Familial Mediterranean Fever

Nonsense or missense mutations in the MEFV (Mediterranean fever) gene appear to cause the disease in many cases. MEFV produces a protein called pyrin (because of the association with predominant fever); the protein is also called marenostrin (derived from the phrase "our sea," because of the Mediterranean heritage of most patients).

Pyrin is expressed mostly in neutrophils. To date, its main functions have been determined to involve the innate immune response, such as inflammasome assemblage and, as a part of the inflammasome, sensing intracellular danger signals, activating mediators of inflammation, and resolving inflammation by the autophagy of regulators of innate immunity.[2]

In patients with FMF, uninhibited pyrin activity results in uncontrolled production of interleukin-1 (IL-1), leading to episodes of inflammation (with accompanying fever) in the peritoneum, pleura, and joints; persistent subclinical inflammation is also common.[3, 4]

FMF attacks are also characterized by the release of neutrophil extracellular traps (NET), which are chromatin filaments ‘decorated’ with neutrophil granular and cytoplasmic proteins, including active IL-1β. NETs restrict their own generation by a negative feedback mechanism, which may help explain the self-limited nature of FMF attacks.[5, 6]

Presumably, the inflammatory episodes in persons with FMF lead to the excess production of amyloid A protein in the acute phase and reactant serum amyloid A with subsequent deposition in the kidneys. However, only patients with specific MEFV haplotypes develop amyloidosis.[7]

FMF is a recessive genetic disease associated with missense and nonsense mutations in the MEFV gene, which is located on the short arm of chromosome 16. This gene codes for the protein known as pyrin or marenostrin.

More than 310 sequence variants in the MEFV gene have been identified, although not all not associated with a disease phenotype.[6]  Most of the pathogenic mutations are in exon 10 of the gene between amino acids 680 and 761. One mutation, in exon 1 at amino acid 148, may represent as many as one quarter of the known mutations. Although certain mutations are more common in particular ethnic groups, patients usually inherit different mutations from each parent.

Homozygotes for M694V (valine for methionine at position 694) may experience more severe disease and may be more likely to develop amyloidosis. Patients with V726A (alanine for valine at position 726) may be at a lower risk of developing amyloidosis, although one study suggests that the combination of V726A and E148Q may be particularly amyloidogenic.[8]

Other genes may be involved in FMF. This possibility is supported by patients who meet criteria for FMF without identifiable mutations in MEFV and who have clinical manifestations that are indistinguishable from patients with MEFV mutations.

Frequency

International

The frequency of FMF in any location depends on the ethnic background of the population. To survive ethnic and religious persecution, many Mediterranean families converted to other religions or intermarried members of other ethnic groups, thus carrying the MEFV gene with them.

In Ashkenazi Jewish people (descended from Eastern European Jewish people and including most European and American Jewish people), the prevalence of FMF is 1 case per 73,000 population, with a MEFV gene frequency now estimated at perhaps 1 per 5, in contrast to previous estimates of 1 per 135.[8] This suggests that not all mutations have equal penetrance.

In Sephardic Jewish people (descended from Jewish people who were expelled from Spain, largely to North Africa, and including other Middle Eastern Jewish populations), the prevalence of FMF is 1 case per 250-1000 population, with a gene frequency of 1 per 8-16.

In Armenian persons (based on epidemiology among Armenian populations in Lebanon and southern California), the estimated prevalence of FMF is 1 case per 500 population, with a gene frequency of 1 per 7.

Turkish people (from one study) may have a prevalence of approximately 1 case per 1000 population.[9]

Arabic people (from one study) may have a prevalence of 1 case per 2600 population in children and a gene frequency of 1 per 50.

Since the development of gene testing, which allows confirmation of FMF in some cases, the disease has been reported in unexpected locations, including by two Japanese groups.[10, 11]

Migrations of guest workers around the world have highlighted the need for physicians to think about formerly uncommon illnesses in their home countries and the need for review articles in national journals.[12]

Sex- and age-related demographics

In adults, FMF is more prevalent in men than in women, with a male-to-female ratio of 1.5-2:1.

Of all persons with FMF, 50-60% are younger than 10 years, 80-95% are younger than 20 years, and 5-10% are older than 20 years at onset. Onset in persons older than 40 years is rare. In a retrospective review, 5 of 18 heterozygous children with onset before age 6 years went into remission at puberty and were able to stop colchicine.[13]

Patients who are compliant with daily colchicine can probably expect to have a normal lifespan if colchicine is started before proteinuria develops. Patients with amyloidosis may develop an acute onset of kidney failure if they are stressed by dehydration, infection, or both.  Even with amyloidosis, the use of colchicine, dialysis, and kidney transplantation should extend a patient's life beyond age 50 years.

Nephrotic syndrome: Before the institution of colchicine therapy, mortality due to nephrotic syndrome was almost universal by age 50 years in North African Sephardic Jewish patients. Among other Sephardic Jewish, Ashkenazi Jewish, and Armenian patients, amyloidosis was extremely rare. The mortality rate among Turkish patients was high, but this high rate may have represented selection bias. No pre–colchicine-therapy data are available from Arabic patients.

Complications

Renal vein thrombosis may occur in nephrotic patients. This condition may manifest as abdominal or flank pain, increasing proteinuria, and worsening kidney function. Acute anticoagulation may stabilize or improve kidney function.

Many patients with undiagnosed FMF have undergone appendectomy because the severity of the peritoneal episodes seemed to indicate appendicitis.

Approximately 5% of patients with FMF develop chronic arthritis that sometimes leads to destructive arthritis of hips or knees and may necessitate joint replacements. Approximately 10% of patients with chronic arthritis develop seronegative spondyloarthropathy.

Approximately one third of female patients with FMF are infertile, and 20-30% of pregnancies result in fetal loss.

Patients with FMF need to understand the importance of strict compliance with daily colchicine therapy. Patient education information on FMF is available through the American College of Rheumatology.

The preeminent feature of familial Mediterranean fever (FMF) is the paroxysm, the classic onset of which occurs without warning, although some patients may be able to detect premonitory symptoms. The paroxysms usually last 48-96 hours, with peak intensity occurring within the first 12 hours. A plateau with resolution follows, usually occurring more slowly than the onset of symptoms.

In paroxysms, the person's temperature rises rapidly to 38-40°C (100.4-104°F). Temperature increases may occur before other manifestations. In mild attacks, fever may be the only manifestation.

Peritoneal symptoms

Almost all patients with FMF experience abdominal episodes. Abdominal pain develops, and may progress to peritonitis. Frequently the clinical presentation is consistent with appendicitis or cholecystitis, so patients commonly undergo appendectomies and cholecystectomies because the abdominal episodes of FMF are not recognized as such. The symptoms may also mimic renal colic.

In many cases, patients develop constipation during the attack and diarrhea after the attack resolves.

Even with recurrent attacks, adhesions are rare.

Pleural and pericardial symptoms

The frequency of pleural and pericardial attacks varies among ethnic groups, with 25-80% of patients reporting pleuritic episodes. Effusions occasionally occur. Pericarditis may develop, but tamponade and constrictive pericarditis are rare.

Synovial symptoms

The rate of synovial symptoms varies from 25-75% in reported series. The episodes may resemble gout in their acute onset and intensity. Knees, ankles, and wrists are the joints most commonly affected. An arthritis that resembles seronegative spondyloarthritis may also occur.

Arthritic symptoms tend to last several days longer than abdominal symptoms. Episodes can be protracted. The joints are normal between attacks, and permanent damage is unusual.

Arthritis may be the only manifestation of FMF. The diagnosis of FMF should be considered in patients who have a family history of FMF or live in an endemic area and experience episodes of arthritis.[14]

Other manifestations

These include the following:

• Dermatologic manifestations - As many as 50% of patients with FMF report erysipelaslike rashes on the lower extremities, particularly below the knees; rash and fever may be the only manifestations of attacks
• Muscle symptoms - Severe myalgia may last 3-6 weeks; symptoms are consistent with fibromyalgia; these episodes do not respond to colchicine therapy
• Pelvic symptoms - Female patients with FMF may have episodes of pelvic inflammatory disease
• Scrotal attacks - In males, inflammation of the tunica vaginalis testis may mimic episodes of testicular torsion
• Vasculitis - An increased frequency of Henoch-Schönlein purpura and polyarteritis nodosa is reported in persons with FMF, even in children; Behçet disease is also more common
• Neurologic manifestations - Headache is common. Other reported findings have included seizures, paresthesias, breath-holding, and ataxia. ^[15]
• Auditory - Subclinical effects on the middle ear and cochlear involvement have been reported in children. ^{[16, 17]}  

Amyloidosis

In a patient of the appropriate ethnic group, the typical progression of amyloidosis in FMF is proteinuria, followed by nephrotic syndrome, and, inevitably, death from kidney failure.

One third of patients with amyloidosis develop renal vein thrombosis. Nephrotic syndrome is reported in patients as young as 14 years. Despite the frequency and extent of amyloid deposits in the renal system, deposits in other organs are only rarely reported as significant.

In a retrospective study of 170 Armenian patients with FMF and suspected nephropathy, biopsy-proven amyloid A (AA) amyloidosis was found in 102 (60%). Recurrent arthritis was significantly associated with an increased risk of AA amyloidosis, and involvement of the joint synovial membrane, which is capable of active serum amyloid A production, was the main predictor of renal amyloidosis.[18]

Prolonged survival resulting from colchicine therapy, dialysis, and kidney transplantation allows additional manifestations of amyloidosis to develop. Some patients have intestinal involvement, which may lead to malabsorption and death.

Some patients with a family history of FMF present with amyloid nephropathy without ever having experienced an amyloid attack. Furthermore, some patients with otherwise typical FMF may develop kidney failure without previous proteinuria.

Temperatures can reach as high as 40°C (104°F), but, in most cases, rapid defervescence occurs within 12 hours. Other physical findings of FMF depend mostly on the serosal surface involved.

A boardlike or surgical abdomen is present with typical findings of peritonitis (ie, abdominal tenderness, decreased bowel sounds). Splenomegaly is common in response to the inflammation. Patients with pleural involvement may have shallow breathing and chest-wall tenderness, but friction rubs are rare.

Joints show typical inflammatory changes, with warmth, erythema, or swelling. Patients with painful myalgia syndrome may have tender muscles.

A well-demarcated, erythematous, warm rash, particularly below the knee, ranging from 15-50 cm2 may develop and may be accompanied by swelling.

Female patients with symptoms mimicking pelvic inflammatory syndrome may experience pain on cervical motion and may develop tender, enlarged ovaries.

Unilateral, erythematous, and tender swelling of the scrotum occurs in scrotal attacks. The typical manifestations of Behçet disease and Henoch-Schönlein purpura may be observed.

Amyloidosis is usually asymptomatic, with hypertension reported in 35% of patients late in the disease. Renal vein thrombosis may develop and manifests as loin pain.

Results of routine blood tests performed during the acute attacks of familial Mediterranean fever (FMF) are nonspecific. Levels of acute-phase reactants (ie, C-reactive protein, erythrocyte sedimentation rate, amyloid A protein, fibrinogen) are elevated. The white blood cell count is usually elevated during an attack. The elevated levels rapidly return to the reference range as the attack abates.

On urine studies, proteinuria should raise a concern about possible amyloidosis. For unknown reasons, hematuria occurs in 5% of patients.

In patients with arthritis during attack, synovial fluid is inflammatory, with cell counts as high as 100,000/µL.

Pyrin, the protein whose uninhibited activty causes the characteristic attacks of FMF, is normally kept inactive by kinases. Magnotti and colleagues reported that in monocytes from FMF patients—but not those from healthy controls or patients with other inflammatory disorders—the kinase inhibitor UCN-01 leads to inflammasome activation, pyroptosis (fast cell death), and interleukin-1β secretion, thus providing a fast diagnostic test for FMF.[19]

Genetic testing is now available for FMF. Testing for a limited number of genes may be appropriate in patients with a known ethnic background. Complete gene sequencing may be more helpful in patients of mixed or unknown ethnicity. Symptomatic patients with at least one MEFV mutation should be considered to have FMF. Patients with no gene mutations who meet criteria for FMF should be offered a trial of colchicine. Given the high gene frequency and low penetrance in certain populations (eg, Ashkenazi Jews, Armenians), gene testing should be closely correlated to clinical findings to avoid false-positive results.

An expert committee of European pediatric rheumatologists has developed the following recommendations for genetic diagnosis of familial Mediterranean fever[20] :

• FMF is a clinical diagnosis; it can be supported but not excluded by genetic testing.
• FMF patients carrying two of the common mutated alleles (homozygotes or compound heterozygotes), especially for M694V mutation or mutations at position 680 to 694 on exon 10, must be considered at risk of having a more severe disease.
• Patients homozygous for M694V mutation are at risk for early-onset disease and at very high risk of developing a severe phenotype; those who are not reporting symptoms should be evaluated and followed closely in order to consider therapy.
• Patients with two pathogenic mutations for FMF who do not report symptoms but have risk factors for AA amyloidosis (eg, country of origin; family history; persistently elevated inflammatory markers, particularly serum amyloid A protein), should have close follow-up and be considered for treatment.
• The E148Q variant is common and of unknown pathogenic significance; its presence as the only MEFV variant does not support the diagnosis of FMF.

Findings during an acute attack in patients with peritonitis, pleuritis, and arthritis are as expected and include air-fluid levels, pleural effusions, and synovial effusions.

Massive amyloid infiltration of the blood vessels and of the endothelial side of the glomerular basement membrane occurs in the kidneys. In the rectal submucosa, the amyloid is found near the blood vessels.

Amyloidosis can be presumed in patients with FMF, particularly those of North African descent who have proteinuria. Renal biopsy or, alternatively, submucosal rectal biopsy, is indicated in these patients.

A recent retrospective review of kidney biopsies in FMF patients found that 40% of the patients had nonamyloid kidney disease (NAKD). While the patients with amyloid kidney disease (AKD) had more proteinuria and more of them had more than 3.5 g of proteinuria, all of these biopsies were in patients with greater than 500 mg of proteinuria. The AKD patients had more severe disease and were more likely to have hypertension. All patients with proteinuria of greater than 500 mg/24 h should have a biopsy.[21]

Colchicine

Colchicine is so effective in preventing attacks of familial Mediterranean fever (FMF) and preventing the development of amyloidosis that the most important aspects of medical care are to make the correct diagnosis and to institute therapy.

Administer colchicine therapy daily in patients at risk of developing amyloidosis (eg, North African Jewish people, Turkish people, Armenian people living in Armenia). Other Sephardic Jewish people and Arabic people are at lower risk but also probably require daily colchicine therapy.

Daily colchicine is customarily given in a dosage of 0.6 or 0.5 mg twice daily, depending on the dosage form available. However, a study in treatment-naive pediatric patients newly diagnosed with FMF found that a single 1-g daily dose was noninferior to 0.5 mg given twice daily.[22] Guidelines from the European League Against Rheumatism (EULAR) recommend the following starting dosages of colchicine[23] :

• Children < 5 years of age: ≤0.5 mg/day (≤0.6 mg/day if tablets contain 0.6 mg)
• Children 5–10 years: 0.5–1.0 mg/day (1.2 mg/day if tablets contain 0.6 mg)
• Children >10 years and adults:1.0–1.5 mg/day (1.8 mg/day if tablets contain 0.6 mg)

After colchicine has been started, EULAR recommends following patients closely for 3–6 months to observe the therapeutic effect.

In patients who do not respond to twice-a-day dosing, administer colchicine three, or even four, times a day. In patients who have difficulty tolerating colchicine, start therapy at once-a-day dosing and gradually increase the dose. In patients whose conditions were not responsive to oral colchicine, the addition of 1 mg IV once a week reduced the number of attacks in 10 of 13 patients and the severity of attacks in 6 of 13 patients.[24]

Colchicine also stabilizes the amount of proteinuria in patients with amyloid nephropathy. Renal disease may resolve in patients with a creatinine level of less than 1.5 mg/dL who are treated with 1.5 mg/d of colchicine.

Ashkenazi Jewish people and Armenian people living in the United States seem to be at extremely low risk of amyloidosis and may need treatment only to prevent attacks. If attacks are rare and patients can determine when they are beginning, treatment with intermittent colchicine therapy at the onset of attacks may be sufficient.

The regimen for acute attacks in patients not taking daily colchicine is 0.6 mg every hour for 4 doses, then 0.6 mg every 2 hours for 2 doses and then 0.6 mg every 12 hours for 4 doses. Colchicine should be started as soon as the patient recognizes that an attack is occurring. If the initial doses are effective, patients may be able to do without the later doses, but this varies from patient to patient.

A Turkish study found that in children who were heterozygous for MEFV variants and required initiation of colchicine treatment after experiencing symptoms of FMF, colchicine may be successfully discontinued in some cases, if very careful follow-up is provided. In this study, the median duration of colchicine treatment was 36 (range, 24-110) months, and colchicine was discontinued after a median attack- and inflammation-free period of 27 (range, 24-84) months. Colchicine was restarted in 2 of the 22 patients because of symptom recurrence.[25]

A group from another Turkish hospital followed 69 children who were heterozygous for MEFV mutations and did not meet criteria for pediatric FMF. Of these, 39 had known pathogenic mutations and 30 had mutations of unknown significance (E148Q or P369S in 26 cases). None of these children developed persistent proteinuria and only 2 patients who were M694V heterozygous experienced febrile episodes often enough to be started on colchicine.[26]

Some patients treated with colchicine develop lactose intolerance and may respond to a lactose-free diet.

Biologics

In patients whose conditions do not respond to colchicine, biologic therapy—in particular, agents directed toward interleukin-1 (IL-1)—may be effective. In FMF, uninhibited pyrin activity results in uncontrolled production of IL-1, which causes inflammation and may be accompanied by joint pain, swelling, muscle pain, and skin rash. Biologic agents used for FMF include the following:

• Interferon-alpha
• The tumor necrosis factor (TNF)–blocking drug etanercept ^[27]
• The IL-1 receptor antagonists anakinra ^{[28, 29]} and rilonacept
• Canakinumab   

Rilonacept, given by once-weekly subcutaneous injection, has been shown, in combination with continuation of colchicine, to reduce the number of attacks in patients who did not respond optimally.[30] Interferon-alpha has been used in an intermittent fashion and as prophylaxis, with varying results.[31, 32, 33]

A systematic review found that in patients who do not respond to colchicine or cannot tolerate it, anti–IL-1 treatment resulted in a complete response to therapy, without a single attack during treatment, in 76.5% of patients treated with anakinra and 67.5% of those treated with canakinumab. In addition, anti–IL-1 treatment proved able to reverse proteinuria in patients with established type AA amyloidosis.[34]

Canakinumab

Canakinumab was approved by the US Food and Drug Administration for FMF in September 2016. Canakinumab is a human monoclonal anti-human IL-1β antibody of the IgG1/kappa isotype. It binds to human IL­1β and neutralizes its activity by blocking its interaction with IL-1 receptors. Approval was based on the phase 3 CLUSTER study, which showed disease control beginning at day 15 and lasting through 16 weeks when compared with placebo.[35]

A systematic review of the literature on canakinumab found that even though most patients included in the studies had a particularly severe phenotype, nearly 80% of patients did not experience a single attack after the initiation of therapy, and almost all the remaining patients had significantly reduced disease activity. Canakinumab therapy also appeared effective at limiting amyloidosis. The drug was also safe and well tolerated, with no patient discontinuing treatment due to adverse effects.[36]

Other therapeutic measures

Additional treatment options include the following:

• Hemodialysis can be used for patients who develop renal failure. Peritoneal dialysis tends to increase the number of abdominal attacks.
• Patients who experience episodes of prolonged myalgia with fever and severe pain may need treatment with prednisone (1 mg/kg) for as long as 6 weeks.
• Patients with exertional lower extremity muscle pain respond to rest.
• Treat patients with fibromyalgia with the usual agents for this condition.
• Treat patients who develop seronegative spondyloarthropathy with nonsteroidal anti-inflammatory drugs as first-line therapy. Some of these patients may require treatment with TNF-alpha blockers and should receive follow-up care by a rheumatologist. ^[37]

Before the advent of colchicine therapy, renal transplantation was performed in patients with end-stage renal disease due to amyloid nephropathy. Currently, renal failure develops only in patients who are not compliant with therapy or cannot tolerate it and those with disease refractory to therapy. 

Since the advent of colchicine therapy, most treated patients are asymptomatic and do not need consultation with a specialist.

Consultation with a rheumatologist is indicated in patients with the following conditions:

• Seronegative spondyloarthropathy not responsive to nonsteroidal anti-inflammatory drugs
• Fibromyalgia not responsive to the usual treatments
• Coexistent Henoch-Schönlein purpura, polyarteritis nodosa, or Behçet disease

Patients with familial Mediterranean fever (FMF) should be seen regularly to ensure compliance with therapy. In one study, only 2% of 906 patients who were at high risk and compliant developed amyloidosis, compared with 49% of 54 patients who admitted noncompliance.

Teenagers are typically a noncompliant group and need long-term daily therapy to prevent chronic complications. For many of these patients, noncompliance is associated with severe symptoms, which may reinforce the need for therapy. Communicating with patients' pharmacies to determine how often they are obtaining refills may be the best way to assess compliance.

Perform a urinalysis at every visit, particularly in patients at risk of developing amyloidosis. If proteinuria is present, assess patients carefully for compliance. Exclude other causes of proteinuria (eg, heavy sports activity). In patients with hypertension, proteinuria of greater than 3.5 g/24 h and severe FMF, amyloidosis is the more likely cause. However, in nonhypertensive patients with milder diseases, other causes of proteinuria may exist and a biopsy should be considered.[21]  If amyloidosis is confirmed, increase the daily dose of colchicine.

For unknown reasons, hematuria occurs in approximately 5% of patients. Its presence, along with prolonged abdominal or muscle pain, suggests the development of polyarteritis nodosa.

Guidelines from the European League Against Rheumatism (EULAR) for the management of familial Mediterranean fever (FMF) include the following recommendations[23] :

• Ideally, FMF should be diagnosed and initially treated by a physician with experience in FMF; after diagnosis and initiation of therapy, patients can also be followed by their primary care physician in conjunction with the referral center, but if possible, patientsshould be seen by a physician with experience of FMF at least once per year in the long term.
• The ultimate goal of treatment in FMF is to obtain complete control of unprovoked attacks and minimize subclinical inflammation between attacks.
• Treatment with colchicine should be started as soon as a clinical diagnosis is made.
• Colchicine can be given in single or divided doses, depending on tolerance and compliance.
• Persistent attacks or subclinical inflammation represent an indication to increase the colchicine dose.
• Compliant patients who continue to have one or more attacks each month despite receiving the maximally tolerated dose of colchicine for at least 6 months can be considered nonresponders or resistant; alternative biological treatments are indicated in these patients; colchicine should be coadministered with biological therapies, as it may reduce the risk of amyloidosis despite persistence of attacks
• FMF treatment needs to be intensified in AA amyloidosis, using the maximal tolerated dose of colchicine and supplemented with biologics as required.
• Periods of physical or emotional stress can trigger FMF attacks, and it may be worth temporarily increasing the dose of colchicine.
• Response, toxicity, and compliance should be monitored every 6 months.
• Liver enzymes should be monitored regularly in patients with FMF treated with colchicine; if elevations greater than twofold the upper limit of normal occur, the colchicine dose should be reduced and the cause further investigated.
• In patients with decreased renal function, the risk of colchicine toxicity is very high, so evidence of toxicity should routinely be sought and if found, the colchicine dose should be reduced accordingly.
• Colchicine toxicity is a serious complication that should be given adequate consideration and be prevented; potential causes include exceeding the recommended dose (maximum recommended oral doses for treatment of FMF are 3 mg daily in adults and 2 mg daily in children), liver or renal failure, and concomitant administration of other drugs metabolized by cytochrome 3A4.
• If an attack is suspected, always consider other possible causes; during attacks, continue the usual dose of colchicine and use nonsteroidal anti inflammatory drugs (NSAIDs).
• Colchicine should not be discontinued during conception, pregnancy, or lactation; current evidence does not justify amniocentesis.
• In general, men need not stop colchicine prior to conception; in the rare case of azoospermia or oligospermia proven to be related to colchicine, temporary dose reduction or discontinuation may be required.
• Chronic arthritis in a patient with FMF might need additional medications, such as disease-modifying antirheumatic drugs (DMARDs), intra-articular steroid injections, or biologics.
• In protracted febrile myalgia, glucocorticoids lead to the resolution of symptoms; NSAID and interleukin-1 blockade might also be a treatment option; NSAIDs are suggested for the treatment of exertional leg pain.
• If a patient is stable, with no attacks for more than 5 years and no elevation in acute phase reactants (eg, serum amyloid A protein, C-reactive protein), dose reduction could be considered after expert consultation and with continued monitoring.

The goals of therapy are to reduce morbidity and to prevent complications. Colchicine is the drug of choice; patients who do not respond to colchicine or cannot tolerate it may benefit from the addition or substitution of biologic agents that inhibit interleukin-1. Of those, canakinumab, anakinra, and rilonacept have demonstrated efficacy, but only canakinumab is approved for use in the United States.

Class Summary

Colchicine is the drug of choice for familial Mediterranean fever (FMF).

Colchicine (Colcrys)

Decreases leukocyte motility and phagocytosis in inflammatory responses.

Class Summary

In patients with FMF, uninhibited pyrin activity results in uncontrolled production of IL-1 which causes inflammation and may be accompanied by joint pain, swelling, muscle pain, and skin rash.

Canakinumab (Ilaris)

Human monoclonal anti-human IL-1beta antibody of the IgG1/kappa isotype. It binds to human IL­1beta and neutralizes its activity by blocking its interaction with IL-1 receptors. It is indicated for the treatment of FMF in adult and pediatric patients.