From the Guidelines
The definitive diagnosis of Familial Mediterranean Fever (FMF) is primarily clinical, supported by genetic testing for MEFV gene mutations, and requires recurrent episodes of fever accompanied by serositis, with symptom-free intervals between attacks. Diagnosis can be confirmed by identifying mutations in the MEFV gene, with M694V being the most common and associated with severe disease 1. However, genetic testing is not always definitive as some patients with clinical FMF may not have identifiable mutations. A therapeutic trial of colchicine (0.5-2 mg daily) with significant symptom improvement strongly supports the diagnosis 1. During acute attacks, elevated inflammatory markers (ESR, CRP, serum amyloid A) are present but normalize between episodes. Family history of FMF, especially in Mediterranean populations (Sephardic Jews, Armenians, Turks, Arabs), increases diagnostic probability. Early diagnosis is crucial to prevent amyloidosis, the most serious complication of untreated FMF.
Some key points to consider in the diagnosis of FMF include:
- Recurrent episodes of fever lasting 12-72 hours accompanied by serositis (peritonitis, pleuritis, or synovitis) 1
- Symptom-free intervals between attacks
- Genetic testing for MEFV gene mutations, with M694V being the most common and associated with severe disease 1
- Therapeutic trial of colchicine (0.5-2 mg daily) with significant symptom improvement strongly supports the diagnosis 1
- Elevated inflammatory markers (ESR, CRP, serum amyloid A) during acute attacks, which normalize between episodes
- Family history of FMF, especially in Mediterranean populations, increases diagnostic probability
It is also important to note that the Tel-Hashomer criteria are commonly used, requiring two major criteria or one major plus two minor criteria, and that genetic testing can confirm the diagnosis by identifying mutations in the MEFV gene 1. Additionally, a therapeutic trial of colchicine with significant symptom improvement strongly supports the diagnosis, and during acute attacks, elevated inflammatory markers are present but normalize between episodes 1.
In terms of monitoring and follow-up, response, toxicity, and compliance should be monitored every 6 months, and more frequent assessments may be needed if APR are repeatedly elevated, the disease is unstable, or at any time when the dose is being adjusted or suspected toxicity develops 1. The Auto-Inflammatory Diseases Activity Index (AIDAI) can be used to monitor response, and patients may need more frequent assessments if they are unstable or have suspected toxicity 1.
Overall, the diagnosis of FMF requires a combination of clinical evaluation, genetic testing, and therapeutic trial of colchicine, and early diagnosis is crucial to prevent amyloidosis, the most serious complication of untreated FMF.
From the Research
Diagnostic Criteria for Familial Mediterranean Fever (FMF)
The diagnosis of FMF primarily relies on clinical criteria supported by genetic testing 2. The clinical criteria include recurrent episodes of fever and inflammation, which can lead to severe pain and complications such as renal amyloidosis if left untreated.
Genetic Testing
Genetic testing is used to support the diagnosis of FMF, with mutations in the MEFV gene resulting in the dysregulation of the pyrin inflammasome, leading to excessive production of inflammatory cytokines 2, 3. The MEFV gene is composed of 10 exons and spans approximately 14 Kb of genomic DNA, with over 35 mutations identified to date 3.
Clinical Manifestations
FMF is characterized by recurrent crises of fever and serosal inflammation, leading to abdominal, thoracic, or articular pain 3. Other symptoms may include erysipela-like erythema, effort-induced myalgia, and renal amyloidosis.
Key Features of FMF Diagnosis
- Recurrent episodes of fever and inflammation
- Serosal inflammation, leading to abdominal, thoracic, or articular pain
- Elevated sedimentation rate and white blood cell count
- Diminished albumin concentrations and elevated fibrinogen, C-reactive protein, beta2 and alpha2 M globulins, haptoglobin, and lipoprotein concentrations during and immediately after crises
- Genetic testing to support diagnosis, with mutations in the MEFV gene
Diagnostic Challenges
The diagnosis of FMF can be challenging, as standard laboratory tests are non-informative except for the high sedimentation rate and white blood cell count 3. Additionally, the clinical manifestations of FMF can be similar to those of other conditions, making it essential to consider FMF in the differential diagnosis of patients with recurrent episodes of fever and inflammation.