Familial Mediterranean Fever: understanding the attacks and why daily colchicine matters

What is familial Mediterranean fever and who gets it?

Familial Mediterranean fever, usually shortened to FMF, is an inherited inflammatory disease that causes repeated episodes of fever and intense pain. The disease was named for the ethnic groups in which it was first clearly described: Armenians, Sephardic Jews, Turks and Arabs from the Levant and North Africa. Today it is well recognised across Syria, Lebanon, Jordan, Iraq, Egypt and the wider Arab world, where it is one of the most common inherited diseases seen in genetics clinics.

The condition is caused by mutations in a gene called MEFV, which codes for a protein called pyrin. Pyrin is part of the body's inflammatory control system. When it is abnormal, the system can misfire, producing bursts of inflammation that have no obvious trigger from the outside. The pattern of disease is the same across all affected groups: unpredictable attacks of illness separated by periods of feeling completely well.

FMF follows an autosomal recessive inheritance pattern. This means a child needs to inherit a faulty copy of the MEFV gene from both parents to develop the full disease. A person who inherits only one faulty copy is a carrier and usually has no symptoms, but can pass the gene to their children. In populations where the carrier rate is high, as it is across much of the Arab world, two carrier parents have a one-in-four chance with each pregnancy of having a child with FMF.

What does an FMF attack feel like?

A typical FMF attack starts quickly, often within hours, and reaches its worst point within a day. The most common feature is fever, which can reach 38 to 40 degrees Celsius. The fever is almost always accompanied by pain, and the location of that pain varies from person to person but tends to be consistent within the same individual over their lifetime.

Abdominal pain is the most frequent type, occurring in around 90 percent of people with FMF. It can be so severe that it is mistaken for appendicitis or a surgical emergency, and some patients have undergone unnecessary operations before the diagnosis was made. Chest pain from inflammation of the lining of the lungs (pleuritis) occurs in about half of patients. Joint pain and swelling, typically in a single large joint such as the knee or ankle, affect a significant proportion and can look exactly like an acute gout attack.

A characteristic rash sometimes appears on the lower legs, resembling erysipelas, a type of skin infection. This rash is not infectious and settles with the attack. Most attacks resolve completely within one to three days, leaving no lasting damage, and the person returns to full health between episodes. This short and self-limiting pattern is one of the key features that distinguishes FMF from other causes of recurrent fever.

How does an attack progress over time?

FMF attacks are not random in length. They tend to be brief and stereotyped, meaning the same patient usually has the same type of attack each time. Understanding this rhythm helps both the patient and their doctor distinguish a genuine FMF flare from another illness happening alongside it.

Several things are known to trigger attacks in some patients, including emotional stress, physical exertion, menstruation, and certain foods. However, many attacks have no identifiable trigger at all. The frequency of attacks varies widely: some people have an attack every week, others go months between episodes. Frequency often falls off somewhat in adulthood compared with childhood.

What tests are used to diagnose FMF?

There is no single test that definitively confirms FMF in all cases. The diagnosis is primarily clinical, meaning a doctor looks at the pattern of attacks, the age they started, the ethnic background of the patient, and the family history. The Tel Hashomer criteria, developed in Israel and later refined, are widely used: they require at least two definite episodes of fever with serosal, synovial or skin involvement, or one definite episode in someone with a positive family history.

Blood tests during an attack show a strong inflammatory response: the white cell count rises, the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) go up, and the serum amyloid A protein can be markedly elevated. Critically, between attacks these markers often return to normal, which can lead doctors to dismiss the diagnosis if they only see the patient when well.

Genetic testing for mutations in the MEFV gene is now widely available and is a valuable part of the workup. However, it has limits that are important to understand. The test checks for the most common mutations but there are many rarer variants, and a negative result does not rule out FMF if the clinical picture is convincing. The most informative scenario is finding two mutations, one on each copy of the gene, in a patient whose attacks fit the typical pattern.

Why is colchicine taken every day, not just during attacks?

Colchicine is the foundation of FMF treatment and has been so for more than 50 years. It is a plant-derived medicine that works by reducing the inflammatory signalling inside cells. The critical point that many patients and families miss is that colchicine needs to be taken every day regardless of whether an attack is happening. Taking it only when an attack starts does not prevent attacks and does not protect against the disease's most serious complication.

That complication is amyloidosis, a condition in which a protein called amyloid A builds up in organs over years of poorly controlled inflammation. The kidneys are most vulnerable. Untreated or under-treated FMF can lead to kidney failure requiring dialysis within a decade or two in people who develop amyloidosis. A 2020 review in the Turkish Journal of Medical Sciences, covering decades of follow-up data, confirmed that daily colchicine both reduces attack frequency and dramatically reduces the risk of amyloidosis. This is why the medicine must be continued for life, even in patients who feel well.

The usual starting dose in adults is 0.5 to 1 mg per day, adjusted upwards if attacks continue. Side effects are mostly gastrointestinal: loose stools and abdominal discomfort are common when starting and usually settle after a few weeks. Taking the tablet with food helps. Colchicine is safe in pregnancy and during breastfeeding, which matters because the disease often becomes apparent in childhood and affects women through their reproductive years.

What if colchicine does not control the attacks?

A minority of patients, estimated at five to ten percent, do not respond adequately to colchicine even at the maximum tolerated dose. Inadequate response is defined as three or more attacks per year on a full dose of colchicine. In these cases, a different class of drugs called IL-1 inhibitors can be very effective. Anakinra and canakinumab are the most commonly used and work by blocking the interleukin-1 pathway that drives the inflammation in FMF.

Before labelling someone as colchicine-resistant, it is worth confirming that the tablets are actually being taken consistently, as poor adherence is a common reason for continuing attacks. It is also worth checking that the diagnosis itself is correct: some conditions that mimic FMF, such as other hereditary fever syndromes, do not respond to colchicine and require different treatment.

Where IL-1 inhibitors are needed, access varies considerably across the region. In countries like Jordan, Lebanon and Syria, specialist centre referral is necessary to access these medications, and cost can be a significant barrier. If a patient is on colchicine and having frequent attacks, asking for a referral to a rheumatologist or a clinical genetics service is the right next step.

The risk of amyloidosis and how to monitor for it

Amyloidosis is the complication that makes consistent colchicine treatment essential rather than optional. It does not develop quickly: it accumulates silently over years of repeated, poorly suppressed inflammation. The first sign is usually protein appearing in the urine, detected on a routine urine dipstick test. This is why annual urine testing for protein is recommended for everyone with FMF, even those who feel their disease is well controlled.

Once protein appears in the urine, a 24-hour urine collection or a urine albumin-to-creatinine ratio can quantify how much is being lost. If amyloidosis is suspected, a kidney biopsy is the definitive test. The good news is that if detected early, when protein loss is modest and kidney function is still preserved, intensive treatment of the underlying FMF can slow or halt the progression. Optimising colchicine, switching to an IL-1 inhibitor if needed, and close monitoring all contribute.

The risk of developing amyloidosis is higher in men, in people with the M694V mutation on both copies of the MEFV gene, and in those with persistent elevation of inflammatory markers between attacks. These patients warrant particularly close follow-up.

Genetic testing and family planning

Because FMF is autosomal recessive, one of the most important conversations is around genetics and family planning. If one person in a family has FMF, their parents are almost certainly both carriers. Siblings of the affected person have a one-in-four chance of also having FMF and a two-in-four chance of being carriers. Genetic testing of family members, particularly siblings and the children of an affected person, can identify carriers who may not have any symptoms.

The question of premarital genetic testing is directly relevant to FMF in populations where the carrier rate is high. In Arab populations from the Levant, carrier rates for the most common MEFV mutations can be substantial, meaning the chance of two carriers meeting is not negligible. If both members of a couple are carriers, each pregnancy carries a one-in-four chance of producing a child with FMF.

Knowing this in advance does not make the decision for anyone, but it allows informed discussion. Some couples choose prenatal diagnosis; others use preimplantation genetic diagnosis where that technology is accessible; others decide to proceed with pregnancy knowing the odds and the fact that FMF, when treated with colchicine, is a manageable condition rather than a life-threatening one. A clinical geneticist or genetic counsellor is the right professional to guide this conversation.

Living with FMF: practical day-to-day management

Between attacks, most people with well-controlled FMF live completely normal lives. The goal of daily colchicine is precisely to get to that point. Adherence is the biggest challenge: the medicine needs to be taken every day, and skipping doses when feeling well is the most common mistake that leads to continuing attacks and rising amyloid load.

Keeping a simple diary of attacks, noting date, duration, site of pain and any possible trigger, is genuinely useful both for the patient's own understanding and for discussions with the treating doctor. If attacks are becoming more frequent or more severe on the same dose, this is the evidence needed to prompt a dose adjustment.

Children with FMF deserve particular attention to school life. Repeated absences due to unpredictable attacks can affect education and be misunderstood by teachers. A letter from the treating doctor explaining the condition and the expected attack pattern is worth having so that families and schools can plan appropriately. With good colchicine control, most children with FMF attend school normally and participate fully in physical activity.

Sources

• Lancieri M, Bustaffa M, Palmeri S et al: An Update on Familial Mediterranean Fever, International journal of molecular sciences, 2023
• Tufan A, Lachmann HJ: Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review, Turkish journal of medical sciences, 2020
• El-Shanti H, Majeed HA, El-Khateeb M et al: Familial mediterranean fever in Arabs, Lancet (London, England), 2006
• Romano M, Piskin D, Kul Cinar O et al: Familial Mediterranean Fever; Recent Advances, Future Prospectives, Diagnostics (Basel, Switzerland), 2025
• Kisla Ekinci RM, Kilic Konte E, Akay N et al: Familial Mediterranean Fever in Childhood, Turkish archives of pediatrics, 2024
• Ozdogan H, Ugurlu S: Familial Mediterranean Fever, Presse medicale (Paris, France : 1983), 2019