2. FMF
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 percent 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
3. Epidemiology
•
•In adults, FMF is more prevalent in men than in
women.
•It mainly occurs in families of Mediterranean
area.
••Age:
•are younger than 10 years50-60%.
•%are younger than 20 years80-95.
%are older than 20 years at onset5-10.
••Onset in people older than 40 years is rare
4. 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
•; the protein is also called marenostrin
derived from the phrase "our sea,"
becauseof the Mediterranean
heritage of most patients
5. •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
6. 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 symptomatic 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
7. •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 patientsimprove
in another third of patients, and remain
unchanged in the rest
Clinical manifestations
8. •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
•YOUNG FMF patients who are treated with colchicine,
an acute attack may occur without fever
9. •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.
10. •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
•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
11. •4-Joint pain
•The joint attacks are usually monoarticular, involving one
of the large joint; 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
12. •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
13.
14. Other rare manifestations
• Exertional myalgia
• Acute pericarditis
• Acute scrotum: unilateral gradual swelling of
the scrotum in childre
• Headache and aseptic meningitis
15. Diagnostic Criteria of Familial Mediterranean
Fever (FMF)
Tel-Hashomer criteria:
Major criteria
Recurrent febrile episodes associated with peritonitis, pleuritis or
synovitis
Amyloidosis of AA-type without a predisposing disease
Favorable response to daily colchicine
Minor criteria
Recurrent febrile episodes
Erysipelas-like erythema
Positive history of familial Mediterranean fever in a first degree
relative
Definite Diagnosis: 2 major or 1 major + 2 minor criteria.
Probable Diagnosis: 1 major + 1 minor criteria.
16. Livneh criteria
Major criteria:
Typical attacks of:
Peritonitis (generalized)
Pleuritis (unilateral) or pericarditis
Monoarthritis (hip, knee, or ankle)
Fever alone
Minor criteria
1-2 Incomplete attacks affecting one or more sites
Abdomen
Chest
Joint
Exertional leg pain
Response to colchicine
Definitive diagnosis: 1 major criterion or 2 minor criteria.
17. Turkish Pediatric Criteria
Fever: axillary temperature >38 °C, duration 6–72 h and
>/=3 attacks
Abdominal pain: duration 6–72 h and >/=3 attacks
Chest pain: duration 6–72 h and >/=3 attacks
Arthritis: duration 6–72 h, >/=3 attacks, and
oligoarthritis
Family history of FMF
Definitive diagnosis: The presence of at least 2 out of 5
criteria.
18. Laboratory Studies
--Results of routine blood tests performed
during the acute attacks of familial
Mediterranean fever (FMF) are nonspecific.
-- Levels of acute-phase reactants (ie, C-
reactive protein, erythrocyte sedimentation
rate, amyloid A protein, fibrinogen) are
elevated.
--The white blood cell count is usually
elevated during an attack
19. Genetic Testing
FMF is a clinical diagnosis; it can be supported
but not excluded by genetic testing.
FMF patients carrying two of the common
mutated alleles (homozygotes or compound
heterozygotes), especially for M694V mutation
or mutations at position 680 to 694 on exon 10,
must be considered at risk of having a more
severe disease.
20. • Patients homozygous
for M694V mutation are at risk for early-
onset disease and at very high risk of
developing a severe phenotype; those
who are not reporting symptoms should
be evaluated and followed closely in
order to consider therapy.
21. • Patients with two pathogenic mutations for
FMF who do not report symptoms but have
risk factors for AA amyloidosis (eg, country of
origin; family history; persistently elevated
inflammatory markers, particularly serum
amyloid A protein), should have close follow-
up and be considered for treatment.
23. 1-The ultimate goal of treatment in
FMF is to obtain complete control of
unprovoked attacks and minimise
subclinical inflammation in between
attacks.
24. 2-Treatment with colchicine should be
started as soon as a clinical diagnosis
is made.
• A starting dose of ≤0.5 mg/day for children
<5 years of age
• 0.5–1.0 mg/day for children 5–10 years of age
• 1.0–1.5 mg/day in children >10 years of age
and in adults is recommended.
25. 3-Dosing can be in single or
divided doses, depending on
tolerance and compliance.
26. • 4-The persistence of attacks or
subclinical inflammation represents an
indication to increase colchicine dose.
Colchicine may be increased up to a daily
dose of 2 mg in children and 3 mg in
adults
27. • 5-Compliant patients not responding to
the maximum tolerated dose of
colchicine can be considered non-
responders or resistant; alternative
biological treatments are indicated in
these patients
28. • IL-1 blockade is a promising second-line
therapy
• Tumour necrosis factor (TNF) inhibitors have
also been used in colchicine-resistant
patients
29. • 6- FMF treatment needs to be
intensified in AA amyloidosis using the
maximal tolerated dose of colchicine
and supplemented with biologics as
required.
• Therapeutic success is ideally monitored by
frequent estimation of SAA protein with the
target being maintenance below 10 mg/L and
by assessment of proteinuria and glomerular
filtration.
30. • 7- Periods of physical or emotional
stress can trigger FMF attacks, and it
may be worth temporarily
increasing the dose of colchicine.
31. • 8- In patients with decreased renal
function, the risk of colchicine toxicity is
very high and therefore evidence of
toxicity should routinely be sought and
the colchicine dose reduced accordingly.
32. • 9-When suspecting an attack, always
consider other possible causes. During
the attacks, continue the usual dose of
colchicine and use non steroidal anti
inflammatory drugs (NSAIDs).
33. • 10- Colchicine should not be
discontinued during conception,
pregnancy or lactation; current evidence
does not justify amniocentesis.
34. • 11-In general, men need not stop
colchicine prior to conception; in the
rare case of azoospermia or
oligospermia proven to be related to
colchicine, temporary dose reduction or
discontinuation may be required.
35. • 12-Chronic arthritis in a patient with
FMF might need additional
medications, such as disease
modifying antirheumatic drugs
(DMARDs), intra-articular steroid
injections or biologics
36. • 13- In protracted febrile myalgia,
glucocorticoids lead to the resolution of
symptoms; NSAID and IL-1 blockade
might also be a treatment option.
NSAIDs are suggested for the treatment
of exertional leg pain.
37. • 14-If a patient is stable with no attacks
for more than 5 years and no elevated
APR, dose reduction could be
considered after expert consultation
and with continued monitoring
