About Familial Mediterranean Fever (FMF)

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About Familial Mediterranean Fever (FMF)

Familial Mediterranean fever (FMF) is a hereditary inflammatory disorder. 149 FMF is an autoinflammatory disease caused by mutations in Mediterranean fever gene, which encodes a 781 amino acid protein called pyrin. While all ethnic groups are susceptible to FMF, it “usually occurs in people of Mediterranean origin including Sephardic Jews, Mizrahi Jews, Armenians, Azerbaijanis, Arabs, Greeks, Turks and Italians”.

The disorder has been given various names, including familial paroxysmal polyserositis, periodic peritonitis, recurrent polyserositis, benign paroxysmal peritonitis, periodic disease or periodic fever, Reimann periodic disease or Reimann’s syndrome, Siegal-Cattan-Mamou disease, and Wolff periodic disease. Note that “periodic fever” can also refer to any of the periodic fever syndromes.

Familial Mediterranean Fever (FMF) is an ethnic disease for Armenians. Recurrent attacks of fever with tonsillitis are also clinical symptom of FMF, especially in early childhood. They are also characteristic of the PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, adenopathy), which can be confused with FMF.

Familial Mediterranean fever is an inflammatory disorder that causes recurrent fevers and painful inflammation of your abdomen, lungs and joints.

Familial Mediterranean fever is an inherited disorder that usually occurs in people of Mediterranean origin including Sephardic Jews, Arabs, Greeks, Italians, Armenians and Turks. But it may affect any ethnic group.

Familial Mediterranean fever is typically diagnosed during childhood. While there’s no cure for this disorder, you may be able to relieve signs and symptoms of familial Mediterranean fever or even prevent them altogether by sticking to your treatment plan.

Familial Mediterranean Fever (FMF) is an inherited disease, characterized by recurrent attacks of fever, inflammation of the abdominal lining (peritonitis), inflammation of the lining surrounding the lungs (pleurisy), painful, swollen joints (arthralgia and occasionally arthritis), and a characteristic ankle rash. This condition is also sometimes referred to as recurrent polyserositis or familial paroxysmal polyserositis.

FMF is considered a rare disease worldwide. However, it is very common in people of Sephardic (non-Ashkenazi) Jewish, Armenian, Arab and Turkish heritage. Among people with these backgrounds, about 1 in 200 has FMF.

The availability of genetic testing has helped identify numerous cases among several additional populations with Mediterranean roots, including: Ashkenazi Jews, Italians, Greeks, Spaniards, and Cypriots, and occasional cases in a broad range of other ethnicities (Northern Europeans and Japanese).

FMF is characterized by relatively short, usually 1- to 3-day, episodes of fever accompanied with serositis, synovitis or skin rash. In some patients, attacks begin in infancy or very early childhood, but 80 to 90 percent of patients experience their first episode by age 20.

Young children sometimes present with recurrent fevers alone. The frequency of FMF attacks is highly variable, both among groups of patients or for any individual patient, with the interval between attacks ranging from days to years. Moreover, the type of attack – whether abdominal, pleural or arthritic – may also vary over time. Between attacks, people commonly are symptom-free.

Other symptoms that may occur include inflammation of the lining surrounding the heart (pericarditis), inflammation of the testis (orchitis), benign, recurrent inflammation of the membrane that surrounds the brain and spinal chord (meningitis), headaches and amyloidosis.

Amyloidosis occurs when a particular protein, called amyloid, builds up in various tissues of the body, primarily the kidney. Potentially, it is the most serious complication of FMF, causing kidney failure. In some cases the amyloidosis can develop even without overt attacks of FMF.

Familial Mediterranean fever (FMF) is an inherited disorder characterized by an inflammatory response recurring with 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 complication that may develop if the disorder is not treated. FMF is most prevalent in people of Armenian, Sephardic-Jewish, Arabic, and Turkish ancestry. The disorder takes its name from the fact that these ethnic groups live in countries along or near the eastern coast of the Mediterranean Sea.

FMF is sometimes grouped together with other periodic fevers in a category called autoinflammatory disorders. The term was invented to describe illnesses caused by genetic defects in the human immune response. Other disorders in this group are TNF-receptor associated periodic syndrome (TRAPS), hyper-IgD syndrome (HIDS), and familial Hibernian fever.

Symptoms

There are seven types of attacks. Ninety percent of all patients have their first attack before they are 18 years old. All develop over 2–4 hours and last anywhere from 6 hours to 4 days. Most attacks involve fever.

Abdominal attacks, featuring abdominal pain, affect the whole abdomen with all signs of peritonitis (inflammation of abdominal lining), and acute abdominal pain like appendicitis. They occur in 95% of all patients and may lead to unnecessary laparotomy. Incomplete attacks, with local tenderness and normal blood tests, have been reported.

Joint attacks mainly occur in large joints, especially in the legs. Usually, only one joint is affected. 75% of all FMF patients experience joint attacks.

Chest attacks include pleuritis (inflammation of the pleura) and pericarditis (inflammation of the pericardium). Pleuritis occurs in 40% of patients and makes it difficult to breathe or lie flat, but pericarditis is rare.

Scrotal attacks due to inflammation of the tunica vaginalis occurs in up to 5% and may be mistaken for acute scrotum (i.e. testicular torsion).

  • Myalgia (rare in isolation)
  • Erysipeloid (a skin reaction on the legs, rare in isolation)
  • Fever without any of the other symptoms listed above (25%)

Signs and symptoms of familial Mediterranean fever usually begin during childhood. They occur in bouts called attacks that last one to three days. Arthritic attacks may last for weeks or months.

Signs and symptoms of familial Mediterranean fever include:

  • Fever
  • Abdominal pain
  • Chest pain
  • Achy, swollen joints
  • Constipation followed by diarrhea
  • A red rash on your legs, especially below your knees
  • Muscle aches
  • A swollen, tender scrotum

Between attacks, you’ll likely feel normal. Symptom-free periods may be as short as a few days or as long as several years.

The recurrent acute attacks of FMF typically begin in childhood or adolescence. These acute episodes of fever and painful inflammation usually last 12–72 hours. About 90 percent of people with FMF have their first attack by age 20. The group of symptoms that characterizes FMF includes the following:

Fever: An FMF attack is nearly always accompanied by a fever, but it may not be noticed in every case. Fevers are typically 100 to 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 only to have the fever and abdominal pain return.

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

Joint pain: About 50 percent 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 eventually becomes chronic arthritis.

Muscle pain (myalgia): Up to 20 percent of individuals with FMF 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 as long as one month have been reported.

Skin rash. A rash described as an erythema (skin reddening) resembling erysipelas accompanies FMF attacks in a minority of people. The rash typically occurs on the front of the lower leg or top of the foot, and appears as a red, warm, swollen area about 4–6 inches (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. The presence and deposition of excess SAA is known as amyloidosis. Amyloidosis may affect the gastrointestinal tract, liver, spleen, heart, and (in males) testes, but its effects on the kidneys are of greatest concern.

The frequency of amyloidosis varies among the different ethnic groups, and its overall incidence is difficult to determine because of the use of colchicine to avert the problem. Left untreated, however, those individuals who do develop amyloidosis of the kidneys may require a kidney transplant or may even die of renal failure. The frequency and severity of a person’s attacks of fever and serositis seem to have no relation to the risk of developing amyloidosis. In fact, a few people with FMF have been described who have had amyloidosis but apparently no other FMF-related symptoms.

Other symptoms: A small percentage of boys with FMF develop painful inflammation around the testes, while girls may experience episodes of inflammation in the pelvis. In other patients, headaches are a common occurrence during attacks. Lastly, certain types of vasculitis (inflammation of the blood vessels) seem to be more common in people diagnosed with FMF.

Diagnosis

The diagnosis is clinically made on the basis of the history of typical attacks, especially in patients from the ethnic groups in which FMF is more highly prevalent. An acute phase response is present during attacks, with high C-reactive protein levels, an elevated white blood cell count and other markers of inflammation. In patients with a long history of attacks, monitoring the kidney function is of importance in predicting chronic kidney failure.

A genetic test is also available to detect mutations in the MEFV gene. Sequencing of exons 2, 3, 5, and 10 of this gene detects an estimated 97% of all known mutations.

A specific and highly sensitive test for FMF is the “Metaraminol Provocative Test (MPT)”, whereby a single 10 mg infusion of Metaraminol is administered to the patient. A positive diagnosis is made if the patient presents with a typical, albeit milder, FMF attack within 48 hours. As MPT is more specific than sensitive, it does not identify all cases of FMF. Although a positive MPT can be very useful.

In making a diagnosis of Familial Mediterranean Fever (FMF), doctors take all of these factors into account:

  • Whether or not the patient has the clinical symptoms common for the disease and whether the symptoms are recurrent.
  • How he or she responds to colchicine treatment (see “How is Familial Mediterranean Fever treated?” below).
  • Usually a positive family history in people of Middle Eastern ancestry.
  • The results of genetic testing.
  • Also helpful in establishing a correct diagnosis of FMF is the patient’s ancestry. Testing for the following can also be helpful:
  • Elevated white blood cell count, which is an indication of an immune response.
  • Elevated erythrocyte sedimentation rate (ESR), which is an indication of an inflammatory response.
  • Elevated plasma fibrinogen, which helps stop bleeding. An elevated amount would indicate that something might be wrong with this mechanism.
  • Elevated serum haptoglobin, which would indicate that red blood cells are being destroyed, a common occurrence in rheumatic diseases, such as FMF.
  • Elevated C-reactive protein, which is a special type of protein, produced by the liver, that is only present during episodes of acute inflammation.
  • Elevated albumin in the urine, which is demonstrated by urinalysis. The presence of the protein albumin in the urine can be a symptom of kidney disease, along with microscopic hematuria (very small – microscopic – amounts of blood or blood cells in the urine), during attacks.

The diagnosis of FMF is often delayed because the symptoms that define the condition are common to many other disorders. Fevers occur for many reasons, and nonspecific pains in the abdomen, chest, and joints are also frequent ailments.

Several infections can result in symptoms similar to FMF (Mallaret meningitis , for instance), and many people with FMF undergo exploratory abdominal surgery and ineffective treatments before they are finally diagnosed. Membership in a less commonly affected ethnic group may also delay or hinder the correct diagnosis.

In many cases the doctor is able to diagnose the disorder only by a slow process of eliminating other diagnostic possibilities. He or she may order x rays or other imaging studies in order to rule out certain types of arthritis.

Direct analysis of the MEFV gene for FMF mutations is the only method to be certain of the diagnosis. While it was as of 2004 not yet possible to detect all MEFV gene mutations that might cause FMF, successful cloning of the MEFV gene has led to a rapid test that can identify the most common mutations of the gene.

Thus, if DNA analysis is negative, clinical methods must be relied upon. If both members of a couple were proven to be FMF carriers through genetic testing, highly accurate prenatal diagnosis would be available in any subsequent pregnancy.

Similar syndromes of periodic fever and inflammation include familial Hibernian fever and hyperimmunoglobulinemia D syndrome, but both are much less common than FMF.

Treatment

Attacks are self-limiting, and require analgesia and NSAIDs (such as diclofenac). Colchicine, a drug otherwise mainly used in gout, decreases attack frequency in FMF patients. The exact way in which colchicine suppresses attacks is unclear. While this agent is not without side effects (such as abdominal pain and muscle 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. Some advise discontinuation of colchicine before and during pregnancy, but the data are inconsistent, and others feel it is safe to take colchicine during pregnancy.

Approximately 5–10% of FMF cases are resistant to colchicine therapy alone. In these cases, adding anakinra to the daily colchicine regimen has been successful.

Colchicine is an anti-inflammatory chemical compound that can be used as a medication and is frequently prescribed for gout. In the late twentieth century, colchicine was discovered to also be effective in reducing the frequency and severity of attacks in FMF. Treatment for FMF in the early 2000s consists of taking colchicine daily.

Studies have shown that about 75 percent of FMF patients achieve complete remission of their symptoms, and about 95 percent show marked improvement when taking colchicine. Compliance with taking colchicine every day may be hampered by its side effects, which include diarrhea , nausea , abdominal bloating, and gas. Colchicine is also effective in preventing, delaying, or reversing kidney disease associated with amyloidosis.

Other medications may be used as needed to treat the pain and fever associated with FMF attacks. The most common drugs used are narcotics for severe pain and nonsteroidal anti-inflammatory drugs (NSAIDs) for arthritis and muscle pain. Dialysis and/or a kidney transplant might become necessary in someone with advanced kidney disease.

Causes

Familial Mediterranean fever is caused by a gene mutation that’s passed from parents to children. The gene mutation causes problems in regulating inflammation in the body.

In people with familial Mediterranean fever, the gene mutation occurs in a gene called MEFV. Many different mutations in MEFV are linked to familial Mediterranean fever. Some mutations may cause very severe cases, while others may be milder.

Risk factors

Factors that may increase the risk of familial Mediterranean fever include:

Having a family history of the disease. If you have a family history of familial Mediterranean fever, your risk of the disease is increased.

Being of Mediterranean ancestry. If your family can trace its history to the Mediterranean region, your risk of the disease may be increased. Familial Mediterranean fever can affect any ethnic group, but it may be more likely in Sephardic Jews, Arabs, Italians, Armenians and Turks.

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