Questions and Answers about FMF
This concept refers to non-infectious recurrent fever diseases that are not caused by viral or bacterial infections. Typically, children who experience these symptoms are healthy between each fever episode. Many of these conditions are inherited from parents and result from genetic mutations. The different syndromes are defined by several characteristics: the genetic mutation, symptoms and signs during physical examination, affected organs and systems (in addition to fever), the child's age at the onset of the disease, family history, duration of the episodes, and the time interval between the attacks.
Many of these syndromes have unique treatments that are mostly based on understanding the problem caused by the genetic mutation. Today, these diseases are referred to as "autoinflammatory syndromes," where the common feature among these diseases is an excessive activity of the natural immune system shared by all humans (and animals) alike.
This is the most common genetic syndrome of recurrent fever. Patients with FMF experience recurrent fever episodes and often suffer from severe abdominal pain, chest pain, swelling, and joint pain. The disease primarily affects individuals of Mediterranean origin, mostly Jews of North African, Sephardic-Spanish, or Iraqi descent, as well as Arabs, Turks, and Armenians. Sometimes the disease is diagnosed through genetic testing, even among populations where the disease is considered extremely rare, such as Ashkenazi Jews, Italians, Greeks, and even Japanese. FMF episodes usually begin before the age of 20 in about 90% of patients, with over half of them experiencing the disease's onset before the age of 10.
Causes of the Disease:
FMF is a genetic disorder. The responsible gene is called MEFV, named after the Mediterranean Sea, and it affects a protein called pyrin, which plays a role in regulating the inflammatory process. When there is a defect in this gene, the inflammatory process cannot be properly controlled, leading to recurrent fever episodes and other symptoms in patients. Infections, physical exertion, trauma (falls, injuries), the start of the menstrual cycle, and emotional stress/excitement (both positive and negative) can trigger additional fever episodes.
FMF is inherited as an autosomal recessive genetic disease, which means that while a child may have the disease, neither of the parents may show signs of the condition. In such a case, the child has received two faulty genes for the pyrin protein, one from the mother and one from the father. The parents are referred to as "carriers." Often, the disease can also occur in another child within the extended family. If there is one affected child, and the parents are carriers, there is a 25% chance that another child will have FMF. If one of the children and one of the parents have FMF, there is a 50% chance that another child will have FMF.
The fever in FMF is not contagious.
The main symptoms of the disease are recurrent fever accompanied by abdominal, chest, or joint pain. Not all children will experience all the symptoms, and the symptoms may vary over time. Fever episodes usually resolve without treatment and typically last between less than a day to three days.
Most children are completely healthy between fever episodes, but some may suffer from frequent fever episodes that do not allow for complete recovery or hinder their proper growth and development. In some cases, the pain can be severe enough to cause concern, and the family may seek medical attention fearing conditions like appendicitis or other serious illnesses. Joint pain can be so intense that it affects walking. Around one-third of patients develop a red rash on the affected joint, often near the wrists and the soles of the feet.
In some children, the only manifestation of the disease may be episodes of joint pain and swelling, which can be mistakenly diagnosed as growing pains or idiopathic juvenile arthritis. Usually, the swelling resolves within 3-10 days. In 5%-10% of cases, the affected joint may become chronically involved. Some children report muscle pain in their legs, especially after physical activity. In rare cases, children may experience pericarditis (inflammation of the heart lining), myositis (inflammation of muscles), encephalitis (inflammation of the brain), or orchitis (inflammation of the testicles). Frequent episodes can significantly impact the child's and their family's life, including their education.
The most severe complication of untreated FMF is the development of Amyloidosis. Amyloid is a protein that accumulates in certain organs as a result of untreated chronic inflammation. The main affected organ is the kidney, but amyloid can also accumulate in the intestines, skin, and heart. Over time, amyloid will lead to excessive protein excretion in the urine, followed by kidney dysfunction and kidney failure. Patients treated with colchicine will not develop this life-threatening complication.
Can FMF also begin in adults?
Yes, it can, but in most cases, the disease will be milder and the classic symptoms will be less evident, making it more difficult to diagnose. The risk of developing amyloidosis is lower when FMF first appears in adulthood.
Although FMF is a genetic disease, the genetic defect is not present in all children with FMF. In about 30% of patients, only one copy of the gene carries the mutation (defect). Therefore, the diagnosis of FMF is based on clinical signs in combination with genetic testing. The suspicion of FMF increases when a child experiences recurrent fevers, and their family has a Mediterranean origin. Other factors that raise suspicion include a family history of FMF, close relatives with the condition, or unexplained kidney dysfunction. Often, children may experience fever episodes without additional symptoms, especially those under the age of 5, making patience and long-term monitoring necessary until a definitive diagnosis is reached.
It is recommended that the family keeps a journal documenting the fever episodes and what happens during them. Photographs of findings such as red rashes or joint and testicular swelling can also be helpful. Since not all children will have typical events, it may take time until FMF is suspected and a final diagnosis is made.
During an event, a physical examination and laboratory tests, such as blood tests to measure inflammation markers or blood cell counts, can assist in the diagnosis. In most cases, laboratory results will show signs of inflammation during an episode and return to normal or almost normal between episodes. However, in children with severe FMF, blood tests may not always return to normal, and fever episodes resemble "volcanic eruptions" over a background of ongoing inflammation. A general urine test, particularly measuring protein levels in the urine, is also accepted. High protein levels in the urine may raise suspicion of amyloidosis.
In children with suspected FMF, a genetic test is performed to search for genetic defects. If the results are positive, the diagnosis of FMF is confirmed. However, a child may have FMF when the defect is present in only one copy of the gene or even in the absence of a defect in the tested section of the relevant gene since genetic testing in Israel examines only specific regions of the entire gene. About 30% of FMF patients do not have a mutation in both copies of the gene. In such cases, the response to colchicine treatment can assist in the diagnosis. There is a high likelihood that children with recurrent fevers who do not experience events or experience significantly reduced frequency while on colchicine treatment indeed have FMF. In most cases, a therapeutic trial is conducted for 3-6 months.
There is no cure for FMF, but the disease can be well managed with the medication colchicine. The medication is taken orally once or twice a day, and the treatment is lifelong. Through pharmacological treatment, FMF episodes can be prevented (complete prevention is achieved in about 2/3 of patients, partial prevention in about 30%, and in 5% colchicine is not effective), and the risk of developing amyloidosis is almost 100% prevented. If the patient stops taking the medication, episodes and the risk of amyloidosis may return (often even missing a single dose can trigger an attack!). It is crucial to strictly adhere to the physician's instructions for taking the medication. If the child regularly takes colchicine, they can live a normal life and expect a regular lifespan. The dosage of the medication should not be changed without consulting the treating physician first. Colchicine prevents new attacks from occurring but does not treat an attack that has already started. Therefore, the dosage should not be increased during an active episode.
Some children may require psychological support to cope with the understanding that the disease and its treatment will accompany them throughout their lives. It is essential for parents to be attentive to this need and ensure that their children receive appropriate professional support.
Children taking colchicine grow and develop normally.
Colchicine is a safe medication when given at the correct dosage. Side effects are minimal and tend to decrease when the dosage is reduced. The most common side effects are diarrhea and abdominal pain. Some children may have difficulty tolerating the initially prescribed dosage due to the development of severe diarrhea. In such cases, the dosage should be reduced until they can manage it, and then gradually increased back to the recommended dosage. Other methods include reducing the intake of dairy products or providing lactose-free milk. In some cases, medication for diarrhea may be necessary.
In rare cases, the medication may cause muscle weakness, especially in patients with kidney problems or when colchicine is discontinued simultaneously with antibiotics from the macrolide group (macrolides). Therefore, such antibiotics should be administered cautiously alongside colchicine, and sometimes the colchicine dosage needs to be reduced.
Blood cell counts may temporarily be affected but usually return to normal with a reduction in dosage. In extremely rare cases, sperm count may decrease (similar problems may also occur due to the disease itself), and in such instances, the doctor might consider reducing the colchicine dosage when planning for family planning.
Female patients do not need to stop taking colchicine during pregnancy or while breastfeeding and recent studies suggest that there is no special justification for performing sperm analysis.
Children receiving colchicine treatment are advised to undergo laboratory tests for blood cell counts, liver and kidney function, and urinalysis twice a year.
Approximately 10% of FMF patients continue to experience frequent attacks despite colchicine treatment or may not tolerate the treatment due to side effects. In recent years, several studies have been conducted, some led by the Pediatric Rheumatology Unit at Shaare Zedek Medical Center, which has shown that administering Interleukin-1 (IL-1) inhibitors can significantly reduce the number of attacks and improve the quality of life for these patients. IL-1 is a crucial protein in the regulation of the natural immune system, and its levels are substantially elevated in FMF patients.
These IL-1 inhibitors, administered through subcutaneous injections, are included in the "health basket" of treatments. Children with FMF, whose main concern is chronic joint inflammation, sometimes receive treatments similar to those provided to children with chronic idiopathic joint inflammation, using drugs that block a protein called TNF.