Familial Mediterranean Fever

Etiology

FMF is an autosomal recessive disease. The gene responsible for FMF is MEFV, located on the short arm of chromosome 16 (16p13.3). The MEFV gene encodes the 781-amino-acid protein pyrin. Around 300 different mutations in the MEFV gene have been identified, some of which can lead to FMF. Mutations commonly occur in exons 2, 3, 5, and 10. Among these mutations, V726A, M680I, E148Q, M694V, and M694I account for around 70% to 80% of cases.[2] About 10% of patients who are diagnosed clinically with FMF have no mutations in the MEFV gene. The carrier rate of the MEFV gene could be as high as 1:3 in some regions.[3]

Although predominantly an autosomal recessive disease, some reports have described a possible autosomal dominant pattern of transmission. The M694V deletion mutation has been the most common mutation identified in families with a dominant pattern of FMF transmission. M694V and M680I mutations are associated with the most severe phenotypic expression of FMF, with a higher risk of complications.[4] Epigenetic mechanisms have also been thought to contribute to the development of FMF.[5]

Epidemiology

FMF is commonly seen in people of Mediterranean and Middle Eastern descent, including Jews, Armenians, Arabs, Kurds, Greeks, Turks, Iranians, and Italians. The carrier rate of FMF is around 1 in 5 healthy individuals in Armenia.[6] For Jews, a higher carrier rate is found in the Jews of North African or Iraqi origin compared to those of Ashkenazi origin.[7] In Turkey, one field survey found the prevalence of FMF to be around 1 in 1,000 children.[8]

The first attack usually occurs in early childhood. The majority (around 90%) of initial attacks occur by the end of the teenage years.[9] In rare cases, FMF can develop for the first time later in life as well. According to most studies, there appears to be no significant difference in the incidence of FMF between males and females. A nationwide survey in Turkey showed that the incidence of FMF was almost equal, with a male-to-female ratio of 1.2:1.[10] In the United States, FMF is usually observed in Ashkenazi Jews and in those individuals who emigrate from the geographical locations mentioned above.

Pathophysiology

Prior hypothesis proposed that FMF mutations caused a loss of pyrin's anti-inflammatory function. [11][12] However, several studies have challenged the loss-of-function theory, and the current consensus is that FMF is caused by autosomal recessive gain-of-function mutations in the MEFV gene. [13] Pyrin, a 781-amino acid protein product of the MEFV gene, is a key innate immune sensor expressed primarily in neutrophils and monocytes. The MEFV mutations lower the activation threshold of the pyrin inflammasome, leading to excessive caspase-1–mediated IL-1β production. Active RhoA GTPase keeps pyrin phosphorylated and bound to inhibitory 14-3-3 proteins, but mutant pyrin escapes this regulatory checkpoint, resulting in uncontrolled inflammatory episodes. [13]

History and Physical

FMF presents as recurrent episodes of fever and serositis, leading to severe pain in the chest, abdomen, or joints. The first attack typically occurs by age 20. Symptoms develop over 2 to 4 hours and last approximately 12 to 72 hours, with patients returning to baseline health between attacks. Attack severity can vary, and intervals between episodes range from 1 week to several years. Many patients experience prodromal symptoms, including irritability, anxiety, nausea, or myalgia. Certain triggers, eg, severe stress, cold exposure, intense exercise, recent infection, surgery, or menstruation, can precipitate attacks. Frequency and intensity of episodes often decrease with age.[14]

Clinical Manifestations

Clinical manifestations of FMF include:

• Fever: Fever constitutes the most common symptom and may occur alone, particularly in children. Temperatures typically range from mild elevations to 38 to 40 °C (100.4–104 °F), though fever may be absent in treated patients.
• Abdominal pain: An abdominal pain attack is the most common type of attack in FMF. Abdominal pain may initially be localized and then become generalized. On physical examination, abdominal distension, guarding, rebound tenderness, and decreased bowel sounds are noted due to peritoneal inflammation. The episode resolves spontaneously within 2 to 3 days.
• Chest pain: Pleural involvement causes predominantly unilateral chest pain that worsens with deep inspiration or coughing. Pericarditis can coexist, producing retrosternal pain. Pleuritis occurs more often in patients from Armenia, Japan, and Italy. Physical examination may detect pleural or pericardial friction rubs. Mild pleural effusions can develop but seldom cause decreased breath sounds.[15]
• Joint pain: Arthralgia is common in non-Ashkenazi Jews. Large joints of the lower extremities are most commonly affected, including the hip, knee, and ankle. The patient often presents with severe pain in 1 joint. Very rarely, multiple joints are affected simultaneously. On physical examination, a limited range of motion of the affected joint is observed. Swelling and redness are less common. Attacks generally resolve completely, though chronic arthritis may occasionally develop.[15]
• Other symptoms
  • Erysipelas-like lesions on the lower extremities, which appear as slightly raised, tender erythema that resolves spontaneously, are more commonly observed in Jewish patients than in Arabs. 
  • Scrotal swelling is unilateral and tender to palpation on exam. Scrotal swelling is caused by transient inflammation of the tunica vaginalis and resolves within 24 hours.[15]
  • Myalgia is nonspecific and may involve the upper or lower extremities. Muscle tenderness is observed on physical examination. Prolonged febrile myalgia is very rare.
  • Aseptic meningitis and oral ulcers are very rarely reported.[16]

Evaluation

FMF diagnosis is primarily clinical, but is supported by genetic testing. The classic presentation of symptoms, supported by a family history and a response to colchicine, helps confirm the diagnosis. Laboratory and radiographic studies may help support the diagnosis or exclude other causes.

Laboratory Studies

Laboratory analysis can reveal an elevated white blood cell count with neutrophil predominance. Elevation of the acute-phase reactants, eg, fibrinogen, erythrocyte sedimentation rate, serum amyloid A (SAA) protein, and C-reactive protein, although common, is nonspecific. They can be monitored during treatment to document the patient's response to therapy.[17] An electrocardiogram (ECG) may reveal diffuse ST-segment elevation in pericarditis. The synovial fluid analysis shows sterile fluid with elevated nucleated cells. A computed tomography scan of the abdomen is commonly performed to exclude other causes of abdominal pain, including acute abdominal conditions. Genetic testing can help confirm the diagnosis in cases of atypical FMF presentation. However, around 10% of patients who meet diagnostic criteria based on the clinical presentation do not have any mutation.

Diagnostic Criteria

Several criteria sets have been published, but the Tel-Hashomer criteria set in Israel is widely used for the diagnosis of FMF, with sensitivities and specificities of more than 95% and 97%, respectively.[18] The typical criteria include fever (rectal temperature of 38 °C), inflammatory pain, 3 or more recurrences, and a duration of 12 to 72 hours. The presence of 1 major or 2 minor criteria, or 1 minor criterion with 5 supportive criteria, can establish the diagnosis.

Tel-Hashomer criteria

Major criteria 

Major criteria include (typical attack with 1 or more of the following):

1. Abdomen
2. Joint (hip, knee, ankle)
3. Chest - unilateral pleuritis or pericarditis
4. Scrotum
5. Skin
6. Muscle
7. Fever alone (usually recurrent attacks with fever only and no other identifiable cause)

Minor criteria

Minor criteria include (incomplete attack, including 1 or more of the following):

1. Abdomen
2. Joints
3. Chest
4. Leg pain on exertion
5. Positive response to colchicine
6. Nephropathic amyloidosis

Supportive criteria

Supportive criteria include:

1. Family history of FMF
2. Vulnerable ethnic origin
3. Early age at onset (younger than 20)
4. Attacks with spontaneous resolution
5. No symptoms between the attacks
6. Severe attacks requiring bed rest
7. Presence of an elevated white cell count or elevated 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 Eurofever/PRINTO classification

The Eurofever/PRINTO classification criteria are a more recent set (2019) that incorporates genetic testing results alongside clinical features [19]. This classification has a sensitivity of 94% and a specificity of 91%. According to this criterion, in patients with a confirmatory MEFV genotype, the presence of at least 1 of the following clinical features is sufficient for classification:

• Attack duration of 1–3 days
• Abdominal pain
• Chest pain 
• Arthritis 

In patients with a nonconfirmatory genotype (including heterozygous or variant of uncertain significance), more clinical features must be present to meet classification, specifically, at least 2 of the following must be present:

• Attack duration of 1–3 days
• Abdominal pain
• Chest pain (pleuritis)
• Arthritis
• Eastern Mediterranean ethnicity (Armenian, Turkish, Arab, Jewish, or other Eastern Mediterranean descent)

If genetic testing is unavailable, not performed, or negative, the patient is classified as FMF if the presence of Eastern Mediterranean ethnicity plus at least 2 of the following clinical features is present:

• Attack duration of 1–3 days
• Abdominal pain
• Chest pain (pleuritis)
• Arthritis

Alternatively, in the absence of Eastern Mediterranean ethnicity, at least three of the four clinical features above must be present.

Treatment / Management

Colchicine

Colchicine has served as the treatment of choice for FMF since the 1970s. Therapy aims to prevent recurrent attacks, normalize inflammatory activity between episodes, and reduce the risk of amyloidosis. Colchicine can also slow or halt the progression of amyloidosis.[20] The drug acts by inhibiting neutrophil chemotaxis, a process that contributes to the inflammatory cascade responsible for FMF attacks.

Colchicine therapy generally requires lifelong administration. Dosing varies according to age and symptom severity. Children younger than 5 years may receive 0.03 to 0.07 mg/kg/day.[21] Dose escalation in increments of 0.5 mg can occur as the child grows. A daily dose of 1 mg generally suits children older than 10 years and adults. Patients with more severe disease, including frequent attacks or existing amyloidosis, may require higher doses ranging from 2 to 2.5 mg if tolerated and if hepatic and renal function remain normal. Patients who undergo renal transplantation for amyloidosis-related end-stage renal disease should continue colchicine therapy after transplantation.(B3)

Common adverse effects include diarrhea and vomiting, which demonstrate dose dependence and occur more frequently at higher doses. Less common adverse reactions include myelosuppression, hepatotoxicity, nephrotoxicity, myopathy, neuropathy, and hypersensitivity reactions. Clinical experience supports the safety of colchicine during pregnancy and breastfeeding.[22] Strong emphasis on adherence remains essential, since poor compliance frequently explains inadequate therapeutic response. Serial monitoring of acute-phase reactants in blood assists with the evaluation of treatment response and adherence. Dividing the daily colchicine dose into 2 or 3 administrations may improve tolerance in patients who discontinue therapy because of adverse effects, particularly diarrhea.

Persistent symptoms despite therapy warrant dose escalation. Lack of improvement in attack frequency and severity despite adherence to the maximum tolerated colchicine dose (up to 3 mg in adults), combined with persistently elevated acute-phase reactants between attacks, suggests colchicine resistance.[23]

Interleukin-1 Inhibitors

Interleukin-1 inhibitors function as second-line therapy for patients with colchicine-resistant FMF or intolerance to colchicine. Evidence on the prevention of amyloidosis with these agents remains incomplete, and low-dose colchicine may continue for this purpose. Dose adjustments may become necessary in patients with renal insufficiency. Anakinra is a recombinant IL-1 receptor antagonist, whereas canakinumab is a human immunoglobulin G antibody directed against IL-1 beta.[24](A1)

Additional Drug Therapies

Additional therapeutic approaches are reported in limited numbers. Investigations from Japan describe the use of prazosin, reserpine, and azelastine in selected patients.[25] Tumor necrosis factor-alpha inhibitors, including thalidomide, infliximab, and etanercept, which bind both TNF-alpha and TNF-beta, have also been reported in some case reports. However, definitive evidence of efficacy remains lacking. Research conducted by Onat et al demonstrated that selective serotonin reuptake inhibitors may reduce attack frequency in FMF, suggesting a potential contribution of stress and depression to disease exacerbations.[26](B2)

Differential Diagnosis

Many diseases can mimic the signs and symptoms associated with FMF. Therefore, a detailed history and physical examination of patients, including histories of attacks and fever, as well as family history, can help differentiate FMF from other diagnoses. Differential diagnoses include:

• Acute abdomen: Peritonitis attacks in FMF can be easily mistaken for an acute abdomen. Patients undergoing radiologic diagnostic studies or surgical procedures to identify the cause of the acute abdomen, eg, appendicitis, cholecystitis, perforated viscus, or other abdominal pathologies, before the diagnosis of FMF is confirmed, is not uncommon.
• Juvenile idiopathic arthritis: Children who present with attacks of arthritis and fever can be misdiagnosed with juvenile idiopathic arthritis.
• Systemic lupus erythematosus and rheumatoid arthritis: Positive antinuclear antibodies test with low complement levels are usually found in systemic lupus erythematosus. Rheumatoid factor and anti-cyclic citrullinated peptide antibodies are found in rheumatoid arthritis. Moreover, in rheumatoid arthritis, the arthritis is symmetric polyarthritis and involves the hands and feet.
• Other familial periodic fever syndromes
  • Periodic fever with aphthous stomatitis, pharyngitis, and adenitis (PFAPA)
    • Aphthous ulcers, pharyngitis, and lymphadenopathy common
    • Abdominal pain is not common
    • Attacks typically last longer than FMF
    • Responds to steroid therapy but not to colchicine
  • Tumor necrosis factor receptor-associated periodic syndrome (TRAPS)
    • Autosomal dominant
    • Attacks last longer than FMF
    • Rash, myalgia, and periorbital edema are common
    • Responsive to treatment with steroids[27]
  • Hyper immunoglobulin D syndrome (HIDS)
    • Mevalonate kinase deficiency
    • Elevated immunoglobulin D levels
    • Fever with cervical lymphadenopathy, vomiting, diarrhea, abdominal pain
    • Conjunctivitis in some cases
  • Muckle-Wells syndrome and familial cold urticaria (FCU)
    • Urticaria is more common
  • Cellulitis
  • Erysipelas-like lesions in FMF can be mistaken for cellulitis. Again, a detailed history of the patient and antibiotic unresponsiveness can help differentiate it from cellulitis.

Prognosis

The prognosis of FMF depends mainly on the frequency of the attacks and the development of complications. Generally, the attacks improve with the treatment and decrease in frequency with age. Certain genotypes, eg, 694V, are associated with a higher risk of complications (eg, renal amyloidosis) and more frequent attacks. Hence, they are associated with an adverse prognosis compared to other genotypes.[28][29]

Complications

Secondary amyloid A amyloidosis is a severe complication of FMF. Although this complication can involve the gastrointestinal tract, spleen, liver, testes, heart, or lungs, renal amyloidosis is more common. The M694V mutation is usually associated with amyloidosis. On the other hand, FMF patients with the mutation E148Q rarely have amyloidosis. Colchicine prevents the development of amyloidosis, so patients who have never been on colchicine or patients who present late in the disease process have a higher chance of developing amyloidosis. However, patients with persistent proteinuria despite colchicine should be evaluated for causes other than amyloidosis. Patients can present with asymptomatic proteinuria, while sometimes nephrotic syndrome or end-stage kidney disease can be the first manifestation of FMF. Male sex and Eastern Mediterranean origin are risk factors for developing amyloidosis.[30]

Glomerulonephritis has also been reported on kidney biopsies of FMF patients with suspected amyloidosis. Henoch Schönlein purpura and polyarteritis nodosa can occur, but rarely in FMF.[10][31] Among other disease complications, testicular amyloidosis can lead to infertility in males, and pelvic and peritoneal inflammation can lead to the development of adhesions and, eventually, small bowel obstruction as well as infertility in females.