Knowledge on rare diseases and orphan drugs

FMF is primarily found in the south-eastern Mediterranean area. Populations having a high prevalence (1/200-1/1000) of the disease are non-Ashkenazi Jews, Turks, Armenians and Arabs. It is not considered rare in Italy, Greece or Spain.

Disease onset usually occurs before the age of 30 with an earlier onset corresponding to a more severe phenotype. FMF can be divided into 2 types: FMF type 1 and 2. Type 1 is characterized by attacks (as often as once a week or every few years) of fever and serositis lasting 1-4 days and resolving spontaneously. Stress, exposure to cold, fat-rich meals, infections, certain drugs and menstrual cycles are possible attack triggers. Mild symptoms (myalgia, headache, nausea, dyspnea, arthralgia, low back pain, asthenia and anxiety) precede attacks and last about 17 hours. Attacks manifest as fever (38°C-40°C lasting 12-72 hours and not responding to antibiotics), diffuse or localized abdominal pain (often mimicking acute abdomen), constipation (diarrhea in children), arthralgias (in large joints), arthritis (in upper/lower limb/knee joints) and chest pain caused by pleuritis and/or pericarditis. In 7-40% of patients cutaneous involvement is also present. Amyloidosis type AA can be a serious long term complication. FMF type 2 describes a phenotype where amyloidosis occurs as the first and only manifestation of the disease.

To date, 218 mutations in the MEFV gene on chromosome 16 encoding the pyrin/marenostrin protein are responsible for the phenotypic variance (M694V homozygous mutations are associated with increased severity) seen in the disease. As not all patients have a mutation in the MEFV gene, other factors may be involved.

The Tel-Hashomer criteria states that 2 major criteria (fever and serositis, amyloidosis AA, effectiveness of colchicine) or 1 major and 2 minor criteria (recurrent attacks of fever, erysipela-like erythema, relatives affected by FMF) must be present for diagnosis. Genetic testing only has a 70-80 % positive predictive value.

Differential diagnoses include hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), TNF receptor-associated periodic syndrome and periodic fever (TRAPS), Marshall's syndrome with periodic fever, transthyretin-related amyloidosis and Behçet's disease.

Antenatal testing is possible, but not advised.

FMF follows an autosomal recessive pattern of inheritance. Genetic counseling for parents with an MEFV mutation can inform them of their risk of passing it on to their children.

Colchicine (oral or by I.V.) is the drug used to treat FMF. It reduces or eliminates FMF attacks and prevents the occurrence of amyloidosis type AA. Dosage ranges up to 0.03mg/kg/body weight/daily, or to a maximum of 3mg/daily, and must be taken regularly on a life-long basis. During an attack a nonsteroidal anti-inflammatory drug can be administered.Patients intolerant to colchicine have no alternative of matching efficacy, but Anakinra, interferon-alpha and selective serotonin reuptake inhibitors (SSRIs) have shown encouraging results in some patients. Annual physical examinations along with regulary monitoring of serum amyloid A protein (SAA) is recommended to prevent amyloidosis; colchicine can enhance B12 malabsorption and in rare cases can causes alopecia and bone marrow suppression. Macrolides, diltiazem, grapefruit and cyclosporine should not be taken with colchicine as fatal toxicity can occur. Dialysis and organ transplantation might be necessary for those with renal amyloidosis.

Although there is no cure for FMF, colchicine treatment improves patient quality of life. Untreated FMF patients and those with renal amyloidosis have a less favorable prognosis.

Last update: January 2012 - Expert reviewer(s): Pr Raffaele MANNA