Familial Mediterranean Fever, or FMF, is a genetic autoinflammatory condition primarily affecting individuals of Mediterranean and Middle Eastern heritage. It is the most common of the periodic fever syndromes. The disease is defined by recurring episodes of fever and inflammation in the linings of the abdomen, chest, or joints. Diagnosing FMF is not always straightforward and relies on a combination of clinical observations, laboratory tests, and the patient’s response to medication.
Clinical Evaluation and Symptoms
The diagnostic process for Familial Mediterranean Fever begins when a patient presents with a distinct pattern of recurrent, self-resolving attacks. A primary indicator is the presence of high fever, with temperatures ranging from 38 to 40 degrees Celsius (100.4 to 104 degrees Fahrenheit). These fevers appear suddenly, developing over two to four hours and lasting for one to four days before disappearing. The time between these episodes can be unpredictable, ranging from a few days to several years.
Accompanying the fever is severe pain caused by serositis, which is inflammation of the serous membranes lining body cavities. Abdominal pain is the most frequent symptom, occurring in about 90% of patients, and can be so intense that it mimics acute appendicitis. Chest pain, affecting 20-40% of individuals, results from inflammation of the pleura, the lining around the lungs, causing sharp pain with breathing. Joint pain is also a common feature, seen in 50-60% of patients, affecting one large joint at a time, such as a knee, ankle, or wrist.
Formal Diagnostic Criteria
To standardize the diagnosis, clinicians often rely on a formal set of guidelines known as the Tel Hashomer criteria. These criteria structure the clinical evaluation by categorizing symptoms into major and minor features. A diagnosis is established if a patient meets at least one major criterion or two minor criteria.
The major criteria include typical recurrent attacks characterized by fever and serositis (inflammation of the peritoneum, pleura, or synovium) or amyloidosis of the AA type without another predisposing disease. A “typical attack” is defined as having at least three recurrent episodes that are febrile (rectal temperature of at least 38°C) and short, lasting between 12 and 72 hours.
Minor criteria encompass less specific but still supportive signs. These include:
- Recurrent febrile episodes that do not meet the full definition of a typical attack
- An erysipelas-like skin rash
- Having a first-degree relative with a confirmed FMF diagnosis
Some frameworks also include “incomplete attacks,” which are recurrent and painful but may lack a high fever or have a slightly different duration, as supportive evidence.
Laboratory and Genetic Testing
While the diagnosis of FMF is based on clinical signs, laboratory and genetic tests provide objective evidence. During an inflammatory attack, blood tests show elevated levels of acute-phase reactants, including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and Serum Amyloid A (SAA). Monitoring these markers both during and between attacks helps to document the inflammatory nature of the episodes.
A complete blood count performed during an attack may also reveal a high white blood cell count with a predominance of neutrophils. These findings, while not exclusive to FMF, support the presence of a significant inflammatory process. When attacks subside, these laboratory values return to normal, reflecting the episodic nature of the condition.
Genetic testing for mutations in the MEFV gene can help confirm the diagnosis, especially in cases with atypical presentations. A diagnosis is supported when an individual carries two mutations, one inherited from each parent. However, genetic testing has its limitations. Approximately 10-20% of patients who meet the clinical criteria for FMF may have only one or no detectable mutations. Therefore, a clinical diagnosis remains valid even without genetic confirmation.
Ruling Out Other Conditions
Diagnosing FMF requires a process of elimination, as several other conditions can present with similar symptoms. This differential diagnosis is necessary to ensure other potential causes of recurrent fevers and pain are not overlooked.
Physicians must consider other hereditary periodic fever syndromes, which can also cause recurrent fevers and inflammation. Conditions such as Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS) and Hyperimmunoglobulinemia D Syndrome (HIDS) share some features with FMF but have distinguishing characteristics. For example, attacks in TRAPS often last much longer than those in FMF. Rheumatological conditions like juvenile idiopathic arthritis and Behçet disease can also present with overlapping symptoms.
The Role of a Therapeutic Trial
In situations where a diagnosis remains uncertain, a physician may suggest a therapeutic trial with colchicine. This medication is the primary and lifelong treatment for FMF, used to prevent attacks and the long-term complication of amyloidosis. A positive response to this medication serves as a strong diagnostic indicator.
The trial involves prescribing a regular dose of colchicine for about six months. During this time, the patient and physician monitor the frequency, severity, and duration of the inflammatory attacks. If the patient has FMF, they will experience a marked improvement, with attacks either stopping completely or becoming much less frequent and severe.
This approach is particularly useful when genetic testing is inconclusive or unavailable, or when the symptoms are atypical. Observing a clear benefit from colchicine helps confirm that the inflammatory episodes are driven by the mechanisms this medication targets.