Familial Mediterranean Fever (FMF)

What is FMF?
Familial Mediterranean Fever, or FMF, is a genetic disorder that is characterised by recurrent episodes of fever, pain in the abdomen and/or inflammation of the joints. The disease generally affects people of Mediterranean and Middle Eastern descent. Most of the patients descend from Sephardic Jews, Turks, Arabs or Armenians.

In certain regions, up to three persons per thousand inhabitants have FMF. In other parts of the world, the condition is rarer.

FMF attacks begin before the age of twenty in at least 90% of the patients. In about half of the patients, these attacks begin in the first ten years of life. Boys are slightly more likely to suffer from FMF than girls.

Causes
FMF is a genetic disease. The responsible gene is called MEFV. This gene causes the production of a protein that plays an important role in the inflammatory response against certain microbes through the signalling agent interleukin-1beta. If there is a mutation of the MEFV gene, as is the case with FMF, the production of interleukin-1beta may occur without there being a reason for it. This leads to episodes of fever and inflammation in the blood and tissues.

Inheritance
FMF is a hereditary disease that is inherited as an autosomal recessive trait. This means that the disease is not gender-specific. This type of inheritance means that an individual will only get the disease FMF if both genes are abnormal. In other words, the gene that comes from the mother, as well as the gene that comes from the father. Both parents are usually carriers of the disease. That is, both parents have one healthy and one abnormal gene. The chance that their child is affected is then 25%. It is also possible that one of the two parents already has the disease FMF and that the other parent is a carrier. In those cases, there is a 50% chance that their child will have FMF.

The child has the disease because the genes that cause the disease are affected. It is important to know that marriages between cousins increase the likelihood that both parents are carriers. In about 25% of patients, the parents are blood relatives.

In rare cases, FMF can occur in people who have only one mutated copy of the MEFV gene.

Symptoms
FMF is not contagious.

The main symptoms of the disease are recurrent episodes of fever, accompanied by abdominal pain, sometimes with chest or joint pain. Episodes of abdominal pain are the most common and are seen in 90% of patients. Episodes of chest pain occur in 20-40% of patients and joint pain in about 50%. Usually, children develop a pattern of episodes that is specific to them, such as recurrent episodes of abdominal pain and fever. Sometimes patients have different types of episodes at the same time, such as abdominal pain or chest pain, or chest pain combined with joint pain.

These attacks will go away without treatment and last 1/2 a day to 4 days. The patient will recover completely from an episode and is completely symptom-free between episodes. Sometimes the episodes are so painful that the patient needs to see a doctor. The episodes of abdominal pain, in particular, resemble the onset of appendicitis. It frequently happens that the appendix of FMF patients is removed when appendicitis is suspected. This is usually before FMF is diagnosed in these patients. Sometimes the episodes of abdominal pain are very mild. In such patients, the disease FMF is much more difficult to recognize. During FMF episodes, the child is often a bit constipated. As the pain subsides, the child’s stool will be a little softer.

Temperatures may vary from one episode of fever to the next. Chest pain is usually unilateral. This pain can be so severe that the child is afraid to breathe deeply. This pain will also disappear completely within a few days. Joint pain is usually limited to one to three joints per episode, most commonly a knee or an ankle. The joint may be so swollen and painful that the child cannot walk. Sometimes there is also a red rash at the site of the affected joint. It takes a bit longer for the joint pain to disappear completely, usually between 4 days and 2 weeks. Sometimes children have these repeated episodes of joint pain and swelling without other symptoms, such as fever or abdominal pain. Such cases can be misdiagnosed as acute rheumatic fever or chronic childhood arthritis (JIA). In about 5 of the cases, the joint pain will become chronic and may result in permanent residual symptoms.

FMF patients may develop a characteristic red, sharply defined, painful rash. This is seen mainly on the lower legs.

Rarer symptoms of this disease include pericarditis (inflammation of the outer layer of the heart), muscle inflammation, inflammation of the membrane surrounding the brain (meningitis), and inflammation of the testicles in boys (orchitis). In addition, some disorders characterised by inflammation of the blood vessels, occur more often in individuals with FMF.

The most severe complication of FMF, especially untreated cases, is the development of amyloidosis. Amyloid is an inflammatory protein that deposits in certain organs, such as the intestines, skin, heart, but especially the kidneys. This protein deposition causes the affected internal organ to function less well. In the case of the kidneys, this may eventually lead to kidney failure and require dialysis or transplantation. Not only FMF patients are at risk of developing amyloidosis, but it can also occur as a complication of other chronic inflammatory diseases that have been inadequately treated. Sometimes the presence of amyloid in the intestine or kidney is a first indication of an underlying disease such as FMF. This dangerous complication is entirely preventable by preventing the inflammation. In most patients, treatment with colchicine succeeds in this.

Course of the disease
The course of the disease is different in every child. Also, the types, severity and duration of the attacks can vary from time to time in the same child. In general, FMF episodes in children are similar to those in adults. However, some aspects of the disease, such as inflammation of the joints and muscles, are more common in children. The severity and frequency of these episodes of joint pain and swelling decrease as the patient gets older. Inflammation of the testes is seen especially in young boys, more than in adults. The age at which FMF first manifests is also important. This is because the risk of developing amyloidosis is higher in untreated individuals who have developed the disease at a very young age.

Diagnosis

1. Usually, suspicion of FMF arises because of the characteristic pattern of the symptoms. Especially after more than three episodes have occurred. Also, a certain ethnic background will be an indication for doctors to suspect this disease. Sometimes, family members of the patient have symptoms. It’s important that the physician inquires extensively with the parents whether they have these kind of symptoms. If FMF is suspected, the physician should observe the child closely for a certain period of time before a diagnosis of FMF can be made. During this period, it is important that the physician sees the child during an episode, for careful physical examination and blood tests. The values of the blood test will be abnormal during the episodes, but the values will return to normal between the episodes. Sometimes it’s not possible that the doctor sees the child during an episode. If that’s the case, it is very important that the parents keep a diary of the symptoms. It may be possible that the local hospital or family doctor does a blood test during an episode.
2. Also, the response to the medicine colchicine can be looked at as support for the diagnosis of FMF. On suspicion of FMF, the physician may prescribe the child a trial treatment of colchicine for 6 months, and observe the response to this medicine closely. Most patients with FMF respond very well to the medicine colchicine.
3. By analysing the MEFV gene, the diagnosis can be made with more certainty. Most hospitals can do this analysis. The clinical suspicion of FMF will be confirmed with this test if the patient has a mutation on all two copies of the MEWFV gene: one mutation from each parent. The mutations currently known are found in 70-80% of individuals with FMF. This means that there are FMF patients that do not have one of these known mutations. This can be explained by a possible mutation in a part of this gene which is not routinely examined in the blood tests. Therefore, to make the diagnosis of FMF, clinical analysis is still very important.
4. Almost all children frequently have a fever as well as abdominal pain. Because of this, it is often not easy to diagnose FMF. It can take many years. This delay in making the diagnosis is important because the risk of amyloidosis increases the longer the patient remains untreated. There are a number of other diseases that show similar episodes of fever, abdominal pain, and joint pain. Most of these diseases are also genetic.

Tests that are performed

1. Blood tests are important in making the diagnosis of FMF. These tests include sedimentation rate, CRP, white blood cell count. These tests are performed during and between the episodes. This allows for comparison of the tests. Between the episodes, the results of these tests should be completely normal. Sometimes the tests do not normalise completely between episodes. Also, in most medical facilities, some blood will be drawn for genetic testing. If children are taking colchicine, blood and urine tests should also be performed twice a year for monitoring of the medicine colchicine.
2. Urine tests. The urine is tested for the presence of protein and for the presence of red blood cells. During episodes, protein excretion and the presence of red blood cells may be elevated. In patients with amyloidosis, the excretion of protein in the urine is also elevated between attacks. This is a serious indication for the physician to perform additional tests to determine the presence of amyloidosis. This includes determining the total amount of protein excretion and in most cases performing an intestinal or renal biopsy.
3. Intestinal or renal biopsy A biopsy of the mucosa of the large intestine may be important when there is a suspicion of amyloidosis. This is a very simple procedure. If the abnormal protein deposit is not found with this intestinal biopsy, a renal biopsy needs to be performed. A renal biopsy usually requires the child to be hospitalised overnight. The tissue obtained from these biopsies is examined under the microscope for the presence of deposits of the abnormal protein amyloid.

Treatment
Colchicine is the best medicine to treat FMF. This medicine is easy to take, inexpensive, and does not have any serious side effects. After diagnosis, the child is to use this medication for the rest of his or her life. If the medicine is taken regularly, the episodes will disappear in about 60% of the affected children, the episodes will decrease in severity or frequency in 30% of the patients; colchicine has little or no effect in about 5 to 10% of the patients. Colchicine therapy not only reduces the episodes, but more importantly reduces the risk of developing amyloidosis. It is therefore incredibly important that doctors explain this to parents and children and keep emphasising how important it is that this medicine is taken every day in the correct dosage. If colchicine is always taken, children with FMF can live a normal life with a normal life expectancy. Changes in the prescribed colchicine dose must always be discussed with the physician.

If a patient does not respond adequately to colchicine or cannot tolerate it, medications that block interleukin-1 are usually effective. The drug best studied is canakinumab. Unlike colchicine, this drug must be injected every 4-8 weeks and is extremely expensive. Anakinra, another drug that blocks interleukin-1, requires daily injections.

Side effects of colchicine therapy

It is not easy for parents to accept that their child must take this medication for life. Parents are usually concerned about the possible side effects of colchicine. In the right dose, this is a safe medicine with only limited side effects and usually a good response when the dose is reduced. The most common side effect is diarrhoea. Some children do not tolerate the prescribed dose and suffer from frequent watery stools. If that happens, the dose should be reduced until the diarrhoea disappears. Then, very slowly, the dose can be increased. Other side effects are nausea, vomiting and abdominal cramps. Very occasionally, muscle weakness occurs. Sometimes there is a temporary reduction in the number of white and red blood cells and platelets, but this always recovers when the dose is lowered. In boys, a reduction in the number of sperm cells is seen in very rare cases. There is no evidence of reduced fertility due to colchicine. Female FMF patients should not stop taking this medication while pregnant or breastfeeding. In fact, the chances of having a healthy baby are reduced if colchicine is stopped.

A large overdose with colchicine can be very dangerous, however. Therefore, this medicine should always be kept out of reach of children.

Side effects of interleukin-1 receptor antagonist

Interleukin-1 is important for the immune system to fight infections. This is why the main side effects of canakinumab and anakinra are an increased risk of bacterial infections, such as ear infections, pneumonia and impetigo. It is therefore very important that children treated with these drugs are fully vaccinated. Any infections should also be treated promptly with antibiotics.

The other important side effect is pain at the injection site. This occurs especially with anakinra.

Long-term prognosis

If adequately treated, children with FMF can lead normal lives. But if the diagnosis is made late or if colchicine is not taken or is taken insufficiently, there is a risk of developing amyloidosis. Amyloidosis has a poor prognosis. Children with amyloidosis sometimes develop severe kidney failure, requiring a kidney transplant. Staying behind in height is actually not a problem in patients with FMF. In some children, the body growth actually improves if the disease is controlled with colchicine. There is no cure for FMF. It is a genetic disease. With careful treatment, the patient will have the opportunity to live a normal life without limitations and without the risk of amyloidosis. For the majority of patients, taking colchicine daily is all that is needed for this.

Daily life

Life is especially difficult for the child and the family before the diagnosis is made. They have to visit the hospital regularly to have the child examined during episodes. Some children are operated by mistake, as the episodes of abdominal pain may resemble appendicitis. After diagnosis of the disease, most children and parents are able to live a pretty normal life. Some even forget that they have the disease FMF. The main problem seems to be the psychological burden of having a lifelong condition. It is important to pay attention to this.

School

The frequent episodes mean that the child may not always be able to go to school. But once the colchicine is taken properly, the need to stay at home will decrease significantly. It’s important to inform teachers of the disease and what they can do if the child has an episode at school.

Sports

Patients with FMF who take colchicine can do any sport they want. The only problem may be prolonged inflammation of the joints that will cause some limitation of movement.

Vaccination

The child can and should receive all vaccinations.

Sexuality, pregnancy, and birth control: patients with FMF mainly experienced problems getting pregnant before colchicine became available as a therapy. Childlessness by circumstance has been rare since then. During pregnancy, it is recommended that the medicine colchicine is taken as usual. Less is known about the safety of interleukin-1 receptor antagonist for pregnant women.