Familial Mediterranean Fever (FMF) - Recurrent Polyserositis

Synonyms: periodic disease.

Familial Mediterranean fever is the most frequent of a group of diseases known as hereditary periodic fever syndromes.¹ It is an autosomal recessive condition, more common in people of Mediterranean descent causing short, recurrent episodes of:

• Peritonitis
• Pleuritis
• Arthritis
• Fever

• Associated with mutations in the MEFV (Mediterranean fever) gene located on chromosome 16.
• The MEFV gene codes for a protein called pyrin (or marenostrin). Pyrin normally blunts neutrophil-mediated inflammation but it is defective in FMF.² This can therefore lead to uninhibited episodes of inflammation in the pleura, peritoneum and joints that are usually associated with fever.³
• 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.³

• Specific ethnic groups have an increased prevalence:³
  • Ashkenazi Jewish people (descended from Eastern European Jewish people) - 1 case per 73,000
  • Sephardic Jewish people (descended from Jewish people expelled from Spain to North Africa and other Middle Eastern Jewish people) - 1 case per 250-1000
  • Armenians - 1 case per 500
  • Turkish people - 1 case per 1000 (figure only from one study)
  • Arabic people - 1 case per 2600 (figure only from one study)
• However, FMF is not restricted to these ethnic groups.
• Male-to-female ratio is 1.5-2:1.³

• The majority present in the first decade of life, and only 1% present after age 40.⁴
• Episodes usually last 48-96 hours (peaking around 12 hours)⁴ 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;⁴ may be mistaken for appendicitis, cholecystitis or renal colic; may be associated constipation followed by diarrhoea; vomiting can occur⁴
  • Pleuritic chest pain - occurs in > 50%;⁴ may be associated with an effusion
  • Pericarditis
  • Joint pain - knees, ankles and wrists most commonly affected;³ small joint involvement is rare;⁴ joint pain can last longer than abdominal pain; joints are normal between attacks³
  • Erysipelas-like rash - occurs in 10-20% of cases;⁴ is usually below the knees³
  • Myalgia
  • Pelvic pain - in females; due to pelvic inflammatory disease
  • Scrotal pain - in males; due to inflammation of the tunica vaginalis³
  • Vasculitis - Henoch-Schönlein purpura,⁵ polyarteritis nodosa⁶ and Behçet disease are more common in those with FMF³
• 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.⁴

• During an attack, expect the following to be raised:
  • Acute-phase proteins including C-reactive protein and fibrinogen
  • 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

• Colchicine is the mainstay of treatment - it prevents attacks and helps symptoms. It is also important in the prevention and treatment of amyloidosis.
• Different ethnic groups seem to have different risks of developing amyloidosis (e.g. 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.³
• Interferon alfa and etanercept have been used as alternatives to colchicine if it is not tolerated/effective.³
• Non-steroidal anti-inflammatory drugs can help arthritis.
• Prednisolone may help severe myalgia.

• Amyloidosis can cause massive albuminuria and can lead to Nephrotic syndrome which may eventually lead to renal failure
• 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%)⁴
• Infertility and miscarriage (due to pelvic inflammatory disease)

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