Transcript Familial Mediterranean Fever - Sanad Hospital

Familial Mediterranean Fever
FMF
Background
• Familial Mediterranean fever (FMF) is also called
recurrent polyserositis. The salient features of
FMF include brief recurrent episodes of
peritonitis, pleuritis, and arthritis, usually with
accompanying fever. FMF occurs within families
and is much more common in individuals of
Mediterranean descent than in persons of any
other ethnicity.
Pathophysiology
• Nonsense or missense mutations in the MEFV (Mediterranean fever)
gene appear to cause the disease in many cases. MEFV produces a
protein called pyrin (derived from the association with predominant
fever) or marenostrin (derived from the phrase "our sea," because of
the Mediterranean heritage of most patients).
• The protein is expressed mostly in neutrophils. Its exact function is
unknown, but it may function as an inhibitor of chemotactic factor
(C5a) or perhaps of interleukin (IL)–8.[1] Individuals with normal
pyrin/marenostrin levels may have the ability to deactivate the target
chemotactic factor when it is produced in response to an
inflammatory stimulus. However, patients with FMF lack this ability,
resulting in uninhibited activity of the chemotactic factor and episodes
of inflammation (with accompanying fever) in the peritoneum, pleura,
and joints. Presumably, these inflammatory episodes lead to the
excess production of amyloid A protein from the acute phase and
reactant serum amyloid A with subsequent deposition in the kidneys;
however, only patients with specific MEFV haplotypes develop
amyloidosis.
Epidemiology
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Frequency
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International
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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.[2]
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.
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.[3, 4]
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.[5]
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Mortality/Morbidity
• 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.
• Appendectomies: Many patients with undiagnosed FMF have
undergone appendectomy because the severity of the peritoneal
episodes seemed to indicate appendicitis.
• Chronic arthritis: 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.
• Fertility and pregnancy: Approximately one third of female patients with
FMF are infertile, and 20-30% of pregnancies result in fetal loss.
Sex
In adults, FMF is more prevalent in men than in women, with a male-tofemale ratio of 1.5-2:1.
Age
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.
History
• 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.
Fever
• Temperatures rise 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. Patients develop abdominal pain that may
progress to peritonitis, resembling a surgical abdomen.
• Patients with FMF frequently have symptoms consistent
with appendicitis or cholecystitis and 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.
• The joints are normal between attacks, and permanent
damage is unusual.
• Arthritic symptoms tend to last several days longer than
abdominal symptoms. Episodes can be protracted.
• Arthritis may be the only manifestation. FMF should be
considered in patients with a family history of FMF or
who live in an endemic area
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
• Recent descriptions more often include reports
of severe myalgia lasting 3-6 weeks. These
episodes do not respond to colchicine therapy.
• Symptoms are consistent with fibromyalgia.
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.
Amyloidosis
• In a patient of the appropriate ethnic group, the typical progression is
proteinuria, followed by nephrotic syndrome, and, inevitably, death
from renal 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.
• Prolonged survival resulting from colchicine therapy, dialysis, and
renal 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
renal failure without previous proteinuria.
Physical
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Physical findings of FMF depend mostly on the serosal surface involved.
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Temperatures can reach as high as 40°C (104°F), but, in most cases, rapid defervescence occurs within
12 hours.
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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.
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Joints show typical inflammatory changes, with warmth, erythema, or swelling.
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A well-demarcated, erythematous, warm rash, particularly below the knee, ranging from 15-50 cm2
may develop and may be accompanied by swelling.
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Patients with painful myalgia syndrome may have tender muscles.
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Female patients with symptoms mimicking pelvic inflammatory syndrome may experience pain upon
cervical motion and may develop tender enlarged ovaries.
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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.
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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.
Causes
• 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.
• Multiple mutations are located on the MEFV gene. Most of the 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.[2]
• Other genes may be involved in FMF. This 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.
Differential Diagnoses
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Acute Rheumatic Fever
Appendicitis
Calcium Pyrophosphate Deposition Disease
Gout
Lyme Disease
Nephrolithiasis
Pericarditis, Acute
Pleurodynia
Systemic Lupus Erythematosus
Laboratory Studies
• Results of routine blood tests performed during the acute attacks of
familial Mediterranean fever (FMF) are nonspecific. Levels of acutephase reactants (ie, C-reactive protein, amyloid A protein, fibrinogen)
are elevated, as is the erythrocyte sedimentation rate. The WBC
count is usually elevated during an attack. The elevated levels rapidly
return to the reference range as the attack abates.
• Proteinuria should raise a concern about possible amyloidosis. For
unknown reasons, hematuria occurs in 5% of patients.
• Synovial fluid is inflammatory, with cell counts as high as 100,000/µL.
• 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.
Imaging Studies
• 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.
Procedures
• 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.
Histologic Findings
• 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.
Medical Care
• 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 (0.6 mg bid or
0.5 mg bid, depending on the dosage form
available) 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.
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.
In patients who do not respond to twice-a-day dosing, administer
colchicine 3, or even 4, 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.[6]
Some patients develop lactose intolerance and may respond to a
lactose-free diet.
In patients whose conditions do not respond to colchicine, the use of interferonalpha, the tumor necrosis factor–blocking drug etanercept,[7] and the IL-1 receptor
antagonist anakinra[8] may be effective. Rilonacept, a once-weekly subcutaneous
injection IL-1 decoy receptor, has been shown, in combination with continuation of
colchicine, to reduce the number of attacks in patients who did not respond
optimally.[9] Interferon-alpha has been used in an intermittent fashion and as
prophylaxis, with varying results.[10, 11, 12]
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 more than 1.5 mg/d of colchicine.
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.
Patients who develop seronegative spondyloarthropathy are treated with nonsteroidal
anti-inflammatory drugs. Some of these patients require remission-type drugs (as
used in rheumatoid arthritis) and receive follow-up care by a rheumatologist.
Surgical Care
• Before the advent of colchicine therapy, renal
transplantation was performed in patients with
end-stage renal disease due to amyloid
nephropathy. Now, renal failure develops only
in patients who are not compliant with therapy
or those who cannot tolerate adequate doses of
colchicine.
Medication Summary
• The goals of therapy are to reduce morbidity
and to prevent complications.
• Class Summary
• Colchicine is the drug of choice for familial
Mediterranean fever (FMF).
Complications
• Patients with amyloidosis may develop an acute
onset of renal failure if they are stressed by
dehydration, infection, or both.
• Renal vein thrombosis may occur in nephrotic
patients. This condition may manifest as
abdominal or flank pain, increasing proteinuria,
and worsening renal function. Acute
anticoagulation may stabilize or improve renal
function.
Prognosis
• Patients who are compliant with daily colchicine
can probably expect to have a normal lifespan if
colchicine is started before proteinuria
develops.
• Even with amyloidosis, the use of colchicine,
dialysis, and renal transplantation should extend
a patient's life beyond age 50 years.
Patient Education
• Patients with FMF need to understand the
importance of strict compliance with daily
colchicine therapy.