Familial Mediterranean Fever

Synonyms: periodic disease, recurrent polyserositis

Familial Mediterranean fever (FMF) is the most frequent of a group of diseases known as hereditary periodic fever syndromes.^[1]

It is an autosomal recessive condition and more common in people of Mediterranean descent. It causes short, recurrent episodes of peritonitis, pleuritis, arthritis and fever.

Pathophysiology

• Associated with mutations in the MEFV (Mediterranean fever) gene located on chromosome 16.^[2]
• Although FMF was originally defined as an autosomal recessive disorder, approximately 10-20% of FMF patients do not carry any FMF gene (MEFV) mutations.^[3]
• The MEFV gene codes for a protein called pyrin (or marenostrin). Pyrin normally blunts neutrophil-mediated inflammation but it is defective in FMF.^[4] This can therefore lead to uninhibited episodes of inflammation, in the pleura, peritoneum and joints, that are usually associated with fever.
• The episodes of inflammation are thought to result in excess production of amyloid A and its deposition in the kidneys in people with specific MEFV haplotypes.

Epidemiology

• FMF is common in people from eastern Mediterranean countries but is not restricted to these ethnic groups.^[5]
• Male-to-female ratio is 1.5-2:1.

Presentation^{[6, 7, 8]}

• The majority present in the first decade of life.
• Episodes usually last 48-96 hours (peaking around 12 hours) and can include:
  • Fever - can be as high as 40°C; may be the only symptom/sign.
  • Abdominal pain with signs of peritonitis - pain can originate in one area and then spread over the whole abdomen; may be mistaken for appendicitis, cholecystitis or renal colic; there may be associated constipation followed by diarrhoea; vomiting can occur.
  • Pleuritic chest pain - occurs in >50%; may be associated with an effusion.
  • Pericarditis.
  • Joint pain - knees, ankles and wrists are most commonly affected; small joint involvement is rare; joint pain can last longer than abdominal pain; joints are normal between attacks
  • Erysipelas-like rash - occurs in 10-20% of cases; is usually below the knees.
  • Myalgia.
  • Pelvic pain - in females; due to pelvic inflammatory disease (PID).
  • Scrotal pain - in males; due to inflammation of the tunica vaginalis.
  • Vasculitis - the following are more common in those with FMF:
  • Henoch-Schönlein purpura^[9]
  • Polyarteritis nodosa^[10]
  • Behçet's disease
• Not all of the above features may be present during an attack.
• Attacks can recur after several days or months but there may be years between attacks.

Investigations

• During an attack, expect the following to be raised:^[6]
  • Acute-phase proteins, including C-reactive protein (CRP) and fibrinogen.
  • Erythrocyte sedimentation rate (ESR).
  • White blood cell count
• Look for proteinuria as a sign of amyloidosis; renal or rectal biopsy may be required to confirm diagnosis.
• DNA samples can be analysed for known FMF gene (MEFV) mutations.
• Synovial fluid will show an inflammatory picture.
• Appropriate abdominal and chest and cardiac investigations should be carried out, depending on the symptoms and signs, to exclude other causes.

Treatment

• Colchicine is the mainstay of treatment - it is very effective, prevents attacks and helps symptoms. It is also important in the prevention and treatment of amyloidosis.^[11]
• Different ethnic groups seem to have different risks of developing amyloidosis (eg, risk in Ashkenazi Jewish people is low) and so daily colchicine may be needed by some, while others may just need treatment at the onset of an attack.^[5]
• Interferon alfa and etanercept have been used as alternatives to colchicine if it is not tolerated/effective.
• Non-steroidal anti-inflammatory drugs can help arthritis.
• Prednisolone may help severe myalgia.

Complications

• Amyloidosis can cause massive albuminuria and can lead to nephrotic syndrome which may eventually lead to chronic kidney disease.
• Amyloidosis can also lead to hypertension and renal vein thrombosis (may present as loin pain).
• Chronic arthritis leading to joint destruction (occurs in about 2%).
• Infertility and miscarriage (due to pelvic inflammatory disease).

Prognosis

This has greatly improved with the advent of colchicine and its role in the prevention of amyloidosis. However, strict compliance is needed.