Familial Mediterranean fever

Author: Delwyn Dyall-Smith FACD, Dermatologist, 2011.

What is familial Mediterranean fever?

Familial Mediterranean fever is an inherited autoinflammatory syndrome characterised by recurrent short episodes of high fever associated with abdominal pain, inflammation of joints and other body sites and skin rash. If untreated, amyloidosis commonly develops and may have a fatal outcome. Familial Mediterranean fever is the most common of the periodic fever syndromes.

In Type 2 familial Mediterranean fever, amyloidosis is the presenting feature with no history of typical febrile episodes.

Who gets familial Mediterranean fever and why?

Familial Mediterranean fever mainly affects specific racial groups originating from around the eastern Mediterranean Sea. These include:

In these groups, 1 in 25 to 1 in 2000 people are affected. By comparison, in west Europeans the prevalence is 2.5 per 100,000 (1 in 40,000) people. The carrier rate can be as high as 1 in 3 in some groups. Although previously believed to affect only Sephardic Jews, Ashkenazi Jews have recently been recognised to suffer a mild form of the syndrome. Two-thirds of patients develop symptoms before the age of 5 years and 90% by 20 years of age.

Familial Mediterranean fever is usually inherited as an autosomal recessive condition, meaning both parents must carry the defective gene and there is a one in four chance of a child being affected (MIM 249100). There is a less common autosomal dominant form (MIM 134610).

Molecular biology and genetics

Familial Mediterranean fever is usually due to mutations in the Mediterranean fever (MEFV) or pyrin gene located on chromosome 16 (16p13.3). Mutations in the MEFV gene have been found in 80% of typical cases. More than 100 different disease-linked mutations have been identified. The most commonly reported mutation, M694V, is associated with severe disease and the development of secondary amyloidosis. Other common mutations are M680I and V726A. 20% of Ashkenazy Jews carry the E148Q MEFV mutation.

The MEFV gene codes for a protein called pyrin (also known as marenostrin) mainly expressed by inflammatory white cells such as neutrophils and eosinophils. The normal form of pyrin suppresses inflammation by down-regulation of pro-inflammatory cytokines (cell messenger proteins), up-regulation of anti-inflammatory cytokines and preventing the production of interleukin 1beta (IL-1β) by inflammasomes. A lack of functional pyrin releases the inflammatory cascade.

There are also environmental effects on the manifestations of familial Mediterranean fever. For example Armenians with familial Mediterranean fever resident in Armenia have an incidence of amyloidosis of 25 – 48%, whereas Armenians resident in the USA have an incidence of amyloidosis of 0%.

Clinical features of familial Mediterranean fever

The most common clinical features of familial Mediterranean fever are:

Onset is almost always before 30 years of age. Children under the age of 2 years often present with fever alone, and progress to more typical attacks by the age of 5 years.

The characteristics of the recurrent acute episodes of familial Mediterranean fever are described in the table below.

SymptomFeatures
Fever
  • high, spiking
  • lasts 1-3 days
Abdominal pain
  • affects 95%
  • due to inflammation of the linings of the abdominal cavity (peritonitis)
  • severe, board-like muscle rigidity, rebound tenderness
  • associated constipation or diarrhoea
  • may mimic symptoms and signs of appendicitis
Chest pain
  • affects 33-50%
  • due to inflammation of the lining around the lungs (pleuritis)
  • associated with shortness of breath or shallow breathing
  • less commonly due to inflamed sac around the heart (pericarditis, 1%)
Joint pain and swelling (arthralgia, arthritis)
  • affect up to 75%
  • due to inflammation of the joint lining (synovitis) with neutrophils
  • arthralgia is common, arthritis is seen in younger patients.
  • Three patterns of arthritis are recognised:
    • asymmetrical non-destructive arthritis presenting as swelling of 1-2 large joints, most commonly ankles, knees or wrists
    • chronic destructive arthritis
    • migratory polyarthritis
Skin rashes
  • affect 40%
  • various presentations (see below)
Scrotal pain (orchitis)
  • affects 5%
  • especially young children
Spleen enlargement (splenomegaly)
  • especially in children
Muscle pain (myalgia)
  • most commonly post-exercise muscle leg pain
  • rarely pain and weakness may last for weeks resulting in an inability to walk (‘prolonged febrile myalgia’)
Neurologic symptoms
  • affect 10-15%
  • due to inflammation of the linings around the brain (aseptic meningitis)
  • headache – one series reported 45% in association with febrile episodes
  • abdominal epilepsy
  • febrile convulsions
Amyloidosis
  • major complication of FMF
  • may result in kidney or liver failure and death
  • can also result in a peripheral neuropathy

What are the features of the skin rash?

Cutaneous features of familial Mediterranean fever
Erysipelas-like lesions
  • most distinctive of the skin changes
  • occur in 15-20% of children
  • well-demarcated, warm, red and painful plaques
  • commonly on the front of the lower legs between the ankle and knee but characteristically the top of the foot or over the medial malleoli of the ankle
  • up to 15cm in diameter
  • often associated with joint pain
  • either unilateral or symmetrical
Henoch-Schönlein purpura
  • reported in 5% of children
Nonspecific purpura
  • reported in 5% of children
  • seen on face, trunk and limbs
  • frequent finding in children
Polyarteritis nodosa
  • rare
  • tends to occur at young age
  • associated with peri-renal haematoma
Angioedema
  • reported rarely
Redness of the palms
  • reported rarely
Raynaud phenomenon
  • reported rarely

What triggers attacks?

The frequency of episodes is variable, ranging from weekly to every few years. Attacks may be triggered by:

Acute attacks settle spontaneously. Between episodes, health is normal.

How is familial Mediterranean fever diagnosed?

Diagnosis of familial Mediterranean fever is made using the Tel-Hashomer criteria:

The diagnosis if definite if 2 major or 1 major + 2 minor criteria are met.

The diagnosis is probable if 1 major + 1 minor criteria are met.

Major criteria

  1. Recurrent febrile episodes associated with peritonitis, pleuritis or synovitis
  2. Amyloidosis of AA-type without a predisposing disease
  3. Favourable response to daily colchicine

Minor criteria

  1. Recurrent febrile episodes
  2. Erysipelas-like erythema
  3. Positive history of familial Mediterranean fever in a first degree relative

Investigations

Blood tests during an attack may show:

X-rays of abdomen often reveal multiple fluid levels suggesting an ‘acute abdomen’

A skin biopsy from the erysipelas-like lesion may show a heavy infiltrate of neutrophils (white blood cells). Leukocytoclastic vasculitis is seen on biopsies from Henoch-Schönlein purpura or polyarteritis nodosa-like lesions.

Investigations for myalgia (muscle pain) reveal normal muscle enzymes, electromyography (EMG) and muscle biopsy.

Amyloidosis most commonly presents as protein in the urine (proteinuria) without red cells or raised blood pressure.

Gene sequencing can be performed by specialised laboratories as targeted mutation analysis (looking for the commonest mutations) or sequence analysis of select exons (looking at exon 10 and possibly others). Once the gene mutations have been identified in the patient, the carrier status of parents, screening of other first degree blood relatives even if asymptomatic, and prenatal diagnosis can be determined. Identification of asymptomatic but genetically affected individuals means treatment can be commenced to prevent the development of amyloidosis.

Treatment of familial Mediterranean fever

Colchicine, taken orally each day for life, is the drug of choice for familial Mediterranean fever to:

Colchicine is potentially toxic so it is very important not to take an excessive dose.

The dose of colchicine is increased stepwise up to a maximum dose of 2.5 mg/day. The dose is usually determined by the frequency and severity of attacks. Colchicine results in a marked improvement in symptoms for 90-95% of patients, and 75% have virtually complete remission. It is not known how it works.

Other treatment

Acute attacks are treated with non-steroidal anti-inflammatory drugs (NSAID) and pain relief.

Prolonged fever with muscle pain responds to systemic corticosteroids.

The most common reason for failure to respond to colchicine is poor compliance due to gastrointestinal upset. However 5-10% do not respond to colchicine and this may be due to ABCB1 gene polymorphisms affecting colchicine uptake by mononuclear cells. Thalidomide and biologic agents, such as daily subcutaneous anakinra (an interleukin-1 receptor antagonist) or etanercept, may then be considered to prevent attacks and the development of amyloidosis. To reduce the severity of an attack, single dose methylprednisolone or anakinra at the start of episodes have been reported to relieve symptoms.

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