Familial Mediterranean Fever

FMF

BYDR MAHMOUD SALAMA

2015

ObjectivesIntroductionBackground & PathophysiologyClinical ManifestationsComplications “Amyloidosis”InvestigationsDifferential DiagnosisDiagnosisTreatmentPrognosis

Introduction Familial Mediterranean fever is an

genetic  autoinflammatory disease characterized by recurrent ,short episodes of high fever associated with abdominal pain,+ -chest pain +- inflammation of joints +- skin rash.

If untreated, amyloidosis  commonly develops and may have a fatal outcome(ch renal failure).

Familial Mediterranean fever is the most common of the periodic fever syndromes.

periodic fever syndromes Six periodic fever diseases have been

well characterized:1- Familial Mediterranean fever (FMF) 2- Hyperimmunoglobulinemia D3- Tumor necrosis factor (TNF)

receptor– associated periodic syndrome

4- Muckle-Wells syndrome (MWS) 5- Familial cold autoinflammatory

syndrome (FCAS) 6- Chronic infantile neurologic

cutaneous articular syndrome

periodic fever syndromes Periodic fever syndromes are rare and heritable

disorders characterized by short and recurrent

attacks of fever and severe localized inflammation

that occur periodically or irregularly .

It is not explained by usual childhood infections.

These attacks undergo spontaneous remission

without antibiotic, anti-inflammatory, or

immunosuppressive treatment.

Between attacks, patients feel well and regain their

normal daily functions until the next episode occurs.

Familial Mediterranean fever (FMF)

Familial Mediterranean fever (FMF), also known as recurrent hereditary polyserositis,

is an autosomal recessive disease that affects people of Mediterranean region, such as those of north-African (Sephardic), Iraqi, Jewish, Arabic, Armenian, Turkish, or Italian descent.

Familial Mediterranean fever is characterized by short febrile attacks caused by neutrophil-induced serosal inflammation and a gradual accumulation of amyloid in kidneys.

Familial Mediterranean fever (FMF)

Is an autosomal recessive disease (familial).

Molecular biology and genetics

Familial Mediterranean fever is usually due to mutations in the Mediterranean fever (MEFV) or pyrin gene located on chromosome 16.

The normal form of pyrin suppresses inflammation by down-regulation of pro-inflammatory cytokines (cell messenger proteins), up-regulation of anti-inflammatory cytokines and preventingthe inflammatory cascade.

A lack of functional pyrin releases the inflammatory cascade.

Molecular biology and genetics

Familial Mediterranean fever (Race)

Primarily affects populations originating in the Mediterranean region

Armenian, Arab, Turkish, Jewish peoples Jews 1 case per 250-1000 populationArmenians 1 case per 500 populationTurks 1 case per 1000 populationArabs 1 case per 2600 population

Sex

The male-to-female ratio of cases about 2:1

AGE

Approximately 90% of patients

are younger than 20 years,

and 60% of patients are younger

than 10 years.

Late-onset disease is usually

more clinically benign than early-

onset disease.

Clinical features of familial Mediterranean fever

Patients with familial Mediterranean fever have recurrent acute febrile painful attacks that last 12 hours to 4 days.

The pain usually involves 1-2 of the following sites at a time: abdomen, chest, joints, muscles, scrotum, and skin.

The typical manifestations of the disease are recurrent attacks of severe abdominal pain and fever, lasting one to three days, and then resolving  spontaneously.

In between attacks, patients feel entirely well.

Clinical ManifestationsAcute attacks:Duration: generally 1-4 days.

Arthritic attacks tend to last longer. Frequency: sometimes occur with

great regularity, but more often the frequency varies over time, ranging from once every few days to several years.

precipitating factors: often unpredictable. Some patients relate them to physical exertion, emotional stress, or menses; pregnancy may be associated with remission.

There are 7 types of attacks:

1. Fever: ◦Nearly always present. ◦Severe hyperpyrexia & febrile seizures may be seen in infants.

◦In 25% it is the only manifestation especially in young children.

2. Abdominal attacks: 90%

◦Acute abdominal pain & signs of peritonitis -resembling appendicitis or choleycystitis.

◦May lead to unnecessary laparotomy & appendectomy.

◦Severity is variable.◦In many cases, patients develop constipation during attack & diarrhea after attack resolves.

◦CT scan may show small amount of fluid in abdominal cavity. A sterile, neutrophil-rich peritoneal exudate is present. Adhesions & ascites are rare.

3. Chest attacks:

◦Pleuritis (25-80%), Pericarditis (rare).

◦Usually manifest as unilateral, sharp, stabbing chest pain that makes it difficult to breathe or lie flat. Friction rub is rare.

◦Radiographs may show atelectasis or effusion.

◦Thoracentesis demonstrates a neutrophil-rich exudate.

◦After repeated attacks, pleural thickening may develop.

◦Symptomatic pericardial disease is rare. Some patients have small pericardial effusions as an incidental echocardiographic finding.

4. Joint attacks: 25-75%

◦Acute Arthritis:

◦Usually monoarticular, affecting knee, ankle, or hip.

◦Large sterile neutrophil-rich effusions are frequent, w/o corresponding erythema or warmth.

◦ Joints are normal b/w attacks, permanent damage is unusual & radiographic changes are rare.

◦Chronic Arthritis:

◦Before colchicine prophylaxis, chronic arthritis of knee or hip were seen in 5% in those with arthritis.

◦10% develop seronegative spondyloarthropathy “chronic sacroiliitis”.

5. Cutaneous manifestation: 50%

◦The most characteristic is erysipelas-like erythema, a raised erythematous rash most common on dorsum of foot, ankle, or lower leg.

6. Myalgia:◦Exercise-induced (nonfebrile) myalgia is

common. ◦A small % develop a protracted febrile

myalgia lasting several weeks.

7. Scrotal attacks: 5%◦Unilateral acute scrotal inflammation (of

tunica vaginalis) may occur in prepubertal boys & mimic acute scrotum.

Aseptic meningitis has been reported, but causal connection is controversial.

Vasculitis, including HSP, PAN & Behçet disease may be seen at increased frequency in FMF.

Episodes of PID in ♀ patients may occur.

Infertility: 1/3 of ♀ FMF patients are infertile & 20-30% of pregnancies result in fetal loss.

Diagnostic criteria

 Major criteria: 1.Painful inflammatory manifestations in the

abdomen, chest, joints, or skin, associated with the fever.

2.Nephropathic amyloidosis.3.Dramatic response to continuous colchicine

treatment in abolishing or reducing febrile attacksMinor criteria:4.Short attacks of fever recurring at irregular

intervals.5. Family history6. Erysipelas like rashDiagnosis:- 2 major or 1 major and 2 minor criteria

Complications “Amyloidosis”

Before colchicine prophylaxis, systemic

amyloidosis was a common complication.

It is caused by deposition of fragment of serum

amyloid A, an acute-phase reactant, in kidneys,

adrenals, intestine, spleen, lung & testes.

As a result, proteinuria, followed by nephrotic

syndrome, & inevitably, death from renal failure

may occur& thus renal function should be

monitored.

Amyloidosis Amyloidosis should be suspected in

patients who have proteinuria between

attacks.

renal or rectal biopsy is used to establish

diagnosis.

Risk factors for developing amyloidosis

include: ◦M694V homozygous genotype,◦+ve family history◦SAA 1 genotype, ◦♂ gender, ◦noncompliance with colchicine therapy,◦having grown up in the Middle East.

Types of FMF

Type 1Recurrent short episodesInflammation and serostisFeverPeritonitisPleuritisPericarditis and Meningitis (less

common)

Type 2Amyloidosis as the first clinical

manifestation of FMF in an otherwise asymptomatic individual

InvestigationsLab features during attacks are consistent

with acute inflammation & include:◦↑ ESR,◦↑ WBC’s, ◦↑ Plt (in children), ◦↑ CRP, fibrinogen, haptoglobin & serum

immunoglobulins.◦Transient albuminuria & hematuria may

be seen.

Differential diagnosis1 - Surgical emergencies as

appendicitis, intussusception, perforated peptic ulcer, etc.

2 - in women, gynecologic disorders.3 - Acute intermittent porphyria4 - Relapsing pancreatitis5 - Systemic lupus erythematosus

and vasculitis6 - Hypertriglyceridemia7 - Abdominal epilepsy and abdominal

migraine8 - Other rare hereditary periodic

fevers syndromes.

DiagnosisFor typical cases, physicians experienced

in FMF can often make diagnosis on clinical grounds alone.

Clinical criteria.Genetic testing can provide a useful

clue in uncertain cases or for physicians not experienced in FMF.

currently available genetic tests do not assess for all mutations associated with FMF

sometimes a therapeutic trial of colchicine may help to confirm diagnosis.

TreatmentAIM OF TREATMENT:

1- Symptomatic relief of the acute attacks

2- Prevent or reduce recurrent episodes

3- Prevention of the development and

progression of amyloidosis

Acute attacksAttacks are self-limiting, require

analgesia & NSAIDs (e.g. diclofenac).Colchicine, taken orally each day

for life, is the drug of choice for familial Mediterranean fever

Each tablet contain ,5 mg = 500 mcg◦ The regimen for acute attacks in

patients not taking daily colchicine is 0.5mg every hour for 4 doses, then 0.5 mg every 2 hours for 2 doses and then 0.5mg every 12 hours for 4 doses.

Colchicine

• COLCHICINE NOT EFFECTIVE IN WELL

ESTABILISHED CRF

• Colchicine completely prevents attacks

in 60% of patients, partially prevents

attacks in 33% of patients, and is not

effective in 5% of patients (“Periodic

Fever Syndrome”).

Colchicine in prophylaxis

Colchicine should be administered orally once

the diagnosis of FMF is confirmed (or as a

therapeutic trial in establishing the diagnosis).

Adult dosing is 1–2 mg/day,

whereas children usually start at 0.25-1 mg/day

according to age and weight and can increase

sequentially up to 2 mg/day depending on how

effectively the attacks are regulated.

Colchicine non responsive

In patients whose conditions were not

responsive to oral colchicine, the

addition of 1 mg IV colchicine once a

week reduced the number of attacks.

In patients whose conditions do not

respond to colchicine, the use of

interferon-alpha, the tumor necrosis

factor–blocking drug (etanercept) and

the IL-1 receptor antagonist (anakinra)

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.

Side effects of colchicineThe most common adverse events are GI and

include nausea, vomiting, diarrhea, and abdominal pain.

Cardiovascular adverse events include hypotension and sinus bradycardia,

CNS effects include confusion, delirium, and seizures.

Dermatologic effects include rash and alopecia,

Endocrine and metabolic effects include dehydration.

Genitourinary effects include azoospermia.If taken by “either” parent at time of conception,

colchicine may cause a small increase in the risk of trisomy 21 (Down syndrome).

Contraindications of colchicine

hypersensitivity to colchicine

severe renal, GI, hepatic, or cardiac

disorders;

blood dyscrasias;

and pregnancy (parenteral).

Colchicine in pregnancycategory C (PO formulation) or D

(parenteral formulation). Colchicine is known to arrest mitotic and

meiotic chromosomal segregation in vitro; therefore, birth defects are a potential concern if the drug is used during pregnancy.

However, none of the studies to date has conclusively demonstrated that colchicine is responsible for chromosomal abnormalities or other birth defects.

Amniocentesis is still suggested to screen for chromosomal defects if either parent is taking the drug.

Colchicine in lactationcolchicine enters breast milk; therefore,

use caution in breastfeeding patient;On the other hand, when the amount

passed to the child was analysed, it was observed to be only one-tenth of the maternal dose.

When children of mothers taking colchicine were evaluated, no side-effects were reported relating to the drug.

Accordingly, it was suggested that breastfeeding is safe in women taking colchicine.

the American Academy of Pediatrics rates this as compatible.

Prognosis

Compliant patients with daily colchicine can

expect to have a normal lifespan if

colchicine is started before proteinuria

develops.

Even with amyloidosis, the use of colchicine,

dialysis & renal transplantation should

extend a patient's life beyond age 50 years.

ConclusionFamilial Mediterranean fever is an

genetic  autoinflammatory diseasePrimarily affects populations originating

in the Mediterranean region. If untreated, Amyloidosis  commonly

develops and may have a fatal outcome(Ch renal failure).

The typical manifestations of the disease are recurrent attacks of severe abdominal pain and fever.

Colchicine for life is the drug of choice in treatment and reduction of frequency of recurrent attacks and in prevention of Amyloidosis.