Familial Mediterranean Fever

FMF is a genetic disorder that is inherited in an autosomal recessive manner. The responsible gene for FMF is the MEFV gene, located in the short arm of chromosome 16. The MEFV gene encodes a protein called pyrin, which consists of 781 amino acids. Three hundred different mutations of this gene have been identified as potential causes of FMF. Mutations commonly occur in exons (i.e., regions of coding DNA) 2, 3, 5, and 10. Mutations in V726A, M680I, E148Q, M694V, and M694I account for around 70 to 80% of cases. Of note, about 10% of the individuals clinically diagnosed with FMF have no identifiable mutations in the MEFV gene. Notably, the most severe phenotypic manifestation of FMF, with the highest risk of complications, is linked to the M694V and M680I mutations.

Familial Mediterranean fever usually presents with periodic fevers and severe chest, abdominal, or joint pain associated with the serositis, followed by periods where individuals remain symptom-free. Some individuals also experience symptoms prior to the episode, such as irritability, anxiety, nausea, skin irritations, scrotal swelling, or even myalgias (i.e., muscle aches). For some, there are specific triggering factors that may cause an attack, such as severe stress, cold exposure, excessive exercise, recent infection or surgery, and even menstruation. The severity, frequency, and duration of episodes may vary each time. As the affected individuals age, the frequency and severity of the episodes tend to decrease. 

Fever

In an FMF crisis, especially in younger ages, fever is the most common symptom and may even be the only symptom present. The individual’s temperature may vary from low-grade fever up 40°C, or 104°F. The fever may not be present during the episode if the individual has already begun the appropriate treatment with colchicine.

Abdominal pain

Episodes of abdominal pain are very common in FMF and typically resolve spontaneously in two to three days. Individuals may initially be able to localize the pain, which later may become more generalized. Due to peritonitis, abdominal distension, guarding, rebound tenderness, and decreased bowel sounds can be observed during a physical examination. 

Chest pain

Chest pain, which is typically unilateral, can develop as a result of the inflammation of the pleura and may worsen when breathing deeply or coughing (i.e., pleuritic chest pain). Along with pleuritic pain, pericarditis can occasionally be present as retrosternal chest pain. Ethnic groups from Italy, Japan, and Armenia are more likely to experience pleuritis during FMF episodes due to shared genetic variations of the MEFV gene among individuals of these respective origins. Pleural and pericardial friction rubs can be audible during auscultation. 

Joint pain

Large joints in the lower extremities, such as the hip, knee, or ankle joints are most commonly affected in an FMF episode. The affected individuals frequently complain of intense pain in one joint. Rarely, multiple joints are simultaneously affected. Physical examination may reveal a restricted range of motion of the affected joint. Redness and swelling are less frequent. While complete recovery from an episode is typical, chronic arthritis can occasionally develop.

Skin lesions

Skin lesions that are red, raised, with distinct margins resembling erysipelas are most commonly identified on the lower extremities (e.g., leg, ankle, or foot) and they tend to resolve spontaneously. Physical examination may reveal red, raised lesions that are tender to the touch. Red or purple-colored spots or patches, like purpura, can be also seen on the face, limbs, and trunk of the affected individuals. Those of Jewish descent experience these symptoms more frequently than those of Arab descent, who do so less frequently.

The diagnosis of FMF is mostly clinical based on characteristic signs and symptoms. Further blood testing and imaging may be used to support or exclude this diagnosis. Elevated white blood cells with a neutrophil dominance on complete blood count (CBC) can often be found in individuals with FMF. An increase in acute-phase reactants, like fibrinogen and C-reactive protein (CRP), can be observed. While these findings are typically non-specific, they can be used to measure treatment progress. When pericarditis is present, an electrocardiogram (EKG) may show diffuse ST-segment elevation. Analyses of the fluids retained between the serous membranes by paracentesis typically reveal sterile fluid or without any pathogenic microorganisms and increased white blood cells. To rule out other causes of abdominal pain, such as an acute abdomen, a computed tomography scan (CT) of the abdomen is frequently performed. Genetic testing can also help confirm the diagnosis in cases with atypical presentation of FMF. 

Diagnostic criteria

In order to facilitate the diagnosis of FMF the Tel-Hashomer diagnostic criteria have been established. They have been proven very accurate, having a sensitivity and specificity of more than 95% and 97%, respectively. To confirm the diagnosis in suspected cases, two or more major criteria or one major plus two minor criteria are required. 

Major criteria (characteristic attack with one or more of the following symptoms):

1. Abdominal pain

2. Joint pain (e.g., hip, knee, ankle)

3. Chest pain (e.g., unilateral pleuritis or pericarditis)

4. Scrotal swelling

5. Skin manifestations

6. Muscle pain

7. Fever alone (usually recurrent attacks with fever only and no other identifiable cause)

Minor criteria (incomplete attack including one or more of the following symptoms):

1. Abdominal pain

2. Joint pain

3. Chest pain

4. Leg pain on exertion

5. Positive response to colchicine

6. Nephropathic amyloidosis

Supportive criteria

1. Family history of FMF

2. Vulnerable ethnic origin

3. Early age at onset (under 20 years old)

4. Attacks with spontaneous resolution

5. No symptoms between the attacks

6. Severe attacks requiring bed rest

7. The presence of elevated white cell count or acute phase reactants in the blood

8. History of laparotomy or appendectomy with no pathology

9. Episodic proteinuria or hematuria

10. Consanguinity of parents

The first-line treatment established for FMF is colchicine, which is a medication used to suppress neutrophil chemotaxis (i.e., directed migration of neutrophils towards inflammatory tissues) and prevent the inflammatory events seen in FMF. Therefore, lifelong administration of this medication is typically suggested. The aim of the treatment is to prevent recurrent episodes, normalize inflammation between the episodes, and prevent the development of amyloidosis. Additionally, it can delay the progression of amyloidosis. Dosing may vary according to age or severity of symptoms; therefore, it is adjusted based on the individual’s needs. If acute phase reactant levels in the blood continue to remain high in between episodes and the maximum tolerated dose of colchicine (up to 3 milligrams in adults) does not reduce the frequency and severity of episodes despite adherence to treatment, colchicine resistance may be suspected.

The second-line treatment for patients with FMF resistant to colchicine or who are intolerant to colchicine is an IL-1 inhibitor, such as anakinra or canakinumab. The effectiveness of IL-1 inhibitors in preventing FMF amyloidosis is not completely established.