Familial Mediterranean Fever · What Is It, Causes, Treatment, and More

Familial Mediterranean fever (FMF) refers to a hereditary autoinflammatory disorder that mainly affects people of Mediterranean and Middle Eastern origin. FMF is characterized by recurrent episodes of fever and serositis (i.e., inflammation of the serous membranes) of the heart, abdomen, or joints. Symptom onset usually occurs during childhood, especially before the age of 20. Most episodes gradually develop over the course of two to four hours and usually resolve spontaneously between six hours to four days after onset. Nonetheless, treatment is necessary to prevent recurring episodes and severe, potentially fatal complications, such as amyloidosis (i.e., accumulation of amyloid protein in tissues) of the kidneys, which can cause kidney failure.

FMF is a genetic disorder with autosomal recessive inheritance. The gene involved in 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. 300 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. A group of mutations (V726A, M680I, E148Q, M694V, and M694I) account for around 70% to 80% of cases. The most severe phenotypic manifestation of FMF, with the highest risk of complications, is linked to the M694V and M680I mutations. Of note, about 10% of the individuals clinically diagnosed with FMF have no identifiable mutations in the MEFV gene. Although this condition is typically autosomal recessive, several instances of autosomal dominant transmissions have been documented, and M694V deletions are the most frequent mutations identified in such cases.

FMF usually presents with periodic fevers, accompanied by severe chest, abdominal, or joint pain associated with serositis, followed by symptom-free periods. Some individuals also experience symptoms prior to the episode, such as irritability, anxiety, nausea, skin irritations, scrotal swelling, or myalgias (i.e., muscle aches). For some, attacks may be triggered by factors 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 affected individuals age, episodes typically become less frequent and less severe.

Fever
Fever is the most common - and sometimes the only - symptom during FMF crises, especially in younger individuals. Body temperature may range from low-grade fever to as high as 40°C, or 104°F. When the affected individual is receiving appropriate treatment, fever may be absent during episodes.

Abdominal pain 
Episodes of abdominal pain are very common in FMF and typically resolve spontaneously in two to three days. While the pain might be initially localized, it typically becomes more generalized over time. Peritonitis, an inflammation of the serous membrane lining the abdominal cavity called the peritoneum, can also occur, presenting with abdominal distension, guarding, rebound tenderness, and decreased bowel sounds on physical examination.

Chest pain 
Chest pain, typically unilateral, can result from inflammation of the pleura, which is the thin serous membrane lining the chest wall and lungs. Pleuritic chest pain is characterized by worsening pain when deep breathing or coughing.  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. Along with pleuritic pain, retrosternal chest pain may occur as a consequence of pericarditis, which is inflammation of the pericardium, the double-walled sac encasing the heart. On physical examination, pleural and pericardial friction rubs can be audible during auscultation.

Joint pain 
During FMF episodes, large joints of the lower extremities (such as hips, knees, and ankles) are most commonly affected.  Affected individuals frequently report intense pain in one joint, while involvement of multiple joints is rarer. Physical examination may reveal restricted range of motion of the affected joint and, less frequently, redness and swelling. Although episodes typically resolve completely, chronic arthritis can occasionally develop.

Skin lesions 
The skin lesions observed during FMF episodes are red, raised, have distinct margins that resemble erysipelas, and they’re tender to the touch. They most commonly appear on the lower extremities (e.g., leg, ankle, or foot) and tend to resolve spontaneously. Red or purple-colored spots or patches, resembling purpura, can develop on the face, limbs, and trunk of affected individuals. Individuals of Jewish descent experience these symptoms more frequently than those of Arab descent.

The diagnosis of FMF is mostly based on characteristic clinical signs and symptoms. Further blood testing and imaging may be used to support or exclude the diagnosis. A complete blood count (CBC) can often reveal elevated white blood cells with neutrophil dominance. An increase in acute-phase reactants (i.e., inflammation markers), like fibrinogen and C-reactive protein (CRP), can also be observed.  Although not specific for FMF, these markers can be used to monitor response to treatment. When pericarditis is present, an electrocardiogram (EKG) may show diffuse ST-segment elevation. When serositis is suspected, analysis of serous fluid obtained by paracentesis typically reveals sterile fluid and increased white blood cells. To rule out other causes of abdominal pain that may require emergency treatment (acute abdomen), an abdominal computed tomography (CT) scan is frequently performed. Genetic testing can help confirm the diagnosis in FMF cases with atypical presentation.

Diagnostic criteria 
The Tel-Hashomer diagnostic criteria were established to facilitate the diagnosis of FMF. They have been proven to be very accurate, with a sensitivity greater than 95% and a specificity over 97%. To confirm the diagnosis in suspected cases, the presence of typical FMF attacks along with at least one major criterion, two minor criteria, or one minor criterion plus five supportive criteria is required.

Major criteria: a typical attack involving one or more of the following	-Peritonitis (generalized)  -Pleuritis (unilateral) or pericarditis  -Monoarthritis (hip, knee, ankle, or elbow joint pain)  -Fever only
Minor criteria: incomplete attack(s) involving one or more of the following	-Abdominal pain  -Joint pain  -Chest pain  -Leg pain on exertion  -Positive response to colchicine
Supportive criteria	-Family history of FMF  -Vulnerable ethnic origin  -Early age at onset (under 20 years old)  -Attacks with spontaneous resolution  -No symptoms between the attacks  -Severe attacks requiring bed rest  -The presence of elevated white blood cell count or acute phase reactants in the blood  -History of laparotomy or appendectomy with no pathology  -Episodic proteinuria or hematuria  -Consanguinity of parents

The first-line treatment for FMF is colchicine, a medication used to suppress neutrophil chemotaxis (i.e., neutrophils migration towards inflammatory tissues) and prevent inflammatory events. Therefore, the lifelong administration of this medication is typically suggested. The aim of treatment is to prevent episodes from recurring, normalize inflammation levels between the episodes, and reduce the risk of developing complications. Dosing may vary according to age or severity of symptoms and is adjusted based on the individual’s needs. Sometimes, high levels of acute phase reactant persist between episodes, and the maximum tolerated dose of colchicine (up to 3 milligrams in adults) does not reduce their frequency and severity despite adherence to treatment. In such cases, colchicine resistance may be suspected.

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

Tumor necrosis factor (TNF)-alpha inhibitors (e.g. thalidomide, infliximab, and etanercept) have also been recommended in some cases; however, their efficacy remains uncertain. Lastly, selective serotonin reuptake inhibitors (e.g., escitalopram, paroxetine) can also minimize the frequency of FMF episodes, suggesting that depression and stress may play a significant role in FMF morbidity.

Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disorder mainly affecting people of Mediterranean and Middle Eastern origin. It is characterized by recurrent fevers and inflammation in the chest, abdomen, or joints, often accompanied by rashes. Onset usually occurs before 20 years of age, with episodes lasting two to four hours and up to four days. FMF arises from mutations in the MEFV gene. Diagnosis of FMF is clinical and can be supported by additional blood tests and genetic testing. Colchicine is the primary treatment, while IL-1 inhibitors are secondary options for resistant cases. Treatment is crucial to prevent complications like kidney failure.