Familial Mediterranean Fever

Familial Mediterranean fever is a hereditary condition that causes repeated episodes of fever and painful inflammation in the abdomen, chest, and joints, mainly affecting people of Mediterranean and Middle Eastern origin.

Table of contents

• What is Familial Mediterranean Fever?
• Other Names for This Condition
• Who Is Affected
• Signs and Symptoms
• Causes and Inheritance
• What Can Trigger Episodes
• Possible Complications
• How It Is Diagnosed
• Treatment Options
• Living with Familial Mediterranean Fever

periodic peritonitis, familial paroxysmal polyserositis, periodic disease, Siegal-Cattan-Mamou disease, Wolff periodic disease, Reimann syndrome

What is Familial Mediterranean Fever?

Familial Mediterranean fever (FMF) is a genetic condition that causes the body to experience repeated episodes of inflammation and fever^[1]. It is an autoinflammatory disease, which means the immune system causes inflammation without an infection or other clear reason^[2].

FMF triggers inflammation in special membranes throughout the body. These include the serous membranes that line the abdomen, chest, and the synovial membranes that surround the joints^[3]. The condition represents the most common of the periodic fever syndromes^[2].

The inflammation occurs in episodes or attacks that typically last between one and three days, though some joint attacks may last for weeks or months^[1]. Between these episodes, people usually feel completely healthy and have no symptoms^[1]. The time between attacks can be as short as a few days or as long as several years^[3].

Other Names for This Condition

Familial Mediterranean fever has been known by several different names throughout medical history. These include periodic peritonitis, familial paroxysmal polyserositis, periodic disease, Siegal-Cattan-Mamou disease, Wolff periodic disease, and Reimann syndrome^[2].

Who Is Affected

FMF primarily affects people whose ancestors came from areas around the Mediterranean Sea and the Middle East^[1]. The condition is most common among people of Armenian, Arab, Turkish, Jewish (both Sephardic and Ashkenazi), Greek, Italian, Kurdish, and Iranian heritage^[3].

In these populations, FMF can affect as many as 1 in 200 to 1 in 1,000 people^[6]. While FMF is most common in Mediterranean populations, it can affect people from any ethnic background^[1].

The first symptoms of FMF usually appear during childhood or the teenage years. In 90 percent of cases, episodes start before age 20, and about 75 percent of people with FMF experience their first symptoms before age 10^[7]. However, in some cases, the first attack can occur much later in life^[6].

Signs and Symptoms

The symptoms of familial Mediterranean fever occur in episodes that develop over several hours. Not everyone experiences every symptom, and fever is the most common sign. In young children, fever may be the only symptom^[3].

Common symptoms during an attack include^[1]:

• Fever, often reaching up to 105 degrees Fahrenheit (40.6 degrees Celsius), frequently with chills
• Abdominal pain and swelling, with rigid abdominal muscles that may cause constipation
• Chest pain that becomes worse with breathing
• Joint pain and swelling, usually affecting one large joint such as the knee, ankle, or hip
• A red, raised skin rash, often appearing on the legs, especially below the knees
• Muscle aches, particularly in the lower body
• Headache, often accompanied by neck stiffness
• In males, scrotal swelling and testicle pain

The abdominal pain can be severe and may be mistaken for appendicitis, sometimes leading to unnecessary surgery^[2]. Chest pain can make it difficult to breathe deeply or lie flat^[5]. Joint swelling typically resolves within one to two weeks^[7].

Some people experience warning signs in the days leading up to an episode. These prodromal symptoms can include anxiety, irritability, headache, nausea, body aches, and a general feeling of being unwell^[3].

Attacks generally resolve on their own after a few days. Between attacks, people typically feel back to their normal health^[1]. Symptoms are often severe in the early years and tend to become less frequent and less intense with age^[3].

Causes and Inheritance

Familial Mediterranean fever is caused by changes (mutations) in a gene called MEFV, which is located on chromosome 16^[2]. The MEFV gene provides instructions for making a protein called pyrin, which is found in white blood cells and plays an important role in controlling inflammation in the body^[6].

When the MEFV gene has mutations, it cannot produce pyrin properly. This causes problems in regulating the inflammatory response in the body, leading to episodes of uncontrolled inflammation^[1]. Around 300 different mutations of the MEFV gene have been identified. The most common mutations are V726A, M680I, E148Q, M694V, and M694I, which are responsible for about 70 to 80 percent of cases^[2].

FMF is usually inherited in an autosomal recessive pattern^[6]. This means a child must inherit two copies of the mutated gene—one from each parent—to develop the condition. Parents who each carry one copy of the mutated gene typically do not show symptoms but have a one-in-four chance with each pregnancy of having a child with FMF^[4].

However, about one-third of people with FMF have only one identified MEFV gene mutation. Experts believe there may be a second mutation that has not been detected by current genetic testing^[6]. About 10 percent of patients who are clinically diagnosed with FMF have no detectable mutations in the MEFV gene^[2].

What Can Trigger Episodes

While episodes of familial Mediterranean fever often seem to occur randomly, some people find that physical or emotional stress can trigger an attack. Common triggers that have been reported include^[3]:

• Exposure to cold
• Exercise or physical exertion
• Recent infection
• Recent injury or surgery
• Severe life stress
• Menstruation or ovulation in women

Possible Complications

The most serious complication of familial Mediterranean fever is amyloidosis^[1]. In this condition, a protein called amyloid A, which is not typically found in the body, builds up in organs and tissues, especially in the kidneys^[1]. This protein accumulation causes inflammation and interferes with how the organs work.

Without treatment, amyloidosis can lead to kidney damage and eventually kidney failure^[2]. Amyloidosis is considered the most fatal complication of FMF^[2]. In some people, amyloidosis may be the first sign of FMF^[1].

Even though episodes of FMF are temporary, going through repeated inflammatory processes can take a toll on the body over time. This is why healthcare providers strongly recommend continuous treatment^[3].

Rare complications include inflammation of the heart (pericarditis), the membrane surrounding the brain and spinal cord (meningitis), muscles (myositis), or testicles (orchitis)^[7].

How It Is Diagnosed

Diagnosing familial Mediterranean fever involves several steps. There is no single test that can definitively diagnose FMF, so doctors use a combination of methods^[8].

The diagnostic process typically includes^[1]:

• Physical examination: The doctor examines the patient and asks about symptoms
• Review of family medical history: A family history of FMF increases the likelihood of having the condition
• Blood tests: During an attack, blood tests may show elevated levels of markers that indicate inflammation, such as elevated white blood cells
• Urine tests: These can detect protein in the urine, which may indicate amyloidosis
• Genetic testing: A blood test can check for mutations in the MEFV gene

Genetic testing can confirm the diagnosis, but it has limitations. Current genetic tests cannot detect every gene change linked to FMF, so a negative test result does not completely rule out the condition^[8]. For this reason, doctors typically do not use genetic tests as the only method of diagnosing FMF.

Diagnostic criteria called the Tel-Hashomer clinical criteria are widely recognized and have more than 95 percent sensitivity and 97 percent specificity^[5].

Treatment Options

While there is no cure for familial Mediterranean fever, treatment can effectively control symptoms and prevent complications^[1]. Early diagnosis and treatment are crucial to reduce symptoms and prevent long-term complications like amyloidosis^[3].

Colchicine

Colchicine is the main treatment for FMF and is taken as a daily oral medication^[8]. Originally used to treat gout, colchicine is now also used to prevent FMF episodes^[15]. This medication reduces inflammation in the body and helps prevent attacks and the development of amyloidosis^[1].

Colchicine prevents episodes before they start but cannot treat an episode once it has begun^[7]. It is so effective that the most important aspects of medical care are making the correct diagnosis and starting treatment^[10]. The medication prevents attacks in more than 90 percent of patients^[4].

Most people with FMF need to take colchicine daily for life. Children with FMF who take colchicine as prescribed can have normal, long lives^[7]. The typical dosage is taken once or twice daily^[8].

Other Medications

If colchicine is not effective or if someone cannot tolerate it, other treatment options are available. These include medications that block interleukin-1, a substance in the body that promotes inflammation^[7]. The three most common interleukin-1 blockers used for FMF are:

• Anakinra (Kineret)
• Canakinumab (Ilaris)
• Rilonacept (Arcalyst)

Monitoring

People with mild symptoms who may not need daily treatment should still have their urine checked for protein every six months to watch for signs of amyloidosis^[13].

Living with Familial Mediterranean Fever

With early diagnosis and proper treatment, most people with familial Mediterranean fever can lead normal lives^[13]. The key to success is taking colchicine as prescribed without skipping doses^[7].

A healthy lifestyle that includes a nutritious diet, exercise, weight control, and stress relief can help manage symptoms and maintain overall health^[13]. By being proactive and getting on treatment in childhood, many people with FMF can avoid damage to their internal organs^[15].

Some children may need psychological support to cope with having a chronic illness that requires lifelong treatment. FMF episodes may affect school attendance, so teachers, school officials, and social workers can help children cope with these challenges^[7].

Genetic counseling is recommended for people newly diagnosed with FMF and for those planning to have children^[13]. This can help families understand the inheritance pattern and the chances of passing the condition to future children.

With regular treatment, children and adults with FMF can stay active, pursue their education, and lead productive lives^[7].