Mediterranean Fever Familial

1
Mediterranean Fever Familial
2
Background

• Familial Mediterranean fever (FMF) is also called
  recurrent polyserositis.
• Features of this disease include brief recurrent
  episodes of peritonitis, pleuritis, and
  arthritis, which are usually associated with
  fever. The disease occurs within families and is
  much more common in individuals of Mediterranean
  descent.
• FMF is more prevalent in men than women (21).
• 80-95 are younger than 20 years. Rare in persons
  older than 40.

3
Pathophysiology

• Nonsense or missense mutations in the MEFV
  (Mediterranean fever) gene appear to cause the
  disease.
• This gene produces a protein called pyrin or
  marenostrin.
• This protien probably functions as an inhibitor
  of chemotactic factor C5a or of IL8.
• Thus in patients with FMF , there is uninhibited
  activity of chemotactic factor and episodes of
  inflammation in peritoeneum, pleura, joints.
• These inflammatory episodes lead to the excess
  production of amyloid A protein with subsequent
  deposition in the kidney.

4
Frequency

• Ashkenazi Jewish people have a prevalence of 1
  case per 73,000 population.
• Armenian persons have an estimated prevalence of
  1 case per 500 population.
• Turkish people (from one study) may have a
  prevalence of approximately 1 case per 1000
  population.
• Arabic people (from one study) may have a
  prevalence of 1 case per 2600 population in
  children and a gene frequency of 150.

5

Mortality/Morbidity

• Nephrotic syndrome.
• Appendectomies in undiagnosed FMF cases.
• Chronic arthritis (5) that sometimes leads to
  destructive arthritis of hips or knees and may
  necessitate joint replacements.
• 10 of patients with chronic arthritis develop
  seronegative spondyloarthropathy.
• Approximately one third of female patients are
  infertile, and 20-30 of pregnancies result in
  fetal loss .

6
History

• The preeminent feature of FMF is the paroxysm,
  the classic onset of which occurs without
  warning.
• The paroxysms usually last 48-96 hours, with peak
  intensity occurring within the first 12 hours.

7
History

• Fever
• Temperatures rise rapidly to 38-40C . May be the
  only manifestation.
• Peritoneal symptoms
• Abdominal pain that may progress to peritonitis,
  resembling a surgical abdomen.
• Symptoms consistent with appendicitis or
  cholecystitis, and they frequently have
  appendectomies and cholecystectomies.
• The symptoms may also mimic renal colic.
• Constipation during the attack and diarrhea after
  the attack resolves.

8
History

• Pleural and pericardial symptoms
• pleuritic episodes.
• Effusions.
• Pericarditis.
• Tamponade and constrictive pericarditis are rare.
• Synovial symptoms
• May resemble gout in their acute onset and
  intensity. Knees, ankles, and wrists are the
  joints most commonly affected. An arthritis that
  resembles seronegative spondyloarthritis may also
  occur.

9
History

• Dermatologic manifestations
• Erysipelas like rashes on the lower extremities.
• Muscle symptoms
• Severe myalgia lasting 3-6 weeks.
• Pelvic symptoms
• Female patients may have episodes of PID.
• Scrotal attacks
• Inflammation of the tunica vaginalis may mimic
  episodes of torsion of the testis.
• Vasculitis
• An increased frequency of Henoch-Schönlein
  purpura ,polyarteritis nodosa and Behçet disease.

10
History

• Amyloidosis
• The typical progression is proteinuria, followed
  by nephrotic syndrome, and, inevitably, death
  from renal failure.
• One third of patients may develop renal vein
  thrombosis.
• Prolonged survival resulting from colchicine
  therapy, dialysis, and renal transplantation
  allows additional manifestations of amyloidosis
  to develop. Some patients have intestinal
  involvement, which may lead to malabsorption and
  death.

11
Physical

• Fever as high as 40C.
• A boardlike or surgical abdomen.
• Splenomegaly.
• Shallow breathing and chest-wall tenderness
  (pleural involvement).
• Joints show typical inflammatory changes, with
  warmth, erythema, or swelling.
• Erythematous, warm rash, particularly below the
  knee.
• Tender muscles (painful myalgia syndrome).
• Pain upon cervical motion and tender, enlarged
  ovaries( pelvic inflammatory syndrome).
• Unilateral, erythematous, and tender swelling of
  the scrotum occurs in scrotal attacks.
• The typical manifestations of Behçet disease and
  Henoch-Schönlein purpura may be observed.
• Amyloidosis is usually asymptomatic.
• Renal vein thrombosis may develop and manifests
  as loin pain.

12
WORKUP

• Lab Studies
• Levels of acute phase reactants (ie, C-reactive
  protein, amyloid A protein, fibrinogen) are
  elevated, as is the erythrocyte sedimentation
  rate. The white blood cell count is usually
  elevated during an attack.
• Proteinuria should raise a concern about possible
  amyloidosis. For unknown reasons, hematuria
  occurs in 5 of patients.
• Synovial fluid is inflammatory, with cell counts
  as high as 100,000/mL.
• From the successful cloning of the MEFV gene,
  researchers have developed a rapid test for the
  most common mutations. The test has a sensitivity
  and specificity of 100.

13
WORKUP

• Imaging Studies
• Findings during an acute attack include air-fluid
  levels, pleural effusions, and synovial
  effusions.
• Procedures
• Renal biopsy or, alternatively, submucosal rectal
  biopsy, is indicated in patients who have
  proteinuria.
• Histologic Findings
• A massive amyloid infiltration of the blood
  vessels and of the endothelial side of the
  glomerular basement membrane occurs in the
  kidneys. In the rectal submucosa, the amyloid is
  found near the blood vessels.

14
Medical Care

• The most important aspects of medical care are to
  make the correct diagnosis and to institute
  therapy .
• Administer colchicine therapy daily (0.6 mg bid)
  in patients at risk of developing amyloidosis
  (eg, North African Jewish people, Turkish people,
  Armenian people living in Armenia). Other Jewish
  people and Arabic people are at lower risk but
  also probably require daily colchicine therapy.
• If attacks are rare and patients can determine
  when they are beginning, treatment with
  intermittent colchicine therapy at the onset of
  attacks may be sufficient therapy.

15
Medical Care

• Some patients develop lactose intolerance and may
  respond to a lactose-free diet.
• In patients whose conditions do not respond to
  colchicine, the use of interferon alfa or the
  tumor necrosis factorblocking drug etanercept
  may be effective.
• Colchicine also stabilizes the amount of
  proteinuria in patients with amyloid nephropathy.
  Renal disease may resolve in patients with a
  creatinine level of less than 1.5 mg/dL who are
  treated with more than 1.5 mg/d of colchicine.

16
Medical Care

• Hemodialysis can be used for patients who develop
  renal failure.
• Patients who experience episodes of prolonged
  myalgia with fever and severe pain may need
  treatment with prednisone (1 mg/kg) for as long
  as 6 weeks.
• Patients who develop seronegative
  spondyloarthropathy are treated with nonsteroidal
  anti-inflammatory drugs and receive follow-up
  care by a rheumatologist.

17
MEDICATION

• Colchicine is the DOC for FMF.
• Action
• Decreases leukocyte motility and phagocytosis in
  inflammatory responses.
• Dose
• 1.2-2 mg PO in divided doses
• Contraindications
• Documented hypersensitivity severe renal,
  hepatic, GI, or cardiac disorders blood
  dyscrasias .
• Interactions
• Sympathomimetic agent toxicity and effect of CNS
  depressants are significantly increased
• Pregnancy
• Safety for use during pregnancy has not been
  established
• Precuations
• In pregnant patients with FMF, treatment may
  improve infertility and miscarriage rates no
  evidence of teratogenic effects in males or
  females may be excreted in breast milk (no
  evidence of adverse effects in breastfed
  children) may cause both myopathy and neuropathy
  in elderly persons and people with renal
  insufficiency

18
Out-patient care

• Perform a urinalysis at every visit, particularly
  in patients at risk of developing amyloidosis. If
  proteinuria is confirmed, increase the daily dose
  of colchicine.
• For unknown reasons, hematuria occurs in
  approximately 5 of patients. Its presence, along
  with prolonged abdominal or muscle pain, suggests
  the development of polyarteritis nodosa.

19
Complication

• Patients with amyloidosis may develop an acute
  onset of renal failure if they are stressed by
  dehydration, infection, or both.
• Renal vein thrombosis may occur in nephrotic
  patients. This condition may manifest as
  abdominal or flank pain, increasing proteinuria,
  and worsening renal function. Acute
  anticoagulation may stabilize or improve renal
  function.

20
Prognosis

• Patients who are compliant with daily colchicine
  can probably expect to have a normal lifespan if
  colchicine is started before proteinuria
  develops.
• Even with amyloidosis, the use of colchicine,
  dialysis, and renal transplantation should extend
  a patient's life beyond age 50 years.