Mediterranean fever, formally called familial Mediterranean fever (FMF), is a genetic disorder that causes recurring episodes of fever and painful inflammation throughout the body. These episodes, called attacks, typically last one to three days and can affect the abdomen, chest, and joints. FMF is the most common autoinflammatory disease worldwide, primarily affecting people of Mediterranean descent.
Who Gets FMF and Why
FMF is an inherited condition caused by mutations in the MEFV gene, which provides instructions for making a protein called pyrin. Pyrin is part of the immune system’s early warning network. It detects danger signals inside cells and activates an inflammatory response. In people with FMF, the mutated pyrin protein is overly sensitive to these signals, triggering intense inflammation even when there’s no real threat to fight off.
The disease follows an autosomal recessive pattern, meaning you need to inherit a defective copy of the gene from each parent. Five specific mutations account for most cases, and they cause the pyrin protein to essentially overreact, launching full-blown inflammatory episodes that resolve on their own but keep coming back.
Certain ethnic groups carry these mutations at remarkably high rates. Among Armenian populations, about 1 in 500 people has FMF. In Turkish populations, the rate is roughly 1 in 1,000. Carrier rates in some Arab communities range from 11% to 23%, meaning these individuals carry one copy of the mutation without necessarily developing the disease. FMF also affects Sephardic Jews, though it’s far less common in Ashkenazi Jewish populations (about 1 in 73,000). People outside these groups can still develop FMF, but it’s much rarer.
What an Attack Feels Like
FMF attacks come on suddenly, often without warning. The hallmark is a fever of 38°C (100.4°F) or higher combined with intense pain in one or more areas of the body. Most attacks last between 12 hours and three days, though joint-related attacks can persist for weeks or even months.
The most common symptoms during an attack include:
- Abdominal pain: The lining of the abdominal cavity becomes inflamed (peritonitis), producing pain severe enough to mimic appendicitis or other surgical emergencies. This is the most frequent symptom and sometimes leads to unnecessary surgery before FMF is recognized.
- Chest pain: Inflammation of the lining around the lungs makes it painful to breathe deeply. This can feel alarming but resolves with the rest of the attack.
- Joint pain and swelling: The knees, ankles, and hips are the most commonly affected joints. Unlike the other symptoms, joint inflammation can linger for weeks.
- Skin rash: Some people develop a red, raised rash on the lower legs, particularly around the ankles.
Between attacks, most people feel completely normal. The frequency varies widely. Some people experience attacks every week, others every few months. Stress, physical exertion, menstruation, and infections can trigger episodes, though many attacks seem to come from nowhere.
How FMF Is Diagnosed
There’s no single test that confirms FMF on the spot. Diagnosis relies on a combination of clinical criteria and genetic testing. The most widely used clinical framework requires that attacks be recurrent (at least three episodes), involve fever, and be short in duration (12 hours to three days). The major diagnostic criterion is recurrent febrile episodes with inflammation of internal linings, specifically in the abdomen, chest, or joints.
Genetic testing for MEFV mutations can support the diagnosis, but a negative result doesn’t rule it out. Some patients carry mutations that standard panels don’t detect. In populations where FMF is common, doctors often recognize the pattern based on symptoms and family history alone, sometimes confirming it by seeing how the patient responds to treatment.
Treatment With Colchicine
The cornerstone of FMF treatment is colchicine, a daily medication that reduces both the frequency and severity of attacks. For most adults, the starting dose ranges from 1.0 to 1.5 mg per day, with adjustments based on how well attacks are controlled. Children receive lower doses based on age. If attacks continue, the dose can be gradually increased up to 2 mg daily in children and 3 mg daily in adults.
Colchicine doesn’t cure FMF, and it doesn’t stop an attack once one has started. Its value is preventive. Taken consistently every day, it reduces attacks in most patients and, critically, protects against the disease’s most dangerous long-term complication. The most common side effects are gastrointestinal: diarrhea, nausea, and cramping, which often improve over time or with dose adjustments.
Doctors typically monitor patients with blood tests every three months, checking markers of inflammation like C-reactive protein. The goal is minimal or no disease activity along with normal inflammatory markers. If attacks persist at the maximum tolerable dose for three to four months, the patient is considered colchicine-resistant.
When Colchicine Isn’t Enough
Roughly 5% to 10% of FMF patients don’t respond adequately to colchicine. For these patients, biologic medications that block a specific inflammatory molecule called IL-1 offer an alternative. IL-1 is a key driver of the inflammation that pyrin triggers, so blocking it addresses the problem closer to its source.
Three IL-1 blocking drugs are available. Canakinumab is the only one with FDA approval specifically for colchicine-resistant FMF in the United States. It’s given as an injection, typically once every four weeks. The other two options, anakinra (a daily injection) and rilonacept, are sometimes used off-label. All three have shown effectiveness in reducing attack frequency and lowering inflammatory markers.
The Risk of Amyloidosis
The most serious long-term consequence of untreated FMF is a condition called AA amyloidosis. When inflammation recurs over and over, the body produces high levels of a protein called serum amyloid A. Over time, fragments of this protein can accumulate in organs, particularly the kidneys, forming deposits that gradually destroy tissue.
The numbers are striking. Studies found that the risk of AA amyloidosis climbed to 60% in untreated Turkish patients and 75% in untreated Jewish patients over the age of 40. This is the primary reason daily colchicine is so important, even when attacks seem manageable. Colchicine dramatically reduces the risk of amyloid deposits by keeping background inflammation in check between attacks, not just preventing the episodes themselves.
Kidney damage from amyloidosis progresses silently. It often shows up first as protein in the urine, eventually leading to kidney failure if left untreated. This is why regular monitoring matters even for patients whose attacks feel well-controlled.
Living With FMF
With consistent colchicine use, most people with FMF live normal, active lives. The condition requires lifelong medication, but the treatment is inexpensive, well-studied over decades, and effective for the majority of patients. Women with FMF can safely take colchicine during pregnancy, and fertility is generally not affected by treatment.
The biggest practical challenge for many patients is the unpredictability of attacks, especially early on before treatment is optimized. Missing doses of colchicine increases the likelihood of a flare. Some patients find it helpful to track potential triggers, though the connection between specific triggers and attacks is inconsistent. For families with a known history of FMF, genetic counseling can help parents understand the likelihood of passing the condition to their children.