Familial Mediterranean fever (periodic disease): symptoms, diagnosis, treatment

Familial Mediterranean fever (FMF, a periodic disease) is an inherited disorder characterized by recurrent episodes of fever and peritonitis, sometimes with pleurisy, skin lesions, arthritis, and very rarely pericarditis. Renal amyloidosis may develop, which can lead to renal failure. The disorder is most common in people of Mediterranean descent. Diagnosis is largely clinical, although genetic testing is available. Treatment includes colchicine to prevent acute attacks, as well as renal amyloidosis in most patients. Prognosis with treatment is good.

Familial Mediterranean fever (FMF) is a disease that occurs in people of Mediterranean descent, primarily Sephardic Jews, North African Arabs, Armenians, Turks, Greeks, and Italians. However, cases have also been reported in other groups (e.g., Ashkenazi Jews, Cubans, Belgians), which cautions against excluding the diagnosis on the basis of ancestry alone. About 50% of patients have a family history of the disease, usually including siblings.

The most common of the diseases described, FMF affects predominantly the nationalities living in the Mediterranean basin (Sephardic Jews, Turks, Armenians, North Africans and Arabs), although one can find descriptions of cases of periodic disease in Ashkenazi Jews, Greeks, Russians, Bulgarians and Italians. The frequency of occurrence depending on the nationality is 1:1000 - 1:100000. It occurs more often in men than in women (1.8:1).

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Causes recurrent illness

Familial Mediterranean fever is caused by mutations in the MEFV gene, located on the short arm of chromosome 16, and is inherited in an autosomal recessive manner. The MEFV gene normally encodes a protein (called pyrin or marenostrin) that is expressed by circulating neutrophils. Its putative function is to reduce the inflammatory response, probably by inhibiting neutrophil activation and chemotaxis. Mutations in the gene result in the synthesis of defective pyrin molecules; it is believed that minor, unknown triggers of the inflammatory response that are normally controlled by intact pyrin are not suppressed because the pyrin is defective. Clinical sequelae include spontaneous episodes of predominantly neutrophilic inflammation in the peritoneal cavity and elsewhere.

Pathogenesis of familial Mediterranean fever

The gene, the defect of which causes this disease, is localized on the short arm of chromosome 16 (Ibr13.3), designated as MEFV, is expressed mainly in granulocytes and codes for a protein called pyrin (or marenostrin). The gene consists of 10 exons regulating the sequence of 781 amino acid residues. 26 mutations have been described, mainly in exon 10, as well as in exon 2. The most common mutation is M694V (methionine to valine substitution) - occurs in 80% of patients examined with periodic disease, is associated with a severe course of the disease and a high risk of amyloidosis. Pyrin belongs to the family of transcription factors, is determined in the cytoplasm of myeloid cells. Based on various studies, it is assumed that pyrin plays a negative regulatory role in the development of the inflammatory process.

Symptoms recurrent illness

Familial Mediterranean fever usually begins between 5 and 15 years of age, but may begin much later or earlier, even in infancy. Attacks recur irregularly and vary within the same patient. They usually last 24-72 hours, but some last a week or more. The frequency of episodes varies from two attacks per week to one attack per year (most commonly one attack every 2-6 weeks). The severity and frequency of attacks tend to decrease during pregnancy and with the development of amyloidosis. Spontaneous remissions may last for years.

The main manifestation is a rise in body temperature to 40 °C, usually accompanied by symptoms of peritonitis. Abdominal pain (usually beginning in one quadrant and spreading to the entire abdomen) is noted in about 95% of patients and may vary in severity from attack to attack. Decreased peristalsis, abdominal distension, abdominal muscle tension, and symptoms of peritoneal irritation often develop at the peak of an attack and are indistinguishable from perforation of an internal organ on physical examination.

Other manifestations include acute pleurisy (in 30%); arthritis (in 25%), usually involving the knees, elbows, and hips; an erysipelas-like rash on the lower legs; and swelling and tenderness of the scrotum caused by inflammation of the testicular membranes. Pericarditis is very rare. However, the pleural, synovial, and cutaneous manifestations of familial Mediterranean fever vary in frequency among different populations and are less common in the United States than anywhere else.

The most serious complication of familial Mediterranean fever is chronic renal failure caused by amyloid deposits in the kidneys. Amyloid deposits may also be found in the gastrointestinal tract, liver, spleen, heart, testicles, and thyroid gland.

Diagnostics recurrent illness

Diagnosis of Mediterranean fever is largely clinical, but gene diagnostic methods are now available and are particularly useful in examining children with atypical clinical manifestations. Nonspecific signs include neutrophilic leukocytosis, accelerated ESR, increased levels of C-reactive protein and fibrinogen. Daily proteinuria above 0.5 g/day indicates the development of renal amyloidosis. Differential diagnosis is carried out with acute intermittent porphyria, hereditary angioedema with abdominal attacks, recurrent pancreatitis and other hereditary recurrent fevers.

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Treatment recurrent illness

Although symptoms are severe during acute attacks, they resolve quickly in most patients and patients remain well until the next episode. The widespread use of prophylactic colchicine has led to a significant reduction in the incidence of amyloidosis and subsequent renal failure.

The prophylactic dose of colchicine is 0.6 mg orally twice a day (some patients require 4 doses of colchicine, while some patients can take it once). This dose provides complete remission or marked improvement in about 85% of patients. In patients with rare attacks that develop with a preceding prodromal period, colchicine can be prescribed only at the development of initial symptoms, and the dose is 0.6 mg orally every hour for 4 hours, then every 2 hours for 4 hours, then every 12 hours for 48 hours. As a rule, the administration of colchicine at the peak of the attack, even if it is administered intravenously, is ineffective. To achieve a good prophylactic effect, children often require adult dosages. Colchicine does not increase the risk of infertility and miscarriage in women with periodic Mediterranean fever, and does not increase the frequency of congenital malformations in the fetus when taken by the mother during pregnancy.

Failure to respond to colchicine is often due to noncompliance with the recommended regimen or dose, but a correlation has also been noted between poor response to colchicine therapy and low colchicine concentrations in circulating monocytes. Weekly intravenous colchicine may reduce the frequency and severity of attacks in patients who do not respond to conventional colchicine prophylaxis regimens. Alternatives to colchicine that have not been studied include interferon alfa 3-10 million units subcutaneously, prazosin 3 mg orally 3 times daily, and thalidomide.

Sometimes opioids may be needed to relieve pain, but they should be prescribed with caution to avoid addiction.

Diagnostic criteria for familial Mediterranean fever (periodic disease)

Main diagnostic criteria	Additional diagnostic criteria
1 Periodically occurring diffuse peritonitis and/or pleurisy (2-3 days), accompanied by severe pain syndrome 2 Fever accompanying pain 3 Amyloidosis 4 Therapeutic effect of colchicine	5. Recurring attacks of arthritis 6. Erysipeloid erythema 7. Onset of the disease in early childhood or puberty 3. Nationality 9. Burdened family history 10. Unjustified repeated surgical interventions in abdominal or mixed form 11. Remission during pregnancy and resumption of attacks after delivery

Forecast

A complication of this pathology is amyloidosis (AA type) with predominant kidney damage. The probability of developing amyloidosis increases with the following factors: the presence of secondary amyloidosis in relatives, male gender, M694V mutation, homozygosity for SAA1-6.