Familial Mediterranean Fever

Rare Inflammatory Disease Seen in Certain Ethnic Groups

Doctor assisting patient with severe abdominal pain
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Familial Mediterranean fever (FMF) is a rare genetic disorder that is primarily seen in certain ethnic populations. It is characterized by recurrent bouts of fever, appendicitis-like stomach pain, lung inflammation, and swollen, painful joints.

As a chronic, recurrent disorder, FMF can cause short-term disability and significantly impair a person’s quality of life.

Fortunately, newer, anti-inflammatory drugs have all but eliminated many of the more severe manifestations of the disease.

FMF is a recessive autosomal disorder, meaning that it is inherited from one’s parents. The disease is associated with mutations in the Mediterranean Fever (MEFV) gene of which there are more than 30 variations. For a person to experience symptoms, he or she would need to have inherited copies of the mutation from both parents. Even then, having two copies doesn’t always confer to illness.

While rare in the general population, FMF is seen more frequently in Sephardic Jews, Mizrahi Jews, Armenians, Azerbaijanis, Arabs, Greeks, Turks, and Italians.  

How Illness Is Caused

As opposed to an autoimmune disease in which the immune system attacks its own cells, FMF is an autoinflammatory disease in which the innate immune system (the body’s first-line defense) simply doesn’t work as it is should.

 Autoinflammatory diseases are characterized by unprovoked inflammation, predominately as a result of an inherited disorder.

With FMF, the MEFV mutation almost always affects chromosome 16 (one of the 23 pairs of chromosomes that make up a person’s DNA). Chromosome 16 is responsible for, among other things, creating a protein called pyrin found in certain defensive white blood cells.

While the function of pyrin is still not entirely clear, many believe that the protein is responsible for tempering the immune response by keeping inflammation in check.

Of the 30-plus variations of the MEFV mutation, there are four that are closely linked to symptomatic disease.

Symptoms

FMF primarily causes the inflammation of the skin, internal organs, and joints. The attacks are characterized by one- to three-day bouts of headache and fever alongside other inflammatory conditions, such as:

  • Pleurisy, the inflammation of the lining of the lungs characterized by painful respiration
  • Peritonitis, the inflammation of the abdominal wall characterized by pain, tenderness, fever, nausea, and vomiting
  • Pericarditis, the inflammation of the lining of the heart characterized by a sharp, stabbing chest pains
  • Meningitis, the inflammation of the membranes covering the brain and spinal cord
  • Arthralgia (joint pain) and arthritis (joint inflammation)
  • A widespread, inflamed rash, typically below the knees

Symptoms range in severity from mild to debilitating. The frequency of the attacks can also vary from every few days to every few years. While the signs of FMF can develop as early as infancy, it more commonly starts in one’s 20s.

Complications

Depending on the severity and frequency of attacks, FMF can cause long-term health complications. Even if symptoms are mild, FMF can trigger the overproduction of a protein known as serum amyloid A. These insoluble proteins can gradually accumulate in and cause damage to major organs, most predominately the kidneys.

Kidney failure is, in fact, the most serious complication of FMF. Prior to the advent of anti-inflammatory drug treatments, persons with FMF-associated kidney disease had an average life expectancy of 50 years.

Genetics and Inheritance

As with any autosomal recessive disorder, FMF occurs when two parents who don’t have the disease each contribute a recessive gene to their offspring.

The parents are considered "carriers" because they each have one dominant (normal) copy of the gene and one recessive (mutated) copy. It is only when a person has two recessive genes that FMF can occur.

If both parents are carriers, a child has a 25 percent chance of inheriting two recessive genes (and getting FMF), a 50 percent chance of getting one dominant and one recessive gene (and becoming a carrier), and a 25 percent chance of getting two dominant genes (and remaining unaffected).

Because there are well over 30 variations of the MEFV mutation, different recessive combinations can end up meaning vastly different things. In some cases, having two MEFV mutations can confer to severe and frequent bouts of FMF. In others, a person may be largely symptom-free and experience nothing more than the occasional, unexplained headache or fever.

Risk Factors

As rare as FMF is in the general population, there are groups in which the risk FMF is considerably higher. The risk is largely constrained to so-called "founder populations" in which groups can trace the roots of a disease back to a common ancestor. Due to the lack of genetic diversity within these groups (often due to intermarriage or cultural isolation), certain rare mutations are more readily passed from one generation to the next.

Variations of the MEFV mutation have been traced back as far as the Biblical times when ancient Jewish sailors began the migration from southern Europe to North Africa and the Middle East. Among the groups most commonly affected by FMF:

  • Sephardic Jews, whose descendants were expelled from Spain during the 15th century, have a one in eight chance of carrying the MEFV gene and a one in 250 chance of getting the disease.
  • Armenians have a one in seven chance of carrying the MEFV mutation and one in 500 of developing the disease.
  • Turkis and Arabic people also have between a one in 1,000 to one in 2,000 chance of getting FMF.

By contrast, Ashkenazi Jews have a one in five chance of carrying the MEFV mutation but only a one in 73,000 chance of developing the disease.

Diagnosis

The diagnosis of FMF is largely based on the history and pattern of the attacks. Key to the identification of the disease is the duration of the attacks which are rarely longer than three days.

Blood tests may be ordered to evaluate the type and level of inflammation being experienced. These include:

A urine test may also be performed to assess whether there is excess albumin in the urine, an indication of chronic kidney impairment.

Based on these results, the doctor may order a genetic test to confirm the MEFV mutation. In addition, the doctor may recommend a provocation test in which a drug called metaraminol can induce a milder form of FMF, usually within 48 hours of an injection. A positive result can provide the doctor with a high level of confidence in making the FMF diagnosis.

Treatment

There is no cure for FMF. Treatment is primarily directed at the management of acute symptoms, most often with nonsteroidal anti-inflammatory drugs like Voltaren (diclofenac).

To reduce the severity or frequency of attacks, the anti-gout drug Colcrys (colchicine) is commonly prescribed as a form of chronic therapy. Adults are typically prescribed a 0.6-milligram tablet to be taken twice daily.

So effective is Colcrys in treating FMF that 75 percent of sufferers report no further recurrence of disease, while 90 percent report marked improvement. Moreover, the use Colcrys is seen to greatly reduce the risk of FMF complications, including kidney failure.

Colcrys can also be used to treat acute attacks, usually prescribed as one, 0.6-milligram dose taken every hour for four doses, followed by 0.6 milligrams taken every two hours for two doses, and ending with 0.6 milligrams taken every 12 hours for four doses.

Side effects of Colcrys include stomach upset, anemia, and peripheral neuropathy (a numbness or pins-and-needles sensation of the hands and feet). These symptoms are largely avoided by taking smaller doses. Overuse of the drug can result in severe toxicity with symptoms of nausea, vomiting, diarrhea, and abdominal pain.

Colcrys cannot be used in persons with kidney dysfunction.

A Word From Verywell

If faced with a positive diagnosis of Familial Mediterranean fever, it is important to speak with a disease specialist to fully understand what the diagnosis means and what your treatment options are.

If prescribed Colcrys, it is important to take the drug every day as directed, neither skipping nor increasing the frequency of does. Persons who remain adherent to therapy can expect to have both a normal lifespan and a normal quality of life.

Even if treatment is started after kidney disease has developed, the twice-daily use of Colcrys can increase life expectancy well beyond the 50 years seen in persons with untreated disease.

Sources:

Fujikura, H. "Global epidemiology of Familial Mediterranean fever mutations using population exome sequences." Mol Genet Genomic Med. 2015; 3(4):272-82. 

Padeh, S, and Yakov, B. "Familial Mediterranean fever." Curr Opin Rheumatol. 2016; 28(5):523-29. DOI: 10.1097/BOR.0000000000000315.

Sonmez, H.; Batu, E.; and Ozen, S. "Familial Mediterranean fever: current perspective." J Inflamm Res. 2016; 9:13-20.