Familial Mediterranean Fever (FMF)

What causes FMF

FMF is caused by variants in the MEFV gene, which makes a protein called pyrin. Pyrin helps regulate the inflammasome, a part of the innate immune system that triggers inflammation. In FMF, faulty pyrin allows inflammation to switch on too easily and without infection, producing bursts of fever and inflammation of the body's linings (serosa).

FMF is usually autosomal recessive: people inherit a variant from each parent. Some people with only one variant also have symptoms. In high-risk populations, carrier rates are as high as 1 in 5 to 1 in 3.

Symptoms of an attack

Attacks start suddenly, often with a fever of 38 to 40 °C (100.4 to 104 °F), and last 12 to 72 hours. Between attacks, people feel completely well. Attacks may occur weekly or only a few times a year.

Triggers can include stress, menstruation, exercise, infections, cold exposure and fatty meals.

Many people with FMF have had unnecessary appendix removal or abdominal surgery before diagnosis, because attacks look like peritonitis or appendicitis.

Complications

• AA amyloidosis: chronic inflammation causes a protein (serum amyloid A) to deposit in organs, especially the kidneys, leading to protein in the urine, nephrotic syndrome and kidney failure. It is the most serious complication and is largely preventable with colchicine.
• infertility from abdominal adhesions or untreated inflammation
• small bowel obstruction from adhesions
• growth problems in children with frequent attacks
• anemia and chronic fatigue

Diagnosis

FMF is diagnosed mainly on the pattern of symptoms:

• recurrent, short attacks of fever with serositis
• typical age of onset and ancestry
• family history
• high inflammatory markers (CRP, ESR, serum amyloid A) during attacks, which normalize between attacks
• genetic testing of MEFV supports the diagnosis but a negative or single-variant result does not exclude it
• response to colchicine helps confirm the diagnosis
• urine tests for protein to screen for amyloidosis

Doctors also consider other periodic fever syndromes, such as PFAPA, TRAPS, mevalonate kinase deficiency and cryopyrin-associated syndromes.

Treatment

Colchicine

Colchicine taken every day for life is the cornerstone of treatment. It:

• prevents attacks in most people and reduces them in nearly all others
• prevents amyloidosis and can stabilize existing kidney involvement

Side effects are mainly diarrhea, nausea and cramps, which often settle when the dose is divided or adjusted. Doses are set and adjusted by a rheumatologist. Colchicine is generally continued during pregnancy and breastfeeding under medical guidance. It interacts with some antibiotics, antifungals and statins, so tell all your clinicians that you take it.

When colchicine is not enough

About 5 to 10 percent of people do not respond adequately or cannot tolerate it. Options are interleukin-1 blockers (anakinra, canakinumab, rilonacept), which are very effective.

During attacks

Rest, NSAIDs such as ibuprofen (follow the label dose), and supportive care. Antibiotics do not help.

Monitoring

Regular checks of inflammatory markers and urine protein, every 6 to 12 months, to ensure control and catch amyloidosis early.

Outlook

With consistent colchicine treatment, most people with FMF live normal lives with few attacks, and amyloidosis is now uncommon in treated patients. Untreated, amyloidosis can lead to kidney failure.

Frequently asked questions

What are the symptoms of familial Mediterranean fever?

FMF causes repeated attacks of fever with severe abdominal pain, chest pain, joint pain or a red, painful rash on the lower legs. Attacks last 1 to 3 days and then go away completely. Symptoms usually start in childhood.

How is familial Mediterranean fever diagnosed?

Doctors rely on the typical pattern of attacks, ancestry and family history, raised inflammatory markers during attacks and genetic testing of the MEFV gene. A good response to colchicine also supports the diagnosis.

Is familial Mediterranean fever inherited?

Yes. It is usually inherited in an autosomal recessive pattern, meaning a child receives a faulty MEFV gene from each parent. Some people with a single variant also have symptoms. Genetic counseling helps families understand risks.

Why is colchicine important for FMF?

Colchicine prevents attacks in most people and, critically, prevents AA amyloidosis, which can cause kidney failure. It must be taken every day for life, even when attack-free. Stopping it raises the risk of complications.

Can FMF be mistaken for appendicitis?

Yes. FMF abdominal attacks cause severe pain, tenderness and fever that closely mimic appendicitis or peritonitis. Many patients have had surgery before diagnosis. Knowing your FMF history helps doctors avoid unnecessary operations.