3. #
Introduction
• FMF is the prototype of a group of
inherited “autoinflammatory” diseases –
hereditary recurrent fever syndromes-
that are characterized by recurrent
episodes of fever with serosal, synovial,
or cutaneous inflammation and, in some
individuals, the eventual development of
systemic AA amyloidosis.
4. #
Background & Pathophysiology
• : 2:1
• Frequency depends on ethnicity. It
affects people originating from around
the Mediterranean Sea.
• Sephardi Jews (and, to a much lesser
extent, Ashkenazi Jews), Cypriots,
Turks, Armenians, Italians & Arabs.
• Occasional cases are found in absence
of known Mediterranean ancestry.
6. #
• FMF is recessively inherited, but +ve
FHx can only be elicited in 50% of cases.
• Carrier frequencies reach as high as 1:3
among affected populations, suggesting
that not all mutations have equal
penetrance.
• Most patients have only a single
demonstrable MEFV/16p13.3 mutation
on DNA sequencing.
7. #
• The FMF gene encodes a 781-amino acid, 95
kDa protein denoted pyrin (or marenostrin)
that is expressed in granulocytes, eosinophils,
monocytes, dendritic cells, synovial &
peritoneal fibroblasts.
• Through a number of mechanisms, pyrin
regulates caspase-1 [ IL-1 -converting
enzyme] & thereby IL-1 secretion.
• Ineffective pyrin doesn't inhibit inflammation
normally & lead to excessive IL-1 production.
8. #
Clinical Manifestations
• Acute attacks:
• Age of onset: Febrile episodes may begin in early
infancy; 90% of pts have 1st attack by age 20.
• 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.
• E&R factors: often unpredictable. Some patients
relate them to physical exertion, emotional stress, or
menses; pregnancy may be associated with remission.
10. #
• 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.
11. #
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.
12. #
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.
13. #
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”.
14. #
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.
– Biopsy demonstrates perivascular
infiltrates of granulocytes & monocytes.
16. #
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.
17. #
• 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.
18. #
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.
19. #
• Amyloidosis should be suspected in
patients who have proteinuria b/w
attacks; renal or rectal biopsy is used to
establish diagnosis.
• Risk factors for developing amyloidosis
include:
– M694V homozygous genotype,
– +ve family hx (independent of FMF mutational
status),
– SAA 1 genotype,
– ♂ gender,
– noncompliance with colchicine therapy,
– having grown up in the Middle East.
20. #
Investigations
• Lab 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.
21. #
Differential Diagnosis
• If a patient is seen during 1st attack, DDx
may be broad, narrowed by specific organ
involvement.
• After several attacks DDx may include:
– Other hereditary recurrent fever syndromes;
– Syndrome of periodic fever with aphthous ulcers,
pharyngitis, and cervical adenopathy (PFAPA);
– Systemic-onset juvenile RA or adult Still's
disease;
– Porphyria;
– Hereditary angioedema;
– IBD;
– & in women, gynecologic disorders.
22. #
Diagnosis
• For typical cases, physicians
experienced in FMF can often make
diagnosis on clinical grounds alone.
• Clinical criteria.
• Genetic testing can provide a useful
adjunct in ambiguous cases or for
physicians not experienced in FMF.
23. #
• Genetic testing may be of prognostic value:
– M694V homozygotes have an earlier age of onset
and a higher frequency of arthritis, rash &
amyloidosis.
– E148Q variant is usually associated with milder
disease.
• In cases where genetic testing is inconclusive,
clinical judgment is very important, and
sometimes a therapeutic trial of colchicine
may help to confirm diagnosis.
• Genetic testing of unaffected individuals is
usually inadvisable, because of the possibility of
nonpenetrance & potential impact of a +ve test
on future insurability.
24. #
Treatment
• Attacks are self-limiting, require analgesia &
NSAIDs (e.g. diclofenac).
• The TOC is daily oral colchicine, which ↓
attack frequency & intensity, & prevents
amyloidosis in compliant patients.
• Colchicine is an alkaloid that may interfere
with microtubule formation, thereby affecting
mitosis and other microtubule-dependent
functions.
• Colchicine & metabolites are excreted
through urinary & biliary tracts.
25. #
• The adult dose of colchicine is 1.2–1.8 mg/d
( ↑ 0.3 mg/day as needed & tolerated; max.
2.4 mg/day)
• It causes substantial reduction in
symptoms in 2/3 of patients & some
improvement in >90%.
• Children may require lower doses, although
not proportionately to body weight.
26. #
• Common side effects of colchicine include:
bloating, abdominal cramps, muscle pain,
lactose intolerance, & diarrhea.
• They can be minimized by: starting at a low
dose & gradually advancing as tolerated,
splitting the dose, use of simethecone for
flatulence, & avoidance of dairy products.
• If taken by “either” parent at time of
conception, colchicine may cause a small
increase in the risk of trisomy 21 (Down
syndrome).
27. #
• Colchicine toxicity include: bone marrow suppression
(3-5 days post exposure), acute renal failure,
rhabdomyolysis & neuromyopathy (proximal muscle
weakness & elevation of creatine kinase). Severe
toxicity results in MOF, convulsions, coma & death.
• IV colchicine should not be administered to patients
taking oral colchicine, because severe fatal toxicity
can occur.
• Cyclosporine inhibits hepatic excretion of
colchicine, sometimes leading to colchicine toxicity
in patients who have undergone renal transplantation
for amyloidosis.
28. #
• There are no established alternatives for
the 5-10% of patients who do not
respond to colchicine or cannot tolerate
therapeutic dosages, although
interferon-α, IL-1 receptor antagonist
& TNF inhibitors are investigational.
• Bone marrow transplantation has been
suggested for refractory FMF, but the
risk-benefit ratio is currently regarded
as unacceptable.
29. #
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.
