Overview of Familial Mediterranean Fever

Familial Mediterranean fever (FMF) is a rare genetic disorder that is primarily seen in some ethnic populations. It is also sometimes called familial paroxysmal polyserositis or recurrent polyserositis. 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, they would need to have inherited copies of the mutation from both parents. Even then, having two copies doesn’t always confer illness.

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

Overview

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 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 (inflammation of the lining of the lungs; characterized by painful respiration)
• Peritonitis (inflammation of the abdominal wall; characterized by pain, tenderness, fever, nausea, and vomiting)
• Pericarditis (inflammation of the lining of the heart; characterized by sharp, stabbing chest pains)
• Meningitis (inflammation of the membranes covering the brain and spinal cord)
• Arthralgia (joint pain) and arthritis (joint inflammation)
• Widespread, inflamed rash; typically occurs below the knees
• Myalgia (muscle pain) that can be severe
• Inflammation of the testes, causing pain and swelling (which can increase risk of infertility)
• Spleen enlargement

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.

Individuals with FMF also appear to have an increased incidence of other inflammatory diseases such as different forms of vasculitis and inflammatory bowel disease (Crohn's disease and ulcerative colitis).

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 severe and frequent bouts of FMF. In others, a person may be largely symptom-free and experience nothing more than an occasional unexplained headache or fever.

Risk Factors

As rare as FMF is in the general population, there are groups in which the risk of 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 biblical times when Jewish sailors began the migration from Southern Europe to North Africa and the Middle East. Following are 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 a one in 500 chance of developing the disease.
• Turkish and Arabic people 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 is rarely longer than three days.

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

• Complete blood count (CBC) (used to detect an increase in defensive white blood cells)
• Erythrocyte sedimentation rate (ESR) (used to detect chronic or acute inflammation)
• C-reactive protein (CRP) (used to detect acute inflammation)
• Serum haptoglobin (used to detect whether red blood cells are being destroyed, as happens with autoinflammatory diseases)

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 healthcare provider may order a genetic test to confirm the MEFV mutation. In addition, the practitioner 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 healthcare provider 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 1 to 1.5 milligrams a day, although up to 3 milligrams might be used in more severe disease. The dose is decreased for liver and kidney disease. No matter your condition, your healthcare provider will work to find the lowest effective dose.

So effective is Colcrys in treating FMF that 90 percent of sufferers report marked improvement. Moreover, the use of Colcrys is seen to greatly reduce the risk of FMF complications, including kidney failure.

Side effects of Colcrys can include nausea, diarrhea, and abdominal pain. Much more rare side effects include bone marrow suppression (causing low white blood cell count, low platelets, or anemia), liver toxicity, rash, muscle injury, and peripheral neuropathy (a numbness or pins-and-needles sensation of the hands and feet). Caution must be taken when using Colcrys in the presence of liver or kidney disease.

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 doses. Persons who remain adherent to therapy can generally 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.