Familial Mediterranean fever: symptoms, causes and treatment

Familial Mediterranean fever, usually shortened to FMF, is a genetic condition in which the body's inflammation switches on repeatedly without an infection to explain it. The NHS describes it as a rare genetic condition and notes that the medicine colchicine is used to prevent its symptoms.

The PRINTO patient information, produced for paediatric rheumatology services in Europe and available in a UK edition, says the disease generally affects people of Mediterranean and Middle Eastern descent, in particular Jewish, Turkish, Arab and Armenian populations, with a frequency of about 1 to 3 in 1,000 in those high-risk groups. It is rare in other ethnic groups, but diagnoses are becoming more frequent in populations where it was once thought to be very rare, since the associated gene was discovered.

FMF attacks start before the age of 20 in approximately 90% of patients, and in more than half of patients the disease appears in the first decade of life, PRINTO says. The disease is life-long.

The main symptoms are recurrent fever accompanied by abdominal, chest or joint pain. PRINTO describes the pattern of each attack type.

• Abdominal attacks are the most common, seen in about 90% of patients. They can be severe enough to mimic acute appendicitis, and some patients have unnecessary abdominal surgery as a result. During the pain the child is usually constipated.

• Chest pain usually affects one side and can be so severe that the person cannot breathe deeply enough. It occurs in 20 to 40% of patients and resolves within days.

• Joint pain and swelling occur in 50 to 60% of patients. Usually only one joint is affected at a time, commonly an ankle or a knee, and it may be too painful to walk. Joint attacks can take from four days to two weeks to resolve fully.

• About one-third of patients get a red skin rash over the affected joint, and some have a rash called erysipelas-like erythema, usually over the lower legs and joints.

• Rarer attack types include inflammation of the lining of the heart (pericarditis), muscle inflammation, meningitis-type inflammation and inflammation around the testicle.

PRINTO says attacks are self-limited, meaning they resolve without treatment, and last between one and four days. Patients recover fully at the end of an attack and feel well between bouts. Joint attacks can last somewhat longer than other attack types.

The type, duration and severity of attacks can differ each time, even in the same person. The frequency of attacks usually decreases as the patient gets older.

Taking extra colchicine during an attack does not help. PRINTO says an increase in dose during an attack is ineffective and that the important thing is to prevent attacks by taking colchicine regularly.

FMF is caused by changes (mutations) in the MEFV gene. PRINTO explains that the gene affects a protein that plays a role in the natural resolution of inflammation, so when the gene is altered this regulation cannot work properly and fever attacks result.

It is mostly inherited as an autosomal recessive condition. This means both copies of the MEFV gene (one from each parent) are altered, and both parents are usually carriers who do not have symptoms. If one parent has FMF and the other is a carrier, there is a 50% chance a child will get the disease, PRINTO says. In a minority of patients one or even both copies of the gene appear normal.

PRINTO says the child has the disease because they carry a fault in the gene and that it cannot be prevented. It is not infectious.

Diagnosis can take time, because fever and abdominal pain are very common in childhood and the attacks may look like other problems such as appendicitis, constipation or gastroenteritis. PRINTO says it can take a couple of years to recognise, and that this delay should be minimised because of the risk of amyloidosis in untreated patients.

PRINTO describes a stepwise approach. FMF is only considered after a child has had a minimum of three attacks, with attention to ethnic background and relatives with similar problems or kidney failure. The child is monitored, ideally seen during an attack for a physical examination and blood tests for inflammation, such as ESR, CRP and a full blood count. Parents are asked to keep a diary of attacks.

Genetic testing can support the diagnosis. PRINTO says the clinical diagnosis is confirmed if the patient carries 2 mutations, one from each parent, but the known mutations are found in only about 70 to 80% of patients, so the diagnosis still depends on clinical judgement. If the picture is highly probable, children are given colchicine for approximately six months and then re-evaluated; in FMF, attacks stop completely or decrease in number, severity and duration.

Several specialists can be involved, including general paediatricians, paediatric or general rheumatologists, kidney specialists and gastroenterologists (PRINTO).

Colchicine is the drug of choice. The NHS says colchicine is used to prevent symptoms of FMF. The NHS Scotland East Region Formulary lists colchicine 500 microgram tablets for prophylaxis of FMF, with an adult dose of 0.5 to 2 mg once daily and, for children, a dose to be checked in the BNF for children.

PRINTO says that if colchicine is taken properly (every day, at a sufficient dose), attacks disappear in about 60% of patients, a partial response is obtained in 30%, and it is ineffective in 5 to 10%. It not only controls attacks but also removes the risk of amyloidosis, so parents and patients should not change the dose without consulting the physician. Biologic agents are used in some patients who are resistant to colchicine.

FMF cannot be cured. If the patient stops taking the drug, attacks and the risk of amyloidosis return, PRINTO says. No complementary therapy is known for FMF.

PRINTO says the most frequent side effect is diarrhoea; if the dose is not tolerated it can be reduced and then slowly increased again, and reducing lactose in the diet for about three weeks can help. Other side effects include nausea, vomiting and abdominal cramps, and rarely muscle weakness. Blood cell counts may occasionally fall but recover with dose reduction. Children on life-long colchicine need blood and urine tests at least twice a year.

The NHS warns not to take doses closer together than your doctor has told you, because too much medicine can build up and cause serious side effects. Possible serious effects include stomach pain with sickness and diarrhoea (toxicity), bone marrow problems, nerve problems, muscle and kidney problems, and allergic reactions. Call NHS 111 if you have taken more than your prescribed dose, and call 999 if you think you might be having anaphylaxis.

The NHS lists medicines that may not mix well with colchicine, including statins, some antibiotics such as erythromycin and clarithromycin, and some heart medicines such as verapamil, diltiazem and digoxin. It says not to drink grapefruit juice while taking colchicine. Tell every prescriber and pharmacist that you take it.

PRINTO describes amyloidosis as the most severe complication of FMF in untreated cases. Amyloid is a protein that deposits in organs such as the kidneys, gut, skin and heart and causes gradual loss of function, especially of the kidneys. Protein in the urine may be a clue, and biopsy confirms it. Children who develop it may need a kidney transplant.

The NHS describes amyloidosis as a group of rare conditions in which amyloid builds up in the body, and says AA amyloidosis is linked to long-term inflammatory conditions. Symptoms include feeling very tired or weak, unexplained weight loss, breathlessness, swollen feet or legs and frothy pee if the kidneys are affected. See a GP if you have these symptoms.

PRINTO says FMF in children generally resembles that in adults, though arthritis and muscle inflammation are more common in childhood and inflammation around the testicle is more often seen in young boys. The risk of amyloidosis is higher among untreated patients whose disease starts early.

With treatment, a normal life is expected. PRINTO says people receiving life-long colchicine can do any sport they wish, can be vaccinated, and that frequent attacks affect school attendance until colchicine improves them. It notes that taking pills for life can be a psychological burden and that adherence may be low in adolescence, which is when psychosocial support and education are particularly helpful.

Diet: PRINTO says there is no specific diet recommended for FMF, and the NHS says you can eat as normal while taking colchicine (apart from avoiding grapefruit juice). Climate does not usually influence the course of the disease.

Pregnancy: PRINTO says female patients do not have to stop colchicine during pregnancy or breastfeeding, and that fertility problems linked to active FMF disappear once the disease is controlled. The NHS says colchicine can be used during pregnancy if needed, tells you to inform your doctor if you are pregnant or become pregnant, and says you may be able to take it while breastfeeding after checking with a doctor or pharmacist.

FMF attacks are usually self-limiting, but severe abdominal pain can also be a surgical emergency, and many other illnesses cause fever. PRINTO notes that severe abdominal attacks can mimic appendicitis. If you or your child have severe or worsening abdominal pain, call NHS 111 or go to A&E, and tell staff about the FMF.

• Call 999 if you think you might be having anaphylaxis from colchicine (NHS).

• Call NHS 111 if you have taken more than your prescribed dose of colchicine (NHS).

• See a GP if you notice symptoms such as persistent tiredness, swelling of the feet or legs, frothy pee or unexplained weight loss, which can signal amyloidosis (NHS).

• Tell your specialist if diarrhoea, muscle weakness or unusual bruising develop on colchicine (PRINTO and NHS).

FMF is usually diagnosed and followed in specialist rheumatology or paediatric rheumatology services, often with genetic testing and kidney monitoring. PRINTO notes that genetic analysis may not be available in every treatment centre. Your GP can refer you if you or your child have repeated unexplained fevers with abdominal, chest or joint pain, especially with a family history.

Because the treatment is long-term, regular blood and urine tests (at least twice a year for children, PRINTO says) are part of ongoing care, usually shared between the specialist team and the GP. Private specialist appointments are possible, but long-term prescribing and monitoring are normally arranged with the NHS team who know your history.