout the body.

DIAGNOSIS:

Symptoms involving one or more of the following broad groups should lead to suspicion of FMF: Unexplained recurrent fevers, polyserositis, skin rash, and/or joint pain; abnormal blood studies; and renal or other disease associated with amyloidosis

LAB STUDIES:

Results of routine blood tests performed during the acute attacks are nonspecific. Levels of acute phase reactants (ie, C-reactive protein, amyloid A protein, fibrinogen) are elevated, as is the erythrocyte sedimentation rate. The white blood cell 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/mL.
From the successful cloning of the MEFV gene, researchers have developed a rapid test for the most common mutations. Compared with gene sequencing, the test has a sensitivity and specificity of 100%. However, not every patient with FMF based on clinical criteria has a mutation as determined by testing for specific mutations. One explanation for this is that, although at least 30 identified mutations exist, 5 of them account for 99% of FMF cases, so testing for all 30 mutations, particularly in defined populations, is not cost-effective.

TREATMENT:

Attacks are self-limiting, and require analgesia and non-steroidal anti-inflammatory drugs (such as diclofenac.

Since the 1970s, colchicine, a drug otherwise mainly used in gout has been shown to decrease attack frequency in FMF patients. The exact way in which colchicine suppresses attacks is unclear. While this agent is not without side-effects abdominal painmuscle pains it may markedly improve quality of life in patients. The dosage is typically 1-2 mg a day.

Development of amyloidosis is delayed with colchicine treatment.


Interferon is being studied as a therapeutic modality.

PROGNOSIS:

For those individuals who are diagnosed early enough and take colchicine consistently, the prognosis is excellent.

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.

COMPLICATIONS:

AA-amyloidosis with renal failure is a complication and may develop without overt crises. AA (amyloid protein) is produced in very large quantities during attacks and at a low rate between them, and accumulates mainly in the kidney, as well as the heart, spleen gastrointestinal tract and the thyroid.

There appears to be an increase in the risk for developing particular vasculitis-related diseases (e.g. Henoch-Schoenlein purpura spondylarthropathy, prolonged arthritis of certain joints and protracted myalgia.