Familial Mediterranean ... Familial Mediterranean Fever Page 1 of 12 Familial Mediterranean fever ¢â‚¬¢

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  • Familial Mediterranean Fever

    Page 1 of 12

    Familial Mediterranean fever

    • Is a hereditary autoinflammatory disorder characterized by recurrent bouts of

    fever and serosal inflammation.

    • The initial attack occurs before the ages of 10 and 20 years in 65 and 90 percent

    of cases.

    • In rare cases, the initial attack can occur in individuals older than 50 years of age.

    • As the name indicates, FMF occurs within families and is much more common in

    individuals of Mediterranean descent than in persons of any other ethnicity

    Epidemiology In adults, FMF is more prevalent in men than in women.

    • It mainly occurs in families of Mediterranean area.

    • Age:

    50-60% are younger than 10 years.

    80-95% are younger than 20 years.

    5-10% are older than 20 years at onset.

    • Onset in people older than 40 years is rare

    Pathophysiology

    • Mutations in the MEFV (Mediterranean fever) gene on chromosome 16 appear

    to cause the disease in many cases. MEFV produces a protein called pyrin

    (derived from the association with predominant fever); the protein is also called

    marenostrin (derived from the phrase "our sea," because of the Mediterranean

    heritage of most patients).

    • Pyrin acts without a known provocation, the outcome of this process is secretion

    of interlukin IL-1,IL-18 and other mediators of inflammation which enhances

    chemotaxis and neutrophilia including an attack of FMF leading to episodes of

    inflammation (with accompanying fever) in the peritoneum, pleura, and joints;

    persistent subclinical inflammation is also common.

    • The inflammatory episodes in persons with FMF lead to the excess production of

    amyloid A protein in the acute phase and reactant serum amyloid A with

    subsequent deposition in the kidneys. Only patients with

    specific MEFV haplotypes develop amyloidosis.

  • Familial Mediterranean Fever

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    Clinical manifestations

    • Episodes last for one to three days and then resolve spontaneously

    • The intervals between episodes are irregular, ranging from one week to several

    months or years, and patients are asymptomatic between attacks.

    • Patients may have a stereotypic prodrome before their attacks; it may include

    various constitutional and physical signs, such as restlessness at the site where the

    symptom is about to occur, anxiety, irritability, increased appetite, and taste

    alterations.

    • vigorous exercise, emotional stress, intercurrent infections, exposure to cold,

    surgery, and menstruation have been associated with an attack in some patients

    • During pregnancy, the course of FMF may worsen in about a third of the patients,

    improve in another third of patients, and remain unchanged in the rest.

    1) Recurrent fever:

    • It is one of the most constant characteristics, presents in almost all cases during

    attacks (38° to 40°C), the duration is brief, lasting between 12 hours and three

    days

    • It may be the first and only symptom of FMF, especially in toddlers.

    • FMF patients who are treated with colchicine, an acute attack may occur without

    fever.

    2) Abdominal pain

    • It occurs in 95% in patients, presents locally and then progress to become more

    generalized.

    • It is caused by inflammation of the peritoneum, signs of peritonitis such as

    guarding; rebound tenderness, rigidity, and a dynamic ileus are often present.

    • These findings can be mistaken for an acute surgical abdomen leading to

    diagnosis delay and sometimes even to futile operations.

    3) Chest pain:

    • It occurs in 33-84 %of patients, depending on the patient’s ethnic origin.

    (Armenian have a higher rate of pleuritic involvement compared with other ethnic

    groups).

  • Familial Mediterranean Fever

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    • May be due to inflammation of the pleura or referred pain from subdiaphragmatic

    inflammation.

    • Manifests as unilateral chest pain that is worse with inspiration or coughing and

    small, transient pleural effusion.

    • Episodes usually resolve within three days, but may last up to one week.

    4) Joint pain

    • The joint attacks are usually monoarticular, involving one of the large joints

    (knee, ankle, hip)

    • The synovial fluid analysis is typically sterile, with a nucleated white cell count

    ranging from 200 to >100,000 white blood cells/mm 3

    • episodes usually lasts 24 to 48 hours, which resolve completely without leading to

    joint destruction, but in severely protracted cases, it can result in permanent

    deformity, functional limitation, osteoporosis around the affected joint, and

    aseptic necrosis.

    5) Erysipelas-like skin lesion:

    • It occurs in 12 to 40%

    • The lesion is typically 10 to 35 cm2 in area, tender, raised, and erythematous and

    occurs on the lower leg, ankle, or foot.

    • Lesions may be transiently warm without associated pain or tenderness

    • In children, it may be misdiagnosed as an infectious erysipelas or cellulitis.

    • Recovery is spontaneous and does not require antibiotics

    Other rare manifestations:

    • Exertional myalgia: involves lower limbs (thighs and calves) in children, not

    treated by colchicine, resolves with rest and NSAIDs

    • Acute pericarditis: include chest pain (sharp and pleuritic, improved by sitting

    up and leaning forward), pericardial friction rub, and widespread ST segment

    elevation on electrocardiogram

  • Familial Mediterranean Fever

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    • Acute scrotum: unilateral gradual swelling of the scrotum in children.

    • Protracted febrile myalgia: have an increased ESR but a normal serum creatine

    kinase level

    • Headache and aseptic meningitis.

    Long-term complications:

    • Secondary (AA) amyloidosis

    • Small bowel obstruction

    • Infertility

    DIAGNOSIS:

    • FMF is suspected in individuals with recurrent febrile episodes accompanied by

    peritonitis, synovitis or pleuritis, recurrent erysipelas-like erythema, repeated

    laparotomies for an acute abdomen with no identifiable underlying pathology, a

    first-degree relative with FMF, and/or membership in an at-risk ethnic group.

    • Genetic testing for FMF serves to support the diagnosis in patients who meet

    clinical criteria for FMF

    • Six-month trial of colchicine therapy that results in a relief of attacks and

    recurrence after cessation of treatment. (In patients who met the clinical criteria

    but genetic testing was not diagnostic).

    FMF is diagnosed in patients with any of the following:

    • ≥1 major criteria

    • ≥2 minor criteria

    Elevation of serum markers of systemic

    inflammation

    Elevated erythrocyte sedimentation rate

    (ESR)

    Elevated C-reactive protein (CRP)

    Elevated serum amyloid A (SAA)

    protein

    Elevated fibrinogen.

    Serum homocysteine and lipoprotein(a)

  • Familial Mediterranean Fever

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    • 1 minor plus 5 supportive criteria

    • 1 minor criterion plus ≥ 4 of the first

    five supportive criteria

    Differential diagnosis:

    * It varies with the patient's predominant clinical features

    • Periodic fever syndromes

    • Systemic juvenile idiopathic arthritis/adult Still's disease

    • Systemic vasculitis involving the abdomen

    • Systemic rheumatic diseases

  • Familial Mediterranean Fever

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    • Infection

    • Malignancy

    Goals of therapy:

    • Prevent acute attacks.

    • Minimize subclinical inflammation in between attacks.

    • prevent the development and progression of amyloidosis

    Pharmacological treatment:

    Colchicine:

    • Trade names: colchicine tabs ® 1mg (available in Jordan)

    colcine ® 0.5 mg tab (available in Jordan)

    colcrys ® 0.6 mg tab.

    • Primarily effective as a prophylactic treatment for the FMF attacks.

    • It is recommended in all patients regardless of the frequency and intensity of

    attacks.

    • Use of intermittent high-dose colchicine only for treatment of acute attacks of

    FMF is not recommended since it does not protect from the development of

    amyloidosis resulting from low-grade inflammation that can occur during

    asymptomatic intervals

    • MOA: affects the motility of neutrophils by reducing their deformability and

    elasticity.

    • Adherence with colchicine is higher with once-daily dosing and its efficacy is the

    same as with splitting the dose into two divided daily doses.

    • Colchicine dose is not split unless the patient does not tolerate once-daily dosing

    due to side effects, which are most commonly gastrointestinal.

    • We generally start with a lower dose and increase the dose by 0.5 to 0.6 mg

    according to the pat