No, familial Mediterranean fever is not a fever you get when you go on a Mediterranean cruise with your family. It is a rare autosomal recessive genetic disease with recurrent fevers, rashes, and painful inflammation of the abdomen, lungs, and joints. The episodes can last up to three days at a time and, if not treated, can lead to certain complications, such as kidney failure. It primarily affects populations emanating from the Mediterranean area. The disease is very ancient – probably beginning over 2500 years ago.
I had the privilege of interviewing Dr. Terri Getzug, who is a specialist in gastroenterology and Associate Clinical Professor of Medicine at the David Geffen School of Medicine at UCLA. Outside of Israel, Dr. Getzug is one of the few experts in Familial Mediterranean Fever (FMF), and at UCLA she directs a premiere dedicated clinic devoted to the recognition and treatment of this complex and challenging disorder.
Dr. Lavin: How do these patients present and what are their symptoms?
Dr. Getzug: Often, patients come to the doctor complaining of recurrent attacks of severe abdominal pain caused by peritonitis (an inflammation of the abdominal cavity) accompanied by fever. Sometimes, chest pain can occur due to pleuritis (an inflammation of the lung cavity). Some patients manifest arthritis (painful swelling of the joints), which occurs in 75% of North African Jews. Others develop a skin rash, and still others present with amyloidosis – a potentially deadly buildup of protein in vital organs, such as the kidney. This is the most severe complication, which, if not prevented and treated, can lead to end-stage kidney failure.
Dr. Lavin: How often do these events occur and at what age?
Dr. Getzug: As FMF is a genetic disease, it can manifest at any age after birth. The peak incidence is between 5 to 15 years of age; although it rarely can begin as late as age 30 (90% of patients are diagnosed by age 20). The frequency of attacks is variable, but specific for each patient; they can occur weekly to once annually. An episode can last 24 – 72 hours, and between attacks, patients are completely well.
Dr. Lavin: Other than the unique clinical presentation, can laboratory tests help make the diagnosis?
Dr. Getzug: Not really. Lab testing during an attack is nonspecific, but genetic testing can help make the diagnosis. This diagnosis generally is based on three factors: (1) typical clinical presentation; (2) a positive response to treatment with a medicine called colchicine; and (3) genetic testing.
Dr. Lavin: What are the long-term complications?
Dr. Getzug: The major cause of morbidity and mortality for FMF patients is secondary amyloidosis, which has declined markedly with the advent of treatment with Colchicine. Amyloid is a protein which forms in response to chronic inflammation. Amyloid deposition occurs in the kidneys, spleen, liver and gut, and to a lesser degree in other organs. The kidney is the most frequently involved organ leading to renal failure if not treated early with colchicine. Another complication is disabling arthritis, usually occurring in the hip joints and sometimes requiring hip replacement.
Dr. Lavin: Tell us about the genetic makeup of patients with FMF.
Dr. Getzug: The cloning of the FMF gene (MEFV) in 1997 made genetic testing possible. Since FMF is inherited as an autosomal recessive trait, two mutations (one from each parent) is required for clinical disease, but some patients have only one mutation and some have none detectable. Currently, with standard genetic testing, we are able to detect 13 of the most common mutations. There is a 1 in 4 chance that a child will inherit normal genes from both parents; therefore, he/she will not get the disease. There is a 2 in 4 chance that a child will inherit one mutated gene from one parent and a normal gene from the other parent; therefore, the child will be a carrier like his parents, but free of disease.
Dr. Lavin: What is the ethnic makeup of these patients?
Dr. Getzug: FMF has been described primarily in Sephardic Jews, Armenians, Turks, North Africans, Arabs and less commonly Greeks and Italians. More than 90% of Jewish FMF patients are of Sephardic or of Middle Eastern origin. In North African Jews, the carrier rate is 1 in 6, with clinical disease occurring in 1 in 256 people of that ethnic population. In Israel, the clinical disease ratio is 1 in 500. FMF affects both sexes in a similar ratio. Even though the prevalence is high, there is incomplete penetrance, so that not everyone who has the two mutated genes has the complete clinical presentation.
Dr. Lavin: What causes FMF? Is it an autoimmune disease?
Dr. Getzug: FMF is not an autoimmune disorder, like lupus for example, since it does not respond to steroids or other immunosuppressant medications, and autoantibodies have never been demonstrated. The specific cause is unknown, but it is probably an inflammatory process in which inflammation sporadically is triggered and runs unchecked, attacking specific tissues in the body.
Dr. Lavin: What is the treatment?
Dr. Getzug: Colchicine (which is used for gout) is the treatment of choice. About 80 – 90% of patients respond with complete remission, and virtually all others show some improvement in attack frequency and severity. Although the exact mechanism of action is unknown, colchicine is believed to exert its effect on a specific type of protein in white cells that may be responsible for the clinical inflammation in this disorder.
Dr. Lavin: Thank you Dr. Getzug for your expertise and your ongoing commitment to enhancing the health of the Jewish Community.
For further information contact:
Terri Getzug, M.D.
Director, Familial Mediterranean Fever Clinic
Division of Digestive Diseases
David Geffen School of Medicine at UCLA