Familial Mediterranean fever (FMF) is an inherited fever syndrome that causes episodes of high fever, inflammation of connective tissue in the abdominal area (peritonitis), lungs (pleurisy), the heart (pericarditis) and joints (Arthritis). The disease is caused by a genetic change that is partly hereditary. The vast majority of those affected are from Turkey (> 40%), Lebanon (16%) and Syria (6,5%) (reference: Mortensen SB, 2020).
- FMF is considered among them periodic fever syndromes / autoinflammatory diseases
Family Mediterranean fever (FMF) is the most common among them Auto-inflammatory diseases / Fever syndromes.
Often debut already in childhood, usually before 5 years of age. The vast majority here got the symptoms before the age of 20. However, it often takes several years before the diagnosis is made. A study from Denmark showed a median delay between the onset of symptoms and a diagnosis of three years, but up to 7 years in some cases.
- Debut age is usually before 20 years (90%)
- Ethnically, FMF is most commonly seen among Jews, Arabs, Turks and North Africans, less frequently among Greeks and Italians.
- Prevalence 1 / 10.000 (0,009%) in Denmark (Mortensen SB, 2020), probably rarer in Norway
- FMF is thus defined as one rare disease
Autosomal recessive inheritance (disease genes from both parents are required to obtain FMF).
- MEFV gene mutation (change in genetic material / gene) in one gene (mono-genetic, hereditary disease) can be detected in many cases. The four most common FMF related mutations among the Turkish population are M694V, M680I, V726A and E148Q, of which the significance of the E148Q mutation is uncertain (Mortensen SB, 2020).
- Genetic test. read more here (Genetikkportalen.no)
Self-limiting episodes of seizures are most often marked by fatigue. Then follow more typical symptoms:
- Strong pain, most often in the stomach area (peritonitis) in 80%, nausea and malaise may occur simultaneously
- High fever (39-40 degrees) lasting 1-3 days
- Attaks can be triggered by physical or emotional stress
- Pain in the chest (lungs) is seen in 15-30% and is caused by pulmonary inflammation (pleurisy) on one or both sides (uni- or bilateral)
- Chest pain may also be pain transfer from the abdominal area (below the diaphragm)
- Joint inflammation (synovitis /arthritis) (swollen and hot joints) are less common, most often among North Africans. Most commonly in the knees and ankles, less frequently in the hip, elbow or iliosacral joint (between lower back and pelvis)
- Arthritis can travel from joint to joint as in Rheumatic fever
- Erysipelas-like rash on the legs, most often in children (25%)
- Pericarditis (symptoms: heart pain) (below 1%)
- Orchitis, pain and swelling in scrotum
- Spontaneous rapid recovery and symptom freedom before the next attack
Inflammation tests with high CRP are seen over 3-5 days, the lowering reaction (SR) increases more slowly.
- Between fever episodes, CRP and SR can be slightly elevated
- Leukocytosis (increased white blood cell count)
- Fibrinogen increased
- Recurrent (recurrent) fever lasting 1-3 days. Asymptomatic periods of weeks-months in predisposed person (heredity)
- Fever episodes with abdominal pain are most common, chest pain somewhat less common. Joints and skin symptoms may occur
- No infection
- Blood tests with increasing CRP during seizures
- Cochicine response (good: 72%, partial: 15%, non-response: 15%)
- Gentest (MEFV gene) (see above)
Incorrect diagnosis (similar conditions / differential diagnoses)
- Acute infection
- Childhood arthritis (most often systemic JIA)
- Other type Periodic Fever Syndrome / Auto-Inflammatory Disease
- Vasculitis diseases
- Perforated (bleeding) Ulcer ventriculi (gastric ulcer) or Acute abdomen (severe abdominal pain) for another reason
- Hereditary angioedema
- Acute porphyria
- Recurrent pancreatitis (Pancreatic inflammation)
- Hyper-trigyceridemi (High blood fat)
- Abdominal epilepsy
- Abdominal migraines
Acute episodes and preventive: Colchicine
- 90-95% has effect
Preventive (also reduces AA-amyloidosisrisk). Colchicine is started when the diagnosis is certain and should be continued for life.
- Colchicine (0,5 mg, NAF, "Pharmacy", reimbursement must in Norway be sought by a doctor for each individual patient (§ 3b - Individual application, for treatment of chronic diseases that are not covered by the reimbursement codes in § 2 of the blue prescription regulations.)
- Prophylaxis dose 0,5-1,5mg / day. This dose rarely causes side effects even though it is used as a lifelong treatment
- 72% good response (judged by frequency, severity and duration of episodes)
- 15% partial response
- 13% without response
- Can also be taken in case of early (prodromal) symptoms. Individual dosage, based on the experience (effect and side effect) in the individual. In case of seizures, the dose of colchicine may be 0,5 mg every hour for four hours, then less frequently (every two hours and at longer intervals)
- Nausea (9%), diarrhea (7%) resolve with reduced dose or if a user Imodium is given for diarrhea
- Azoospermia (reduced sperm count in men) can occur, but is also seen in amyloidosis (which can be developed if one is not treated over time)
- Colchicine can also be used during pregnancy if needed
- In case of severe renal impairment (GFR <10ml / min) the dose is halved
- Patient information about Kolkisin (on the indication gout) can be found here
- anakinra (Kineret)
- Up to 76% has effect (reference: Pecher AC, 2017)
- Canakinumab (Ilaris)
- Effect as with anakinra, but more expensive medication
- Experimental: Thalidomide (initially 100mg / day), etanercept (25mg x2 / week), infliximab
- EULAR recommendations here (reference: Ozen S, 2015)
Most people with FMF can carry out normal pregnancies, but this usually presupposes that treatment with Kolkisin continues. Colchicine is not associated with increased fetal harm, miscarriages and infertility are similar to those reported without such treatment. A survey from Turkey showed that most gave birth to approx. four weeks premature, in week 36 of pregnancy (reference: Yazicioglu A, 2014).
- One should usually continue with colchicine throughout pregnancy