Family Mediterranean fever (periodic illness): symptoms, diagnosis, treatment

Familial Mediterranean fever (FMF), a recurrent disease, is a hereditary disease characterized by recurrent episodes of fever and peritonitis, sometimes with pleurisy, skin lesions, arthritis and very rarely pericarditis. Can develop amyloidosis of the kidneys, which can lead to kidney failure. Most often, this disease occurs in the descendants of the inhabitants of the Mediterranean basin. The diagnosis is largely clinical, although a genetic examination is available. Treatment includes colchicine for the prevention of acute attacks, as well as amyloidosis of the kidneys in most patients. Prognosis for treatment is favorable.

Family Mediterranean fever (FSS) is a disease that occurs in people originating from the inhabitants of the Mediterranean basin, mainly Sephardic Jews, North African Arabs, Armenians, Turks, Greeks and Italians. At the same time, cases of the disease are also observed in other groups (for example, Ashkenazi Jews, Cubans, Belgians), which cautions against the exclusion of the diagnosis only on the basis of origin. Approximately 50% of patients have a family history of the disease, usually including siblings.

The most common of the described diseases, FMF affects mostly nationalities living in the Mediterranean basin (Sephardic Jews, Turks, Armenians, North Africans and Arabs), although it is possible to find a description of cases of periodic illness among Ashkenazi Jews, Greeks, Russians, Bulgarians , Italians. Frequency of occurrence depending on nationality - 1: 1000 - 1: 100000. In men, it appears more often than in women (1.8: 1).

[1], [2], [3], [4], [5]

Causes of the family Mediterranean fever (recurrent disease)

What causes familial Mediterranean fever?

Family Mediterranean fever is caused by mutations of the MEFV gene located on the short arm of the 16th chromosome, and is inherited in an autosomal recessive type. The MEFV gene normally encodes a protein (called pirin or marenostrin) that is expressed by circulating neutrophils. Its putative function is to reduce the inflammatory response, probably by inhibiting the activation and chemotaxis of neutrophils. Mutations of the gene lead to the synthesis of defective pyrin molecules; suggest that minor, unknown triggers of the inflammatory response, which are normally controlled by intact pyridine, are not suppressed, since the pyrine is defective. Clinical consequences include spontaneous episodes of predominantly neutrophilic inflammation in the abdominal cavity, as well as elsewhere.

The pathogenesis of familial Mediterranean fever

The gene whose defect causes this disease is localized on the short arm of the 16 chromosome (1b 13.3), referred to as MEFV, is expressed predominantly in granulocytes and encodes a protein called pyrin (or marenostrin). The gene consists of 10 exons that regulate the sequence of 781 amino acid residues. There are 26 mutations, mainly in exon 10, and also in exon 2. The most common mutation, M694V (replacement of methionine on valine), occurs in 80% of patients with periodic disease, is associated with a severe course of the disease and a high risk of amyloidosis. Transcriptional factors, is determined in the cytoplasm of myeloid cells.According to various studies it is assumed that the pyrine plays a negative regulatory role in the development of the inflammatory process.

Symptoms of the family Mediterranean fever (recurrent disease)

Symptoms of familial Mediterranean fever

Family Mediterranean fever debuts, usually between 5 and 15 years, but there may be a much later or early onset, even in infancy. Attacks recur intermittently and vary in the same patient. Usually their duration is 24-72 hours, however some last a week or more. The frequency of episodes varies from two attacks per week to one attack per year (most often 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 can last for years.

The main manifestation is an increase in body temperature up to 40 ° C, usually accompanied by symptoms of peritonitis.The pain in the abdomen (usually starting in one quadrant and spreading to the entire abdomen) is noted in about 95% of patients and can vary in severity from attack to attack. Peristalsis, abdominal enlargement, muscle tension of the anterior abdominal wall and symptoms of peritoneal irritation often develop at the peak of the attack, and they can not be distinguished from the perforation of the internal organ during physical examination.

Other manifestations include acute pleurisy (in 30%); arthritis (in 25%), usually with knee, elbow and hip joints; rye-like rash on the lower part of the legs; edema and soreness of the scrotum, caused by inflammation of the testicles. Pericarditis develops very rarely. At the same time, pleural, synovial and skin manifestations of familial Mediterranean fever vary in frequency among different populations and are least frequent in the United States than elsewhere.

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

Diagnostics of the family Mediterranean fever (recurrent disease)

Diagnosis of familial Mediterranean fever

Diagnosis of Mediterranean fever is largely clinical, but now available methods of gene diagnosis, which are especially useful in examining children with atypical clinical manifestations. Nonspecific signs include neutrophilic leukocytosis, an acceleration of ESR, an increase in the level of the reactive protein and fibrinogen. Daily proteinuria above 0.5 g / day indicates the development of amyloidosis of the kidneys. Differential diagnosis is performed with acute intermittent porphyria, hereditary angioedema, with abdominal attacks, recurrent pancreatitis and other hereditary recurrent fevers.

[6], [7], [8], [9], [10]

Treatment of the family Mediterranean fever (recurrent disease)

Treatment of familial Mediterranean fever (periodic disease)

Despite the severity of the symptoms during acute attacks, in most patients they quickly disappear, and patients feel healthy until the next episode. The widespread use of colchicine for prophylactic purposes led to a significant reduction in the incidence of amyloidosis and subsequent renal failure.

Prophylactic dose of colchicine is 0.6 mg orally 2 times a day (some patients need 4 times of colchicine, and some patients may take it once). This dose provides a complete remission or a clear improvement in about 85% of patients. Patients with rare attacks that develop with the previous prodromal period, colchicine can be prescribed only with the development of initial symptoms, with a dose of 0.6 mg orally every hour for 4 hours, then every 2 hours for 4 hours, then every 12 hours within 48 hours. As a rule, the appointment of colchicine at the peak of the attack, even under the condition of its intravenous administration, is ineffective. To achieve a good preventive effect, children often need adult doses. Colchicine does not increase the risk of infertility and miscarriages in women with periodic Mediterranean fever, nor does it increase the frequency of congenital malformations in the fetus when taken by the mother during pregnancy.

The lack of effect in the administration of colchicine is often associated with a failure to comply with the recommended regimen for its administration or dose, but there is also a correlation between a poor response to colchicine therapy and a low concentration of colchicine in circulating monocytes. Weekly intravenous colchicine can reduce the frequency of attacks and their severity in patients not responding to conventional preventive regimens with colchicine. Alternatives to colchicine, which, however, have not yet been investigated, are interferon alpha 3-10 million units subcutaneously, prazosin 3 mg orally 3 times daily, as well as thalidomide.

Sometimes, to ease the pain, it is necessary to prescribe opioids, but you should carefully approach their purpose so as not to become addictive.

Diagnostic criteria of familial Mediterranean fever (periodic disease)

Basic diagnostic criteria	Additional diagnostic criteria
1 Periodically occurring diffuse peritonitis and / or pleurisy (2-3 days), accompanied by severe pain syndrome 2 Fever associated with pain 3 Ailioidosis 4 Therapeutic effect of colchicine	5. Recurring attacks of arthritis 6. Erytipeloid erythema 7. Onset of the disease in early childhood or puberty 3. National affiliation 9. Weighed down family history 10. Unjustified repeated surgical interventions in abdominal or mixed form 11. Remission during pregnancy and resumption of seizures after delivery

Forecast

What is the prognosis of a family Mediterranean fever?

Complication of this pathology is amyloidosis (AA-type) with a predominant kidney damage. The probability of amyloidosis increases with the presence of the following factors: the presence of secondary amyloidosis in relatives, male sex, M694V mutation, homozygosity according to SAA1-6.