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      Drugs & Diseases > Rheumatology

      Familial Mediterranean Fever Workup

      Updated: Oct 10, 2023
      • Author: John O Meyerhoff, MD; Chief Editor: Herbert S Diamond, MD  more...
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      Workup

      Laboratory Studies

      Results of routine blood tests performed during the acute attacks of familial Mediterranean fever (FMF) are nonspecific. Levels of acute-phase reactants (ie, C-reactive protein, erythrocyte sedimentation rate, amyloid A protein, fibrinogen) are elevated. The white blood cell count is usually elevated during an attack. The elevated levels rapidly return to the reference range as the attack abates.

      On urine studies, proteinuria should raise a concern about possible amyloidosis. For unknown reasons, hematuria occurs in 5% of patients.

      In patients with arthritis during attack, synovial fluid is inflammatory, with cell counts as high as 100,000/µL.

      Pyrin, the protein whose uninhibited activty causes the characteristic attacks of FMF, is normally kept inactive by kinases. Magnotti and colleagues reported that in monocytes from FMF patients—but not those from healthy controls or patients with other inflammatory disorders—the kinase inhibitor UCN-01 leads to inflammasome activation, pyroptosis (fast cell death), and interleukin-1β secretion; thus, UCN-01–based inflammasome assays would provide a fast and reliable diagnostic test for FMF. [23]

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      Genetic Testing

      Genetic testing is available for FMF. Testing for a limited number of genes may be appropriate in patients with a known ethnic background. Complete gene sequencing may be more helpful in patients of mixed or unknown ethnicity. Symptomatic patients with at least one MEFV mutation should be considered to have FMF. Patients with no gene mutations who meet criteria for FMF should be offered a trial of colchicine. Given the high gene frequency and low penetrance in certain populations (eg, Ashkenazi Jews, Armenians), gene testing should be closely correlated to clinical findings to avoid false-positive results.

      An expert committee of European pediatric rheumatologists has developed the following recommendations for genetic diagnosis of familial Mediterranean fever [24] :

      • FMF is a clinical diagnosis; it can be supported but not excluded by genetic testing.
      • FMF patients carrying two of the common mutated alleles (homozygotes or compound heterozygotes), especially for M694V mutation or mutations at position 680 to 694 on exon 10, must be considered at risk of having a more severe disease.
      • Patients homozygous for M694V mutation are at risk for early-onset disease and at very high risk of developing a severe phenotype; those who are not reporting symptoms should be evaluated and followed closely in order to consider therapy.
      • Patients with two pathogenic mutations for FMF who do not report symptoms but have risk factors for AA amyloidosis (eg, country of origin; family history; persistently elevated inflammatory markers, particularly serum amyloid A protein), should have close follow-up and be considered for treatment.
      • The E148Q variant is common and of unknown pathogenic significance; its presence as the only MEFV variant does not support the diagnosis of FMF.
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      Imaging Studies

      Findings during an acute attack in patients with peritonitis, pleuritis, and arthritis are as expected and include air-fluid levels, pleural effusions, and synovial effusions.

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      Histologic Findings

      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.

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      Biopsy

      Amyloidosis can be presumed in patients with FMF, particularly those of North African descent who have proteinuria. Renal biopsy or, alternatively, submucosal rectal biopsy, is indicated in these patients.

      A recent retrospective review of kidney biopsies in FMF patients found that 40% of the patients had nonamyloid kidney disease (NAKD). While the patients with amyloid kidney disease (AKD) had more proteinuria and more of them had more than 3.5 g of proteinuria, all of these biopsies were in patients with greater than 500 mg of proteinuria. The AKD patients had more severe disease and were more likely to have hypertension. All patients with proteinuria of greater than 500 mg/24 h should have a biopsy. [25]

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