Familial Mediterranean Fever

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Fast Facts

  • Familial Mediterranean Fever (FMF) is an inherited disorder manifested by with episodic fevers, often with pain in the abdomen, joints, or chest. 
  • FMF is a clinical diagnosis that can be confirmed by a gene mutation in the majority of cases.
  • Life-long treatment is used to prevent fever episodes and long-term injury to internal organs.

Familial Mediterranean Fever (FMF) is a genetic disorder that causes recurrent episodes of fever that are typically accompanied by pain in the abdomen, chest, or joints. It most often occurs in individuals of Mediterranean and Middle Eastern descent, and the first episodes typically begin in childhood.

The disease generally affects people of Mediterranean and Middle Eastern descent, typically Sephardic Jews, Turks, Arabs, and Armenians. Since the discovery of the gene defect, it is being diagnosed more frequently, even among populations where it was thought to be very rare, such as Italians, Greeks, Ashkenazi Jews, and even Asian populations. FMF episodes start before the age of 20 years in approximately 90% of the patients. In about 75% of patients, fever appears before the age of 10 years. 

What are the main symptoms of Familial Mediterranean Fever?

The main symptoms of Familial Mediterranean Fever are recurrent episodes of fever, accompanied by abdominal, chest, or joint pain. Not all children will have all the symptoms, and symptoms may change over time. Episodes usually last one to three days and go away without treatment. Most children look and feel healthy between episodes, but some children have such frequent episodes they do not fully recover or do not grow properly. Some of the episodes may be so painful that the patient or family seeks medical help in the emergency department. Severe abdominal pain may look like appendicitis, and some patients may undergo surgery to remove the appendix. The chest pain may be so severe that it is difficult to breathe deeply.

Joint pain may accompany the episodes of fever. Usually, only one joint is affected at a time, most commonly an ankle or a knee. The joint may be so swollen and painful that the child cannot walk. One-third of patients may have a red rash over the lower extremities, usually near the ankles and feet. In some children, the only finding of the disease may be episodes of joint pain and swelling, which can be misdiagnosed as acute rheumatic fever or juvenile idiopathic arthritis. Usually the joint swelling resolves over 5 - 14 days, but sometimes may become chronic (long-term).

Some children report muscle pain in the legs, especially after physical exertion. Rarely, children have recurrent pericarditis (inflammation of the outer layer of the heart), myositis (muscle inflammation), meningitis (inflammation of the membrane surrounding the brain and spinal cord), or orchitis (testicular inflammation). Children less than five years old may only have episodes of recurrent fever without other symptoms.

What causes Familial Mediterranean Fever?

FMF is genetic disease caused by mutations in the MEFV gene. While initially thought to be a recessive disease requiring two abnormal copies of the MEFV gene—one from the mother and one from the father—children can have FMF even if with only one mutated gene. Often, someone in the extended family has the disease. Rarely, patients may be diagnosed with FMF even when no abnormal gene is found.

The MEFV gene makes a protein called pyrin. Pyrin plays a role in the natural control of inflammation. When the MEFV gene does not work correctly, inflammation gets out of control, and patients experience episodes of fever and pain in the absence of an infection. Triggers for FMF flares include infection, trauma, strenuous exercise, menstrual periods, or psychological stress.

How is Familial Mediterranean Fever diagnosed?

A test to look for gene mutations may be done in cases where FMF is suspected. It is possible to have FMF and have a defect in just one gene or none at all. In the United States, more than 30% of the patients with FMF do not have mutations in both genes. Therefore, the diagnosis of FMF is still based on symptoms and physical examination by the physician, and can be difficult to make.

FMF is suspected in children with episodic fever and an ethnic background common for FMF. A family member may also have FMF or unexplained kidney failure. Children, especially those younger than five years of age, may have periodic fevers without the other symptoms, so it takes careful observation to make a diagnosis. Families can help by keeping a diary documenting when the fevers happen. Examining the child during a fever and obtaining laboratory tests that show signs of inflammation can be helpful.

In some cases a medication called colchicine, will be given for three to six months as a test to see if episodes of pain and fever become less frequent or severe, which may support diagnosis of FMF.

How is Familial Mediterranean Fever treated?

FMF cannot be cured, but it can be controlled with life-long use of colchicine, a medication that is taken by mouth one to two times a day. Colchicine prevents episodes from starting, but does not treat an episode that has already started. If the patient stops taking the medicine, episodes may return even after missing only one dose. If colchicine is taken regularly, the vast majority of children with FMF can live a normal life with a normal life expectancy. Do not change the medication dose without first discussing it with your doctor.

The most common side effects of colchicine are abdominal pain and diarrhea. If this occurs, the dose can be reduced until it is tolerated and then slowly increased back to the appropriate dose. Reducing the intake of milk or other dairy products, or consuming lactose-free milk may help. Other side effects are nausea, vomiting, and abdominal cramps. In rare cases, colchicine may cause muscle weakness, especially when taking antibiotics from the erythromycin (macrolide) family or statins (cholesterol medications). Therefore, these medications need to be given with caution with colchicine. The blood counts (white and red blood cells and platelets) may decrease occasionally and there may be mild elevations in liver enzymes, but these usually recover with dose reduction. Children taking colchicine grow normally.

Female patients do not have to stop taking colchicine during pregnancy or breast-feeding. Children treated with colchicine should have blood and urine tests at least twice yearly.

About ten percent of patients do not respond adequately or cannot tolerate colchicine. Recent research has found that medications that block interleukin-1, an important protein involved in the inflammatory process, may be effective for the majority of these patients. These medications include rilonacept (Arcalyst), anakinra (Kineret), and canakinumab (Ilaris).

Broader health impacts of Familial Mediterranean Fever and how to prevent them

The most severe complication of untreated FMF is the development of amyloidosis. Amyloid is a protein that deposits in the organs of patients who have chronic inflammatory diseases that are not well-controlled. The most common organ involved is the kidney, but amyloid can deposit in the intestines, skin, and heart. Eventually, amyloid causes a loss of function, especially in the kidneys. If this occurs, dialysis or a kidney transplant might be necessary. Life-long treatment with colchicine has been shown to prevent development of amyloid; this complication is exceedingly rare in the United States. Patients with amyloidosis in the kidney will have high levels of protein in urine tests. Patients with FMF should have urine tests at least twice a year.

Living with Familial Mediterranean Fever

Some children initially need psychological support to cope with a disease that requires taking medications for their entire lives. Frequent episodes can affect the both the child and family life, including school attendance, so involvement of teachers, social workers, tutors, and other community members may be helpful. Most children, however, adapt to the treatment, and when well controlled, FMF should not interfere with a normal education and productive adult life.

Updated May 2019 by Jonathoan Hausmann, MD, and reviewed by the American College of Rheumatology Committee on Communications and Marketing.

This information is provided for general education only. Individuals should consult a qualified health care provider for professional medical advice, diagnosis and treatment of a medical or health condition.

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