Familial Mediterranean Fever

FMF is caused by:

• Mutations in the MEFV gene on the short arm of chromosome 16

FMF is characterized by incomplete penetrance and highly variable expressivity. Mutations are classically inherited in an autosomal recessive manner (ie, biallelic pathogenic mutations are present) (1). However, clinical symptoms have been observed in patients with only one identified pathogenic mutation (heterozygotes, ie, autosomal dominant manner with partial penetration). In addition, rarely, FMF symptoms may be present in patients with no known pathogenic MEFV mutation. Conversely, asymptomatic patients have been incidentally found to carry MEFV mutations (pathogenic, nonpathogenic, or an as-yet-unidentified variant).

FMF mutations are gain-of-function, that is, they confer new or enhanced activity on a protein, with a gene dosage effect (ie, more copies of the abnormal gene convey a greater effect). The MEFV gene normally codes a protein called pyrin (also known as marenostrin), which is expressed in circulating neutrophils.

Pyrin plays a role in innate immunity. It senses modifications in the activity of the small GTPase RhoA, a molecular switch that regulates a variety of signal transduction pathways including cytoskeletal organization. Pathogen virulence toxins (such as Clostridioides difficile, Burkholderia cenocepacia, and Vibrio cholera) downregulate RhoA activity and cause an assembly pyrin along with other proteins into a pyrin inflammasome, which eventually results in the production of the proinflammatory cytokine interleukin-1 beta (IL-1 beta). MEFV pathogenic variants favor the active state of pyrin and give rise to cell membrane rupture (pyroptosis) and the release of proinflammatory cytokines (2).

There is strong evidence to support the hypothesis that Yersinia pestis, the cause of bubonic plague, led to the positive selection of FMF-associated MEFV mutations (3). These mutations may have evolved to confer a selective advantage to certain people exposed to Y. pestis.

Alterations in the gut microbiome have been associated with genotypic and phenotypic interactions in FMF (4). In one case-control study, gut microbiota of patients with FMF were found to have increased proinflammatory bacteria compared to controls without FMF; resistance to colchicine was also associated with specific microbiota alterations.

Onset of FMF is usually between the ages of 5 and 15 years but may occur much later or earlier, even during infancy.

The most common manifestation is an acute febrile attack with associated pain and systemic symptoms (eg, abdominal pain, arthritis, rash).

Attacks have no regular pattern of recurrence. They usually last 12 to 72 hours but may sometimes last longer. Frequency ranges from 2 attacks/week to 1 attack/year (most commonly, once every 2 to 6 weeks). Physical and/or emotional stressors (eg, physical trauma, infection, menstruation) may trigger attacks (1). The severity and frequency of attacks do not appear to be consistently influenced by pregnancy status (2). Spontaneous remissions may last years.

Up to 50% of patients experience a characteristic prodrome heralding an attack that may consist of dysgeusia and mood alterations such as anxiety, irritability, and restlessness (3). Fevers as high as 40° C can occur and are usually accompanied by peritonitis. Abdominal pain (usually starting in one quadrant and spreading to the whole abdomen) occurs in about 95% of patients and can vary in severity with each attack (4). Decreased bowel sounds, distention, guarding, and rebound tenderness are likely to occur at the peak of an attack and cannot be differentiated from a perforated viscus by physical examination alone. Consequently, some patients undergo urgent laparotomy before the correct diagnosis is made. With pleural involvement, dyspnea due to pleuritic pain may occur in 30% of patients (5).

Other manifestations of FMF include arthritis (in 75%), usually involving the knee, ankle, and hip (4); an erysipelas-like erythema or rash of the lower leg; and scrotal swelling and pain caused by inflammation of the tunica vaginalis of the testis. Pericarditis occurs rarely. The pleural, synovial, and skin manifestations of FMF vary in frequency among different populations (6).

Despite the severity of symptoms during acute attacks, most patients recover swiftly and remain asymptomatic until their next attack.

Autoinflammatory Periodic Fever Disorders

CAPS = cryopyrin-associated periodic syndromes; FMF = familial Mediterranean fever; NOMID = neonatal-onset multisystem inflammatory disease; PFAPA = periodic fevers with aphthous stomatitis, pharyngitis, and cervical adenitis; TRAPS = tumor necrosis factor receptor–associated periodic syndrome. Adapted from Sag E, Bilginer Y, Ozen S: Autoinflammatory diseases with periodic fevers. Curr Rheumatol Rep 19(7):41, 2017. doi: 10.1007/s11926-017-0670-8

• History and physical examination

• Genetic testing

The diagnosis of familial Mediterranean fever is based mainly on clinical symptoms and is supported by genetic testing, which is particularly useful in the evaluation of atypical cases. However, current genetic testing is not infallible; some patients with phenotypically unmistakeable FMF have only a single mutated gene or occasionally no evident mutations in the MEFV gene. Approximately 10 to 20% of patients who meet the diagnostic criteria for FMF do not have MEFV mutations, which suggests epigenetic and environmental factors contribute to the disease pathogenesis (2). The Tel HaShomer criteria (see table Tel HaShomer Criteria for the Diagnosis of Familial Mediterranean Fever) are the most widely used clinical criteria used in adults (1).

Nonspecific findings include elevations in white blood cells with neutrophil predominance, erythrocyte sedimentation rate, C-reactive protein, and fibrinogen. Urinary excretion of > 0.5 g protein/24 hours may suggest renal amyloidosis.

Differential diagnosis includes acute intermittent porphyria, hereditary angioedema with abdominal attacks, relapsing pancreatitis, and other hereditary relapsing fevers.

• Daily colchicine

• In patients who are colchicine-resistant or -intolerant, interleukin-1 (IL-1) inhibitors

• Analgesia (eg, ibuprofen)Analgesia (eg, ibuprofen)

Daily prophylactic colchicine should be initiated as soon as the diagnosis is made to prevent attacks as well as Daily prophylactic colchicine should be initiated as soon as the diagnosis is made to prevent attacks as well asamyloidosis (1). Colchicine causes remarkable symptomatic improvement in almost 95% of patients (2). With daily colchicine use, 75% of patients achieve near-complete remission, thus significantly reducing the risk of amyloidosis and kidney injury. If attacks or subclinical inflammation persist, the ). With daily colchicine use, 75% of patients achieve near-complete remission, thus significantly reducing the risk of amyloidosis and kidney injury. If attacks or subclinical inflammation persist, thecolchicine dose should be increased. Initiation of colchicine at the peak of an attack is not beneficial. Children require a dose adjustment for colchicine that is typically based on age, weight, and severity of phenotype and genotype (3–5). Dose adjustments should also be made for patients with liver or kidney dysfunction. Upon initiation of colchicine, close monitoring is recommended for 3 to 6 months to assess clinical response, particularly frequency and severity of attacks.). Dose adjustments should also be made for patients with liver or kidney dysfunction. Upon initiation of colchicine, close monitoring is recommended for 3 to 6 months to assess clinical response, particularly frequency and severity of attacks.

Colchicine does not add to the increased risk of infertility or spontaneous abortion among affected women; when taken during pregnancy, it does not increase the risk of teratogenic events. Lack of response to colchicine is often caused by poor adherence to the regimen.

Patients who are colchicine-resistant or -intolerant may be treated with IL-1 inhibitors: anakinra once a day, rilonacept once a week, or canakinumab every 4 weeks (-resistant or -intolerant may be treated with IL-1 inhibitors: anakinra once a day, rilonacept once a week, or canakinumab every 4 weeks (canakinumab can also be given on-demand (4–6). However, the role of IL-1 inhibitors in preventing amyloidosis remains unknown, and patients taking IL-inhibitors should continue taking colchicine if tolerated.). However, the role of IL-1 inhibitors in preventing amyloidosis remains unknown, and patients taking IL-inhibitors should continue taking colchicine if tolerated.

Nonsteroidal anti-inflammatory drugs (eg, ibuprofen) and acetaminophen are sometimes needed for analgesia.Nonsteroidal anti-inflammatory drugs (eg, ibuprofen) and acetaminophen are sometimes needed for analgesia.