Familial mediterranean fever
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Transcript of Familial mediterranean fever
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.
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.
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
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.