Familial Mediterranean Fever – FMF

Familial Mediterranean Fever –FMF is the commonest inherited fever syndrome. It is caused by changes (mutations) in a gene called MEFV which lead to production of an abnormal form of a white blood cell protein called pyrin. We don’t know how the abnormal pyrin causes fever. It is thought that pyrin may make white blood cells ‘overactive’ so that attacks of inflammation occur spontaneously.

FMF is usually inherited by autosomal recessive inheritance. This means that people with FMF have two abnormal copies of the MEFV gene and both parents are asymptomatic carriers of the condition.

More rarely, (when the deletion of M694 mutation is present), FMF may be inherited by autosomal dominant inheritance. This means that one abnormal copy of the gene can cause the disease, and people with FMF may have one affected parent.

We see FMF most often among people of Mediterranean ancestry (Turks, Armenians, Arabs and Sephardi Jews) but FMF can occur in almost any ethnic group. In most cases the first attack of FMF occurs in childhood, but in 10% of patients the first attack occurs after age 40.

A child with FMF, who has no known Mediterranean ancestry

 Symptoms and diagnosis

Attacks of FMF may occur without apparent cause, or may be precipitated by stress, menstruation or diet.

Attacks usually last up to 3 days and may include:

  • high fever
  • severe pain in the abdomen or less frequently the chest
  • joint pain and swelling (usually in the legs)
  • rash (usually round the ankles)
  • rarely (less than 5%), testicular pain and swelling, in children

Typical ankle arthritis and rash in an FMF attack

The pain may be so severe that the first attack is thought to be appendicitis. Between attacks, affected individuals feel entirely well and grow and develop normally.

Some patients experience muscle pain on exertion between attacks, usually affecting the calves.

The frequency of the attacks varies from once every week to several times a year. The symptoms and severity vary between different patients, sometimes even amongst members of the same family.

Blood test results always suggest that there is a lot of inflammation, and include:

  • high white cell count
  • high CRP
  • high SAA
  • high ESR

Doctors in countries where FMF is common may be familiar with this condition and quick to raise the possibility.

However, most doctors in the UK have seen few patients with FMF and it may take some time till the condition is diagnosed.

In some parts of the country there are large immigrant communities from countries where FMF is common. Doctors in these areas may become more familiar with FMF.

Sometimes patients know that there is a family history and recognise the symptoms themselves.

Treatment

The treatment for FMF is a drug called colchicine. Colchicine was originally derived from a flower called the autumn crocus or meadow saffron. This flower has been known to possess medicinal powers since the time of ancient Greece. Interestingly, it grows mainly in the Mediterranean region, as well as parts of Asia.

The autumn crocus flower: the original source of the drug colchicine

Colchicine has been used successfully to treat FMF since 1972. Nowadays colchicine tablets are synthesised in the laboratory rather than being extracted from the flower. It is effective at preventing attacks in the vast majority of patients, so long as sufficient doses are taken. It is taken as tablets once or twice a day. Colchicine has been very widely used and more than 30 years of experience in FMF has shown it to be very safe at the usual doses of 0.5 to 2mg per day. It may be safely given to children with FMF even before the age of 1 year. Children taking colchicine grow and develop completely normally. It is also safe during pregnancy. For more information see the section on colchicine in pregnancy.

The main side effect of colchicine is an upset gut with diarrhoea. This can usually be avoided by increasing the dose slowly and in some individuals cutting out milk products for a period. Colchicine is dangerous if taken as an overdose and should always be kept out of reach of children.

During acute attacks, pain suppressing drugs may be helpful.

FMF and AA amyloidosis

A serious complication of FMF is development of AA amyloidosis, which may lead to kidney failure. As well as preventing FMF attacks, regular colchicine treatment is effective in preventing development of AA amyloidosis in most patients with FMF.

Some FMF patients taking colchicine may have on-going auto-inflammation despite experiencing few attacks. SAA is a very sensitive marker of inflammation, so we monitor the SAA levels regularly in all our FMF patients. This is the best way to ensure that they are receiving sufficient doses of colchicine to suppress inflammation and prevent development of AA amyloidosis.

Colchicine is usually effective in treatment of FMF patients who have already developed AA amyloidosis. It can lead to regression of AA amyloid deposits and improved kidney function.

Who should have genetic testing for FMF?

Anyone with symptoms and laboratory findings suggestive of FMF should have genetic tests performed, even if they are not from an ethnic background where FMF is common, as  FMF can occur in any ethnic group. These tests are performed at the Periodic Fever clinic at the NAC.

The consultants are happy to discuss genetic testing of siblings of FMF patients even if they do not report any symptoms.

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