Familial Mediterranean fever (FMF) is a rare autoinflammatory disease. Its symptoms may include fever accompanied by pain in the abdomen, joints, or chest. FMF is caused by mutations in the so-called Mediterranean fever (MEFV) gene passed on from one generation to the next.
What is FMF?
The disease FMF is an inherited autoinflammatory disorder that typically affects people of Mediterranean or Middle Eastern ancestry.1,2 It is characterised by recurring episodes of fever and painful inflammation in the abdomen, chest, and joints.
It is caused by mutations (changes) in the MEFV gene that produces a protein called pyrin, which helps regulate the immune system. In people with FMF, mutations in the MEFV gene cause the immune system to overreact to stimuli that would not normally cause inflammation. This leads to episodes of fever and pain.3,4
Symptoms of FMF typically begin in childhood or adolescence. Eighty per cent of people with FMF first experience symptoms by the age of 20.5 Inadequate control of the chronic inflammation may lead to severe complications such as renal AA amyloidosis which may ultimately lead to kidney failure.6 Although FMF is a chronic lifelong condition, people with the disorder can manage their symptoms effectively with appropriate treatment, and the long-term outlook is generally good.7,8,9
Autoinflammatory and autoimmune disorders: what’s the difference?
Autoinflammatory and autoimmune conditions are two different types of disorders that involve the immune system.
- Autoinflammatory disorders cause inflammation that may occur without an obvious trigger or infection. These conditions are caused by genetic mutations that affect the innate immune system.10 In autoinflammatory disorders, the body’s immune system is activated inappropriately, and this leads to excessive inflammation and tissue damage. Familial Mediterranean fever is the most common autoinflammatory syndrome.11
- Autoimmune disorders occur when the immune system mistakes the body’s own healthy tissues as foreign and attacks them.12 These diseases can affect any part of the body and can have a wide range of symptoms. Examples of autoimmune disorders include immune thrombocytopenia (ITP) and paroxysmal nocturnal haemoglobinuria (PNH).
How common is FMF?
Although rare in most parts of the world, FMF is the most common hereditary autoinflammatory disease. This disease most commonly affects Sephardic Jews, Armenians, Turks, Arabs, and Moroccans – whose familial origin can be traced to the Mediterranean basin.13 FMF can affect people of any ethnic group. It is considered a rare disease, although the rates are much higher for these Mediterranean populations, where as many as one in 200 individuals may be affected.14 FMF is not considered rare in Turkey, Israel and Armenia.
Within some Jewish populations, the proportion of individuals carrying the mutated gene, but not affected, may be as high as 6% to 39%.15
FMF affects males and females in nearly equal numbers.16
What are the symptoms of FMF?
Symptoms may include abdominal pain, chest pain, swelling and pain in the joints, fever, rashes and headache17.
For most people with FMF, their first episode will occur in childhood or puberty. The attack typically lasts two to three days. As to how often the attacks occur, this can vary from every few days to years apart. About half of people with the condition experience mild discomfort before an attack begins.18
Possible complications of FMF
Without treatment, protein deposits called amyloids can build up in organs and tissues throughout the body. Amyloidosis is the name given to a group of rare, serious conditions caused by a build-up of amyloids. Amyloidosis especially affects the kidneys and can lead to kidney failure.19
Amyloidosis can also affect the testes and ovaries and can therefore cause infertility in both males and females.20
How is FMF diagnosed?
Diagnosing FMF can be challenging because the symptoms may be similar to those of other inflammatory disorders. A doctor will look for recurring fever and inflammation alongside other symptoms – abdominal pain, chest pain, joint pain, and skin rashes. These are the criteria for the diagnosis of familial Mediterranean fever.21
Challenging to diagnose
As familial Mediterranean fever is a rare disease in many countries, some healthcare providers may not be familiar with it or may not consider it as a possible diagnosis. This can lead to delays in referral for appropriate testing or specialist care. Or it can lead to an incorrect diagnosis. For example, an affected individual’s first sudden attack of abdominal pain can be mistaken for appendicitis.22
Genetic testing
When FMF is suspected, genetic testing can be used to diagnose it. Genetic testing involves taking a blood sample and analysing a person’s DNA to look for mutations in the genes associated with FMF. A positive genetic test result, along with a pattern of recurrent symptoms, can confirm a diagnosis of FMF.23,24
What causes FMF?
Familial Mediterranean fever is caused by mutations (changes) in the MEFV gene, which provides instructions for making a protein called pyrin. Pyrin helps to regulate the body’s inflammatory response by controlling the production of certain proteins that promote inflammation.25
In people with FMF, mutations in the MEFV gene cause pyrin to malfunction, leading to excessive inflammation in the body. This inflammation can cause damage to various tissues and organs. 26
FMF is not contagious. And is not considered idiopathic – meaning that it can’t occur spontaneously. FMF is hereditary, not acquired. The disease is mostly passed on in an autosomal recessive fashion.
What is autosomal recessive inheritance?
- Recessive means that It is possible for an individual to be a carrier and not have symptoms.
- Autosomal means that the gene is carried on a chromosome other than the sex chromosome, so males and females are equally likely to be affected (or to be carriers).27
Normally, only an individual whose parents both have the FMF mutation can develop FMF. The mutation can be passed on through several generations on both sides of the family before a child is born who is affected by the condition.
Episodes of FMF can occur with no identifiable trigger. But certain triggers have been identified in some cases. Triggers include infection, trauma, vigorous exercise, stress, and fatigue. In women, onset of their period can trigger an episode.28
Risk factors
The main risk factors are ethnicity and family history. 29,30
- Ethnicity – the disease mainly affects people of Mediterranean ethnic groups – those whose family origin can be traced to the Mediterranean basin.
- Family history – since FMF is inherited, it follows that individuals whose close family members are known to have FMF are at greater risk of developing the condition themselves.
What is pyrin?
Scientists do not fully understand how pyrin works. It is believed to help in controlling the process of inflammation. Inflammation is what happens when the immune system sends special molecules and white blood cells to an injured or diseased area to fight off harmful invaders and help with healing. Once that job has been done, in a healthy individual the body stops the inflammatory response, to avoid harming its own cells and tissues. In a person with FMF, pyrin malfunctions and the inflammatory response may not stop.31
Slows down or stops inflammatory responses
Pyrin is made in certain types of white blood cells which are involved in inflammation and fighting infections. Pyrin is believed to guide these white blood cells to the places where inflammation is happening. It then slows down or stops the inflammatory response when it's no longer necessary. Pyrin also interacts with other molecules to form structures called inflammasomes, which are involved in the inflammation process.
Research suggests that pyrin helps regulate inflammation by interacting with the cell's structural framework. This framework, called the cytoskeleton, helps give cells their shape, size, and ability to move.
Pyrin is also known as marenostrin.32
What treatments are available for FMF?
There is no cure for FMF but it can usually be treated effectively once diagnosed.33 Treatment for FMF involves medications that can help reduce inflammation and control symptoms, including:
- Non-steroidal anti-inflammatory drugs (NSAIDs)
- Painkillers (analgesics)
- Corticosteroids
- Drugs that inhibit the activity of microtubules – microscopic tubular structures present in the cytoplasm of cells
- Biologic agents – medications developed from white blood cells or from recombinant DNA34
More than 90% of affected individuals who take medication to inhibit the microtubule activity show a marked improvement in the duration and frequency of episodes. In cases where FMF is resistant to microtubule inhibitors, interleukin-1 blockers may be indicated.35,36
How can people living with FMF improve their lives?
Early diagnosis and treatment can help most people with FMF live normal lives.37
Diet, exercise, weight control, stress relief – and medication
Leading a healthy lifestyle with a good diet, exercise, weight control, and stress relief can help people manage pain and stay healthy.38 Medications exist that in many cases not only manage but actually prevent symptoms. 39,40,41
FMF and diet42
There are no specific foods that are generally known to trigger FMF attacks. However, some individuals with FMF may have personal triggers or sensitivities to certain foods. Foods suggested as potential triggers of FMF attacks in some individuals include certain fatty and salty foods, cow’s milk, formulas, and wheat.
Keeping a food diary and monitoring how different foods affect a person’s symptoms can help identify any dietary triggers that may need to be avoided. A balanced diet that includes a variety of fruits, vegetables, whole grains, lean proteins, and healthy fats is usually recommended.43
Keeping a food diary and monitoring how different foods affect a person’s symptoms can help identify any dietary triggers that may need to be avoided.
Outlook – leading as near normal a life as possible
Living a near-normal life is achievable for individuals with FMF. Most people with FMF can effectively control their symptoms and engage in regular activities. There is always the chance of an attack. But proactive management strategies can minimise the impact of an attack. Individuals with FMF can thus pursue fulfilling personal, social, and professional lives. 44,45
Getting help
- By consulting healthcare professionals who specialise in FMF, such as rheumatologists or geneticists, people with FMF can receive expert guidance and personalised treatment options. Identifying and taking the appropriate medication tailored to their specific needs plays an important role in managing FMF symptoms effectively.
- Additionally, connecting with patient advocacy organisations and support groups can provide a supportive network of individuals who understand the challenges of living with FMF. With the right help, tailored medication, and a positive outlook, individuals with FMF can navigate their condition and embrace an optimistic future.46,47
Related links
Explore the following resources to learn more about Familial Mediterranean fever:
EURORDIS – Rare Diseases Europe
A non-profit alliance of rare disease patient organisations
https://www.eurordis.org/
Immunology
The role of the immune system
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Apr, 2024