Familial Mediterranean Fever

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Familial Mediterranean fever

• Is a hereditary autoinflammatory disorder characterized by recurrent bouts of

fever and serosal inflammation.

• The initial attack occurs before the ages of 10 and 20 years in 65 and 90 percent

of cases.

• In rare cases, the initial attack can occur in individuals older than 50 years of age.

• As the name indicates, FMF occurs within families and is much more common in

individuals of Mediterranean descent than in persons of any other ethnicity

Epidemiology In adults, FMF is more prevalent in men than in women.

• It mainly occurs in families of Mediterranean area.

• Age:

50-60% are younger than 10 years.

80-95% are younger than 20 years.

5-10% are older than 20 years at onset.

• Onset in people older than 40 years is rare

Pathophysiology

• Mutations in the MEFV (Mediterranean fever) gene on chromosome 16 appear

to cause the disease in many cases. MEFV produces a protein called pyrin

(derived from 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 acts without a known provocation, the outcome of this process is secretion

of interlukin IL-1,IL-18 and other mediators of inflammation which enhances

chemotaxis and neutrophilia including an attack of FMF leading to episodes of

inflammation (with accompanying fever) in the peritoneum, pleura, and joints;

persistent subclinical inflammation is also common.

• 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. Only patients with

specific MEFV haplotypes develop amyloidosis.

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Clinical manifestations

• Episodes last for one to three days and then resolve spontaneously

• The intervals between episodes are irregular, ranging from one week to several

months or years, and patients are asymptomatic between attacks.

• Patients may have a stereotypic prodrome before their attacks; it may include

various constitutional and physical signs, such as restlessness at the site where the

symptom is about to occur, anxiety, irritability, increased appetite, and taste

alterations.

• vigorous exercise, emotional stress, intercurrent infections, exposure to cold,

surgery, and menstruation have been associated with an attack in some patients

• During pregnancy, the course of FMF may worsen in about a third of the patients,

improve in another third of patients, and remain unchanged in the rest.

1) Recurrent fever:

• It is one of the most constant characteristics, presents in almost all cases during

attacks (38° to 40°C), the duration is brief, lasting between 12 hours and three

days

• It may be the first and only symptom of FMF, especially in toddlers.

• FMF patients who are treated with colchicine, an acute attack may occur without

fever.

2) Abdominal pain

• It occurs in 95% in patients, presents locally and then progress to become more

generalized.

• It is caused by inflammation of the peritoneum, signs of peritonitis such as

guarding; rebound tenderness, rigidity, and a dynamic ileus are often present.

• These findings can be mistaken for an acute surgical abdomen leading to

diagnosis delay and sometimes even to futile operations.

3) Chest pain:

• It occurs in 33-84 %of patients, depending on the patient’s ethnic origin.

(Armenian have a higher rate of pleuritic involvement compared with other ethnic

groups).

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• May be due to inflammation of the pleura or referred pain from subdiaphragmatic

inflammation.

• Manifests as unilateral chest pain that is worse with inspiration or coughing and

small, transient pleural effusion.

• Episodes usually resolve within three days, but may last up to one week.

4) Joint pain

• The joint attacks are usually monoarticular, involving one of the large joints

(knee, ankle, hip)

• The synovial fluid analysis is typically sterile, with a nucleated white cell count

ranging from 200 to >100,000 white blood cells/mm3

• episodes usually lasts 24 to 48 hours, which resolve completely without leading to

joint destruction, but in severely protracted cases, it can result in permanent

deformity, functional limitation, osteoporosis around the affected joint, and

aseptic necrosis.

5) Erysipelas-like skin lesion:

• It occurs in 12 to 40%

• The lesion is typically 10 to 35 cm2 in area, tender, raised, and erythematous and

occurs on the lower leg, ankle, or foot.

• Lesions may be transiently warm without associated pain or tenderness

• In children, it may be misdiagnosed as an infectious erysipelas or cellulitis.

• Recovery is spontaneous and does not require antibiotics

Other rare manifestations:

• Exertional myalgia: involves lower limbs (thighs and calves) in children, not

treated by colchicine, resolves with rest and NSAIDs

• Acute pericarditis: include chest pain (sharp and pleuritic, improved by sitting

up and leaning forward), pericardial friction rub, and widespread ST segment

elevation on electrocardiogram

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• Acute scrotum: unilateral gradual swelling of the scrotum in children.

• Protracted febrile myalgia: have an increased ESR but a normal serum creatine

kinase level

• Headache and aseptic meningitis.

Long-term complications:

• Secondary (AA) amyloidosis

• Small bowel obstruction

• Infertility

DIAGNOSIS:

• FMF is suspected in individuals with recurrent febrile episodes accompanied by

peritonitis, synovitis or pleuritis, recurrent erysipelas-like erythema, repeated

laparotomies for an acute abdomen with no identifiable underlying pathology, a

first-degree relative with FMF, and/or membership in an at-risk ethnic group.

• Genetic testing for FMF serves to support the diagnosis in patients who meet

clinical criteria for FMF

• Six-month trial of colchicine therapy that results in a relief of attacks and

recurrence after cessation of treatment. (In patients who met the clinical criteria

but genetic testing was not diagnostic).

FMF is diagnosed in patients with any of the following:

• ≥1 major criteria

• ≥2 minor criteria

Elevation of serum markers of systemic

inflammation

Elevated erythrocyte sedimentation rate

(ESR)

Elevated C-reactive protein (CRP)

Elevated serum amyloid A (SAA)

protein

Elevated fibrinogen.

Serum homocysteine and lipoprotein(a)

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• 1 minor plus 5 supportive criteria

• 1 minor criterion plus ≥ 4 of the first

five supportive criteria

Differential diagnosis:

* It varies with the patient's predominant clinical features

• Periodic fever syndromes

• Systemic juvenile idiopathic arthritis/adult Still's disease

• Systemic vasculitis involving the abdomen

• Systemic rheumatic diseases

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• Infection

• Malignancy

Goals of therapy:

• Prevent acute attacks.

• Minimize subclinical inflammation in between attacks.

• prevent the development and progression of amyloidosis

Pharmacological treatment:

Colchicine:

• Trade names: colchicine tabs ® 1mg (available in Jordan)

colcine ® 0.5 mg tab (available in Jordan)

colcrys ® 0.6 mg tab.

• Primarily effective as a prophylactic treatment for the FMF attacks.

• It is recommended in all patients regardless of the frequency and intensity of

attacks.

• Use of intermittent high-dose colchicine only for treatment of acute attacks of

FMF is not recommended since it does not protect from the development of

amyloidosis resulting from low-grade inflammation that can occur during

asymptomatic intervals

• MOA: affects the motility of neutrophils by reducing their deformability and

elasticity.

• Adherence with colchicine is higher with once-daily dosing and its efficacy is the

same as with splitting the dose into two divided daily doses.

• Colchicine dose is not split unless the patient does not tolerate once-daily dosing

due to side effects, which are most commonly gastrointestinal.

• We generally start with a lower dose and increase the dose by 0.5 to 0.6 mg

according to the patient’s response and tolerance without exceeding the maximum

recommended daily dose of colchicine, which is 2 mg for children under 12 years

and 3 mg for adults.

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• High-dose colchicine is associated with significant side effects such as blood

cytopenias, rhabdomyolysis or myopathy, peripheral neuropathy, liver failure, or

severe cutaneous eruption.

Dosing and administration

• <5 years of age: ≤0.5 mg/day (≤0.6 mg/day in case tablets contain 0.6 mg).

• 5-10 years of age: 0.5 to 1 mg/day (0.6 to 1.2 mg/day in case tablets contain 0.6

mg).

• >10 years of age and adults, 1 to 1.5 mg/day (1.2 to 1.8 mg/day in case tablets

contain 0.6 mg).

• The tablet can be split in half.

• In patients with preexisting complications (Eg. Renal amyloidosis) or greater

disease activity (high frequency of attacks, long duration of each attack,

involvement of multiple sites during the attack, and joint involvement), higher

initial doses (up to 2 mg/day) are needed.

Acute attacks:

• As soon as the patient recognize than an attack is coming, 0.5mg every hour for 4

doses, then 0.5mg every 2 hours for 2 doses, and then 0.5mg every 12 hours for 4

doses.

Dose Adjustments:

Adult Renal adjustment:

• CrCl 30 to 80 mL/minute: Monitor closely for adverse effects; dose reduction

may be necessary.

• CrCl <30 mL/minute: Initial dose: 0.3 mg daily; use caution if dose titrated;

monitor for adverse effects.

• Dialysis: 0.3 mg as a single dose; use caution if dose titrated; dosing can be

increased with close monitoring; monitor for adverse effects. Not removed by

dialysis

Pediatric renal adjustment:

• Children ≥4 years and Adolescents: Colcrys: Oral:

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• CrCl 30 to 80 mL/minute: Monitor closely for adverse effects; dose reduction

may be necessary.

• CrCl <30 mL/minute: Initial dose: 0.3 mg daily; use caution if dose titrated;

monitor for adverse effects.

• Dialysis: Nondialyzable: 0.3 mg as a single dose; use caution if dose titrated;

dosing can be increased with close monitoring; monitor for adverse effects

Adult and pediatric Hepatic Impairment:

• Mild to moderate impairment: Use caution; monitor closely for adverse effects.

• Severe impairment: There is no specific dosage adjustment provided in the

manufacturer's labeling; dosage adjustment should be considered.

Monitoring

Patients should be followed closely for three to six months to observe its therapeutic

effect on attack frequency and severity.

Laboratory monitoring:

• Complete blood count (CBC): to assess for leukopenia.

• Erythrocyte sedimentation rate (ESR)

• C-reactive protein (CRP)

• Serum amyloid A (SAA).

• Urine for proteinuria, which may be the first sign of renal amyloidosis.

• Liver and kidney function tests annually.

Safety:

• It’s not likely to be effective in patients who already have chronic renal failure,

since irreversible glomerular injury is probably present

• It’s safe even when given continually over decades

• Side effects, most commonly gastrointestinal (such as diarrhea, nausea, vomiting),

are uncommon at low doses (0.5 to 1.2 mg per day), even when given

continuously over years.

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• Less common (<1 %) side effects include bone marrow suppression,

hepatotoxicity, and myotoxicity.

• Pregnancy category C: The benefits of continued colchicine therapy through

pregnancy outweigh any risks to the fetus

• Safe in Lactating women.

Interactions:

Drug interactions:

• Digoxin, folic acid: may increase the serum concentration of Colchicine.

• Multivitamins/Fluoride: colchicine may decrease absorption of cyanocobalamin

(vitamin B12).

Food interactions:

• Grapefruit Juice: May increase the serum concentration of Colchicine. Risk X:

Avoid combination.

Reassessment:

When the 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.

In rare cases of heterozygous FMF patients who are asymptomatic for several

(more than five) years and do not display elevated acute phase reactants, it may be

possible to discontinue colchicine

Patients who fail to respond to colchicine fall into one of the following categories:

• Patients whose symptoms are not due to FMF: ( tumor necrosis factor (TNF)

receptor-1 associated periodic syndrome (TRAPS))

• Patients who are nonadherent or incompletely adherent with therapy

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• Colchicine-resistant FMF: patients who still experience frequent attacks despite

the maximal tolerable dose of colchicine (up to 3 mg daily in adults and 2 mg in

children) are considered to have crFM.

Patient Education:

• Colchicine is not a pain medication and should not be used to relieve other causes

of pain.

• Take this medication by mouth with or without food, exactly as directed by your

doctor.

• For pediatric , we can crush tablets

• Taking more than the recommended dose may not increase this drug's

effectiveness and may increase your risk for side effects.

Colchicine resistance or intolerance: We give concomitant colchicine at a tolerable dose (or approximately 1.5 to 2 mg daily)

in order to prevent amyloidosis.

1) Interleukin-1 inhibition

A-Canakinumab ( Ilaris® )

• generally preferred due to its efficacy and convenience since it is given as a

subcutaneous injection every four to eight weeks.

• It’s a human immunoglobulin G (IgG) antibody directed against IL-1-beta

• SubQ: 150 mg (wt > 40 Kg), 2mg\Kg (wt <= 40 Kg) every 4 weeks.

May increase the dose to 300 mg (>40Kg) or 3mg\Kg (wt <=40Kg) every 4

weeks if response is inadequate.

• Does not need renal nor hepatic adjustments.

B-Anakinra (Kineret®)

• is a recombinant version of the IL-1 receptor antagonist

crFMF: is the occurrence of one or more attacks each month despite

receiving the maximally tolerated dose for at least six months

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• SubQ 100 mg once daily

• Dose Adjustment Renaly: CrCl < 30 mg\min or ESRD consider dosing every

other day.

• Doesn't need hepatic adjustment.

C- Rilonacept (Acralyst ®)

• Is a dimeric fusion protein consisting of the extracellular portions of the human

IL-1 receptor and the Fc region of human IgG1 that binds and neutralizes IL-1

• Dose: SubQ initial dose 320mg as two separate injections

maintenance dose: 160mg once weekly

• Cat C in pregnancy

• Does not need dose adjustment.

Other agents:

• Thalidomide (Thalomid ®)

• Etanercept (Enbrel ®)

• Adalimumab (Humira ®)

• Infliximab (Remicade ®)

• Tocilizumab (Actemra ®_)

MANAGEMENT OF SPECIFIC FEATURES:

• Chronic arthritis:

sulfasalazine and/or methotrexate

• Protracted febrile myalgia:

prednisone 1 mg/kg daily for one to two weeks and then decrease the dose

gradually over four to eight weeks.

• Exertional myalgia:

Exercise-induced myalgia improves with resting or treatment with (NSAIDs).

NSAIDs may be given once the patient experiences muscle pain, and the

symptoms typically resolve with a single dose and in some

cases acetaminophen is effective too.

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References:

• Eldad Ben,Chetrit, MD. (2018). Clinical manifestations and diagnosis of familial

Mediterranean fever. Monica Ramirez Curtis, MD, MPH, Shilpa Grover, MD,

MPH, AGAF (Ed.), UpToDate. Retrieved

October,1,2018,from https://www.uptodate.com/contents/screening-for-

depression-in-adults

• Eldad Ben-Chetrit, MD. (2018). Management of familial Mediterranean fever.

Monica Ramirez Curtis, MD, MPH, Shilpa Grover, MD, MPH,

AGAF (Ed.), UpToDate. Retrieved

October,1,2018,from https://www.uptodate.com/contents/management-of-

familial-mediterranean-fever?

• Colchicine.Lexi-drugs.Lexicomp.Lolters Kluwer

Health,Inc.Riverwoods,IL.Available at https://online.lexi.com. Accessed

September 30,2018

Done By:Pharm D students:

Ranya mohammed & Sara Dabbas

Supervised by : Pharm D Eshraq Al-abweeny