Fmf tricks in 20 m

FMF tricks
BY:
Dr, Walaa Manaa
PEDIATRIC & FEVER SPECIALEST
‫ـيخ‬‫ش‬‫ال‬‫ـفر‬‫ك‬ ‫ـيات‬‫م‬‫ح‬‫ـستشفى‬‫م‬

Introduction
• It frequently occurs among Turks, Armenians, Jews and
Arabs.
• Although it has been known about for a long time, it was
first mentioned in the literature in 1908 by Janeway and
Mosenthal,who reported recurrent fever and abdominal
pain in a 6 year-old Jewish girl.
• Its first definition as a disease was based on a case
report, published under the title “benign paroxysmal
peritonitis” by the allergy specialist Siegal from New York,
as a compilation of Jewish patients with similar complaints

FMF is also known by many other
names.
• Recurrent hereditary polyserositis,
• Benign paroxysmal peritonitis,
• Familial paroxysmal polyserositis
• Paroxysmal polyserositis,
• Familial recurrent polyserositis
• Periodic fever,
• Periodic amyloid syndrome,
• Periodic peritonitis syndrome,
• Reimann periodic disease,
• Reimann syndrome,
• Siegel-Cattan-Mamou syndrome,
• Armenian syndrome

• The periodical fever definition was first
used by Reimann in 1948, and Sohar et
al.defined the disease as FMF in 1955.
• Prior to the use of colchicine, the disease
was fatal, but a new era in the treatment
of FMF began with the introduction of
colchicine in 1972.
• In 1992, it was reported that the
abnormality associated with FMF is found
on chromosome 16,
• and the gene responsible for the disease
was identified in 1997

• FMF shows a marked
ethnic distribution.
• Frequently observed in
Turkish, Armenian,
Jewish and Arabic
communities.
• Geographically, the
disease is more
commonly observed
among the nations of
the Mediterranean
region

•
• Most frequently seen in Turkey with a
prevalence varying between 1:150 and
1:10,000.
• The second most frequently affected ethnic
group is Armenians; studies carried out in
Armenia report a prevalence of 1:500
• In studies conducted in Israel, it was claimed
that FMF incidence varies according to the
ethnic group being studied (Ashkenazi or non-
Ashkenazi Jews), but that it is observed at a
rate of 1:1000 on average

• No precise information is available about the prevalence
of FMF among Arabs.
• On the other hand, recent studies conducted in
countries such as Greece,Cyprus and Italy indicate that
this disease occurs more frequently than previously
believed .
• FMF has also been identified in other countries. In
Brazil, in the Middle East and Eastern Europe.
• In a nationwide study conducted in Japan in 2009,
cases of clinical FMF were investigated however, in
participating centres, around 170 FMF cases were
identified.

• FMF is an autosomal recessive
hereditary disease and occurs as a
result of point mutations in the
Mediterranean Fever (MEFV) gene on
the short arm of chromosome 16.
• This gene encodes a protein called
pyrine, essentially responsible for
the regulation of apoptosis,
inflammation and cytokines, and is
mainly expressed in neutrophils,
eosinophils, dendritic cells and
fibroblasts

• MEFV gene mutation lack
of pyrine protein which
prevent neutrophils
accumulation.
• lack of pyrine 
neutrophils attack body
cavities in periodic manner.
• it is assumed that the
primary function of pyrine
is to suppress the
inflammatory response.
(suppressing IL-1β
production)

• The MEFV gene on the short arm of chromosome
16 consists of 10 exons.
• Most of the mutations identified occur in exon 10
(e.g., M680I, M694V, M694I and V726A).
• Apart from this, mutations in exon 2 (E148Q) and
other exons have also been identified .
• To date, 288 mutations have been identified in
Infevers
(http://fmf.igh.cnrs.fr/ISSAID/infevers), which
is an online databank for mutations that play a
role in autoinflammatory diseases.

• The majority of these mutations
are rare, without causing any
clinical phenotype, and are
mainly observed in populations in
which FMF is not prevalent.
• It has been shown that the
E148Q, M680I, M694V,
M694I and V726A mutations are
responsible for more than 80%
of FMF cases in the Middle
Eastern region.
• On the other hand,because
E148Q has a high carrier rate
(>10%) and does not cause an
FMF phenotype, even in
homozygous case

• In Turkey, the rate of carriers is reported to
be 20%.
• This high rate is similar to the carrier rate
determined among the Ashkenazi and North
African Jews.
• In Turkey, the most frequent mutation
determined in carriers is E148Q; this is followed
by the M680I, M694V and V726A mutations

The Phenotype-Genotype
Relationship
Individuals who are homozygous
for the M694V mutation present
with a more serious and severe
disease course.
Amyloidosis, is reported at a
higher incidence in homozygous
M694V cases.
fever and abdominal pain, are
more frequent in individuals with
an M694V or M680I genotype.
• The disease develops earlier in
M694V mutation carriers.

• FMF is a disease that is
characterised by recurrent fever and serositis
(e.g.,peritonitis, pleuritis, synovitis) symptoms.
• Individual and ethnic differences may be seen in both
the frequency and course of the clinical symptoms.
• Even in the same patients, clinical symptoms may differ
over time.
• Attacks develop quite spontaneously and continue for at
least 12 hours.

• Most symptoms resolve within 3-4 days.
• The interval between attacks is clinically
relatively symptom-free.
• However,arthritis and myalgia may have a
prolonged course.
• Onset is under 20 years of age in 90%.
is under 10 years 60% of cases.
may develop after the first years
of life.
• Sex distribution, a slight male dominance.

• triggering factors of those
attacks has not been studied
well.
• It is supposed that physical
stresses such as cold
exposure, tiredness
emotional stresses,
menestuation and pregnancy
could provoke attacks.

The prodromal phase
• In 50%of FMF patients, various
constitutional and physical signs,
including restlessness at the site
where the symptom is about to
occur, anxiety, irritability,
increased appetite.
• The period between the prodromal
signs and the onset of the attack
has been reported to average 20
hours

Fever
• High fever is the most important symptom of
FMF and one of the essential symptoms in the
diagnosis.
• Body temperature is generally above 38°C.
• Fever typically emerges spontaneously,
increases rapidly, and is followed by a plateau
and a rapid decrease, which completes the
cycle. This course generally lasts 1-3 days.
• Non-specific findings such as weakness,
fatigue, myalgia, arthralgia, headache, lower
back and back pain commonly accompany high
fever.

• Peritonitis :
Abdominal pain is observed in more than 90%
• Abdominal pain starts in any region and quickly
spreads to the whole abdomen.
• In order to alleviate the pain, the patient lies
without moving in the flexion position.
• On examination, there are signs relating to
peritoneal irritation (such as abdominal swelling,
tenderness, sensitivity stiffness, a decrease in
bowel sounds, defence and rebound),
• numerous air-fluid levels on direct graphs and
leucocytosis in laboratory tests, and increased
acute phase symptoms

• These symptoms resemble a surgical
acute abdomen .
• In some patients, haematuria may
be occur so may not diagnosed
correctly.
• Although there is generally no gas
or stool excretion,
• about 10-20% of patients may
experience diarrhoea.
• Abdominal pain relief is achieved
within 6-12 hours; however, it
generally takes 24-48 hours for it
to resolve completely.

• Patients describing
abdominal attack
experience various forms
of pain on a mild to severe
range throughout their
lives. Some patients may
undergo unnecessary
surgery, due to
misinterpretation of the
acute abdominal clinical
picture emerging during
the course of the disease.

• In a retrospective study, it was found
that abdominal surgeries in FMF
patients predominantly occurred 90%
prior to the FMF diagnosis and that,
after the diagnosis was made, this
rate decreased to around 10% .
• According to the same study, whereas
surgeries performed prior to the FMF
diagnosis were mainly done with the
suspicion
• Of acute appendicitis, surgeries
following FMF diagnosis were more
frequently performed due to ileus

• In a trial conducted in Turkey,
it was determined that about
20% FMF patients was operated
on for a suspicion of acute
appendicitis .
• Although a number of
researchers claim that elective
appendectomy may protect FMF
patients against unnecessary
examinations and surgical
intervention, this is not
recommended and, moreover, can
increase adhesions of the
peritoneal lining.

• In previously performed
studies, during an attack,
hyperaemia in the peritoneal
lining and, in some patients,
fluid accumulation in the
peritoneum was shown. This
fluid was found to be rich in
fibrin and polymorphonuclear
leukocytes and exhibits
exudate characteristics.
• On the other hand, in a
C.T.,peritoneal fluid may
even be detected during the
asymptomatic period .

• Recurrent accumulations of the
exudative fluid and its resolution may
cause adhesions in the peritoneal lining
over time, and may thus lead to
complications such as mechanical bowel
obstruction, volvulus and strangulation.
• Too many neutrophils in the peritoneal
fluid are believed to increase the risk
of adhesion.
• In FMF patients with no previous
surgery, the occurrence of intestinal
obstruction is reported to be 3%.
• As a result of recurrent attacks, some
patients develop sclerosing peritonitis
(encapsulated peritonitis)

Spleen and lymph node
symptoms
• Splenomegaly was reported 10%-50%
• In general, this occurs as a result of reactive
changes secondary to the inflammation. However,
although rare, it may also occur as a result of
amyloid accumulation.
• Peripheral and abdominal lymphadenopathy 14%.
• Sometimes, cases undergoing laparotomy due to an
enlargement of the mesenteric lymph node have also
been reported.
• The biopsy assessment of the lymph nodes revealed
non-specific lymphoid hyperplasia

liver
• Hepatomegaly (approximately 5%).
• Cryptogenic hepatic cirrhosis is more
frequently observed in FMF patients,
there might be a relationship between the
diseases.
• (NASH) is observed in FMF at a higher
rate than expected.
• Although an increase in the incidence of
cholelithiasis in FMF was shown in some
studies , others do not support this
finding

Mesothelioma
• Observational studies
produced data indicating
that mesothelioma is
increased
• Due to chronic
inflammation causes
malignant transformations
in the serous membrane.
• However, other
observational studies do
not confirm the finding of
increased mesothelioma in
FMF

Other GIT symptoms
• Irritable bowel syndrome 5%.
• This might lead to abdominal pains that
are not related to the attacks.
• Another condition causing abdominal pain
is colchicine intolerance, which may also
be accompanied by diarrhoea.
• Although rare, another condition is
diarrhoea and malabsorption due to the
accumulation of amyloid in the small
intestine

Musculoskeletal system symptoms

Arthralgia and arthritis
• Arthralgia and arthritis
20% and 70% .
• it can be the baseline
symptom of the disease .
- monoarticular
-large joints of the
-lower extremities
-(knee > ankle).

• Arthritis attacks tend to
resolve within a 1 week.
• In some cases, leukocyte
numbers in the synovial fluid
may increase dramatically,and
this may be confused with
septic arthritis .
.

• Some 5-10% of FMF patients may
experience protracted arthritis attacks
lasting more than a month, sometimes
even years .
• In protracted arthritis, mainly the
knees and, to a lesser extent, the hip
joints are affected . The inflammation
in the knee joint is usually resolved
without sequelae, with massive fluid
accumulation
. However, protracted hip arthritis may
exhibit destructive characteristics. In
trials, it has been shown that
approximately 30% of patients with hip
manifestation required a total hip
arthroplasty operation.

Clinical manifestations in the
axial spine
• In a study in which
approximately 3000 FMF
patients were evaluated,
SpA prevalence was
reported to be 0.4%.
• In a study conducted in
Turkey, 503 FMF patients
were evaluated, and
sacroiliitis was detected by
x-ray in up to 10.5% of
these patients

Muscle symptoms
• During the course of FMF disease,
various muscle symptoms may emerge,
and the incidence in this patient
series is about 20-40% . Types of
myalgia that may occur during the
course of FMF can be categorised as
1-muscle pain occurring in childhood after
exercising.
2-disseminated muscle pain due to fibromyalgia.
3-protracted febrile myalgia (PFM).
4-muscle pain accompanying the attack.
5-myalgia and myopathy related to colchicine
treatment

• In colchicine myopathy,
-in addition to weakness of proximal muscles,
-an increase in laboratory muscle enzyme
levels,
-a myopathic pattern in (EMG)
-autophagic vacuoles histopathologically
visible in non necrotic muscle fibrils, and
lysosomal storage will probably be observed .

1-Pleural involvement occurs in
approximately 40% of FMF
patients. Pain is usually one-sided,
gets worse with breathing and can
expand to the shoulder. Similar to
the other attacks, it lasts for 1-4
days.
• Mild pleural effusion can be
observed during attacks.
• Fluid analysis is exudative and
neutrophils are dominant.
• In some patients, thickening and
adhesion have been reported in the
pleura as a result of repeated
attacks.

2-Pleural inflammation can be
accompanied by atelectasia
and, where pleurisy and
fever co-exist, this situation
can be diagnosed as
pneumonia by mistake.
3-Increased risk of pleural
mesothelioma; however,
there is insufficient evidence
to prove this.
4-Pulmonary amyloidosis.
5-Systemic vasculites
pulmonary
thromboembolism

Pericardial involvement
• The incidence of pericarditis as 0.7% in a series of
approximately 4000 patients.
• Pericarditis attacks last for 1-14 days and patients
often experience more than one pericarditis attack.
• Pericardial attack follows a benign course, with no
sequelae .

• 3.6% of patients have pericardial
effusion during attacks.
• It was observed that the amount of
effusion determined in this study
was around 5 mm on average.
• According to the current data, FMF
involves the pericardium less
compared with other serosal
membranes, and this finding appears
as a relatively later clinical finding
of the disease may cause pericardial
thickening, and fluid is not expected
in massive amounts.

Other CVS findings:
• early atherosclerosis is
observed .
• Various biomarker studies
in FMF have
demonstrated findings of
endothelial cell damage
both during and between
attacks.

Renal findings other than
amyloidosis

• In 22% of FMF patients, defined kidney problems other
than amyloidosis.
• These include temporary or permanent haematuria
and/or proteinuria, recurring acute pyelonephritis,
tubulointerstitial nephritis and glomerulonephritis (GN).
• However, vasculitic manifestations that accompany FMF
may also cause different types of kidney involvement.
• Various types of GN such as diffuse proliferative,
membranous and mesangioproliferative GN may occur
during the course of FMF.
• Some researchers have suggested that colchicine
prevents glomerular disease, and that the irregular use
of this drug triggers GN attacks .

Dermal findings:
• Various rashes have been
defined during the course of
FMF.
urticaria, diffused
erythema on the palms and
soles, subcutaneous nodules.
• An updated review of FMF
angioneurotic oedema, pyoderma,
Raynaud’s phenomenon, dermal
findings related to accompanying
vasculites .

1-Inflammation of the tunica
vaginalis,
= which is an extension of
the peritoneum, may lead to
acute scrotal attack.
=This mostly occurs in children
and young adults.
=It is usually one-sided.
Other clinical findings:

• CNS
findings are rare, and have
usually been reported as
case reports. Some
observational studies have
investigated the
relationship between FMF
and multiple sclerosis, and
have suggested that this
condition is seen 2 : 4 fold
more in FMF patients than
in the normal population

• Eye is rare. There are
publications, usually as
case reports, of findings
of eye involvement,
scleritis, pre-uveitis,
pan-uveitis, papillitis .

• The most important factors determining the prognosis of
FMF are the development of amyloidosis and subsequent
progression to end-stage renal failure of the patient.
• The most important factor in the development of amyloidosis
is the increase in production of the SAA protein, which is
synthesised in the liver . Increased synthesis of this
insoluble protein, and hence decreased elimination of it, leads
to accumulation of the molecule in extracellular areas and
the development of amyloidosis .
• In the pre-colchicine period, in FMF patients aged 40 years
and above, the incidence of amyloidosis has been reported to
be at quite high levels of 60-75%.

• amyloidosis complications are
still a problem, especially in
communities where the disease
is common.
• Although FMF carries a
potential risk of amyloidosis,
not everyone with FMF
develops amyloidosis.
• The incidence of amyloidosis
has decreased markedly with
the regular use of colchicine.

Increase the incidence of amyloidosis:
1-Amyloidosis in FMF patients who are
homozygous for the M694V mutation in the
MEFV gene. performed a study conducted on
2246 patients,
and reported that FMF patients who are
M694V homozygotes carry a 6-fold risk of
amyloidosis compared with FMF patients
carrying other MEFV gene mutations.
2-male gender,
3-family history of amyloidosis.

Complication of amyloidosis
• Amyloid structures first accumulate in the spleen, liver and
kidneys, and then in various tissues such as testicles, adrenal
glands, the gastrointestinal system and the nervous system.
1- The development of nephrotic syndrome and renal failure.
2-Malabsorption and diarrhoea
3-Storage of amyloid in the testicles can cause azoospermia
and infertility.
5- cardiac failure can be seen as a result of cardiac storage.
6-Storage in joints can lead to amyloid arthropathy

Diagnosis
• All patients followed up with the
diagnosis of FMF should also be
regularly examined for
amyloidosis by urinalysis.
• (Tissue diagnosis can be
required in patients with
proteinuria between attacks ).
• Renal biopsy is the most
sensitive method 88%.
• Rectal biopsy is less
sensitive,less invasive 75%,

• bone marrow biopsy
and fat tissue biopsy
75%..
• gingival biopsy
material is 19%.

Relationship between FMF
and Vasculitis
• Studies have found that vasculites such
as polyarteritis nodosa (PAN) and
Henoch-Schonlein purpura (HSP) are
more common compared with the normal
population.
• According to some researchers,
Behçet’s disease (BD) is also more
common in FMF

Polyarteritis nodosa
• is a vasculitis that causes
necrotising inflammation in
small and medium-sized
arteries.
• the incidence of PAN in
FMF has increased
approximately 200 times.

• Classic PAN usually emerges at ages
40-60 years. However, FMF-related
PAN occurs at younger ages .
• Classic PAN is usually seen in men,
FMF-related PAN is seen equally in
men and women.
• spontaneous perirenal hematoma, which
is rarely seen in classic
PAN,accompanies almost half of PAN
cases with FMF .
• It has been reported that FMF-related
PAN cases follow a better course.

Henoch-Schonlein purpura
• Henoch-Schonlein purpura is a
vasculitis of small vessels that
involves skin, kidneys, joints and
the gastrointestinal system, and
is the most common vasculitis of
childhood.
• the incidence of HSP
accompanying FMF 2.7-7.2%.
• the incidence of this vasculitis
has increased almost 4-fold.

Behçet’s disease
• some studies have reported
that the incidence of BD
increases in FMF.
• (BD) is also more common in
FMF; however, this
relationship is less common
than that observed with PAN
and HSP

Reproductive System and Pregnancy
in FMF

• As FMF especially affects individuals
in fertile age groups, it raises various
concerns among both patients and
doctors regarding reproduction and
pregnancy.
1- can cause infertility.
2- abortion or premature birth .
3- teratogenic effect of colchicine.

• In a study conducted in
Israel, Italy infertility was
reported in 1/3 of fertile
women with FMF not
getting treatment for their
disease (ovulatory
dysfunction and peritoneal
adhesions)
Female infertility

• the majority of infertile
women in this group
consisted of women who
had not been receiving
colchicine treatment
• peritoneal adhesions can
be decreased with
colchicine treatment.

• male infertility can be
increased in FMF
(inflammation of the tunica
vaginalis can lead to testicular
insufficiency or amyloidosis),
negatively affect
spermatogenesis.
• Semen analysis may be
suggested for men who have
amyloidosis and want to have
children.
Male infertility

Pregnancy
• the incidence of spontaneous
abortions before colchicine
treatment is around 25-30% .
• This is probably because FMF
attacks (both peritonitis and
fever) cause or increase uterine
contractions.
• Additionally, some studies have
reported that premature births
and spontaneous abortions are
also increased in patients
treated with colchicine.

• the incidence of
attacks may increases
during pregnancy.

Teratogenicity
• This drug acts on the microtubular
structure of cells. Therefore,
colchicine use may affect various
cellular processes such as mitosis.
• Trisomy in the children of women using
colchicine in some case presentations
have resulted in serious concerns on
this issue,
• As a result, the manufacturing
company has added a statement to the
package leaflet stating that it should
not be used during pregnancy .

• So physicians recommen the
discontinuation of colchicine
treatment for at least 3 months
before pregnancy.
• Some physicians have continued with
this drug, suggesting that the
frequency of abortion increased due
to the non-use of colchicine,
however,they recommended
amniocentesis and karyotyping for
their patients in the 5th gestational
month because of the possibility of
foetal malformation .

• Subsequent animal studies
have found that colchicine
did not result in any
chromosome aberrations .
• No difference in
cytogenetic abnormalities
was observed in patients
taking colchicine during
pregnancy compared with
those not taking colchicine.

• This attracted attention because some
animal studies have reported the toxic
effect of colchicine on sperm .
• In fact, the colchicine dose used in these
studies was 30- to 50-fold greater than
the human dose.
• In addition, various studies have reported
that there was no abnormality in the
hormone values and sperm counts of
patients on regular colchicine treatment

Lactation and postpartum period
• Colchicine may be excreted into breast milk.
• Studies have reported that the drug reached
the maximum level in breast milk 1-2 hours
after administration. On the other hand,
when the amount passed to the child was
analysed, it was observed to be only 1/10 of
the maternal dose.
• Accordingly, it was suggested that
breastfeeding is safe in women taking
colchicine.
• Available data show that breastfeeding does
not increase the frequency of episodes

Diagnosis of Familial Mediterranean
Fever

• Diagnosed clinically. People with an appropriate ethnic
origin, with recurrent findings and fever accompanied by
serositis ongoing for 1-4 day are diagnosed with FMF.
• In the past, various criteria were suggested for
diagnosis. One of the most commonly used criteria
includes.
• the Tel-Hashomer criteria and diagnosis sets
recommended by Livneh et al.
• According to Tel-Hashomer, two or more major or one
major plus one minor finding was sufficient for FMF
diagnosis

• Genetic diagnosis
tests can be used to detect MEFV
mutations that are frequently observed in
patients with symptoms suggesting FMF but
without a certain diagnosis.
• In countries where the disease is observed
frequently with an accordingly high rate of
carriers, the presence of two mutations in
the MEFV gene is interpreted in favour of
the disease.

• However, the initiation of colchicine
treatment (1.5 mg/day; 6-12 months) is
recommended for cases with no detected
mutations or with a single mutation.
• Then, colchicine is discontinued and the
response is evaluated in these cases. Any
response to treatment and occurrence of
episodes after discontinuation is evaluated in
favour of FMF.

• In some situations, there may be cases
without any clinical signs of FMF which were
studied for MEFV mutation analysis for
another reason.
• Concerning the cases without clinical signs,
the presence of a single or even a double
mutation in the MEFV gene does not result in
a treatment indication for these patients.
(It is recommended to follow-up the cases)

• No laboratory tests specific to FMF.
• Acute phase markers such as (ESR), CRP,
fibrinogen and serum amyloid A(SAA) are
frequently increased during episodes.
• Among these tests, CRP was reported to
increase during almost every episode,
accompanied by an increase in
ESR 90%, fibrinogen 60% and leukocyte
50%

• It was reported that there was
no significant change in platelet
levels in the acute episode
period.
• CRP renain higher than normal
in 50% of the cases within
inter-episode period, called the
subclinical period

• SAA levels, which are
considered to be related to
amyloidosis, were reported
to be high in nearly 30% of
cases in the inter-episode
period.
• It was reported that levels
of IL-6, increased during
the episode.
• IL-1, has been studied

• Thus, the levels of RF,ANA, anti-
CCP in patients with FMF showed no
difference between patients and
healthy control groups .
• a slight increase in both direct and
indirect bilirubin levels in nearly 25%
of cases during episodes, and this
was reduced to normal limits in the
subclinical period .
• transaminases were normal.

• Urinalysis was performed both
during episodes and in the inter-
episode period in, and it was
reported that
transient haematuria and
proteinuria might occur during
episodes .
• Presence of occult blood in faeces
in nearly 50% of cases during
episodes. (increase in vascular
permeability during episodes) .

The targets in the treatment
1-treatment of acute episodes
2- prevention of episodes.
3- suppression of subclinical inflammation in the inter-
episode period.
4- prevention of amyloidosis development and stopping
progression in amyloidosis cases.
5- treatment of other clinical findings accompanying FMF

• Colchicine has been used in
the treatment of FMF since
the 1970s and still.
• The efficacy of colchicine in
preventing acute episodes has
been demonstrated in various
randomized controlled studies.

• Dose:0.02-0.03 mg/kg/day
maximum:2mg/day
in 1-2divide
• It is also recommended to give
the total dose once and divide the
dose in case of side-effects.

It was reported
that
with the use of an
appropriate colchicine
dose,
1-complete remission was
in 60%.
2-partial remission was
achieved in 30%.
3-No response 10% of
patients
4- no amyloidosis
complications developed
in the cases using regular
and appropriate doses of
colchicine

5-In the cases who developed amyloidosis but did
not progress to end-stage renal failure,
disease progression and the decrease in
proteinuria was reported with the use of
colchicine at a dose of 1.5 mg or higher.
6-In cases undergoing renal transplantation, it
was recommended to use 2 mg/day colchicine
if tolerated by the patient, without taking the
clinical symptoms into consideration.
7-In cases with serious renal failure (GFR<10
mL/min), the colchicine dose should be reduced
by 50% because of possible colchicine toxicity.

• The first action in cases with a
suspected lack of response to
colchicine is to evaluate drug
compliance.
• In conclusion, colchicine is an
indispensable drug for the
treatment of this disease. Even if it
does not reduce FMF episodes to
the desired level, the drug should
not be discontinued because of its
protective effect against
amyloidosis.
Resistant to, or intolerant
of colchicine.

Alternative therapies
• In several studies with a limited number of cases were
tested for the treatment of acute episodes.
1- a single intravenous dose of 40 mg of
methylprednisolone administered in the initial phase of
an FMF episode was significantly more efficient than
placebo in reducing symptoms.
2-In some case studies, interferon alpha treatment
administered in the early phase of an episode had
partial efficacy.
3- IL-1 receptor antagonist

• According to the data from case
presentations,it was reported that anakinra
(a human IL-1 receptor antagonist binding
competitively to IL-1α and IL-1β) and
canakinumab (an anti-IL-1β monoclonal
antibody) treatments had a positive effect
on both the development and the intensity of
episodes.
• this drug was reported to significantly
reduce episode frequency compared with
placebo.

4-Anti-tumour necrosis factor (TNF)
drugs were effective in reducing episode
frequency in patients unresponsive to
colchicine,
• Colchicine treatment should be
maintained while administering
alternative treatments to colchicine-
resistant patients.

Ttt FMF episodes
• As there is no effective therapy for
acute episodes, supportive therapies
such as bed rest, paracetamol or NSAD
can be administered.
• It was suggested that increasing the
colchicine dose during an episode did not
provide any benefit and might even lead
to diarrhoea, resulting in the worsening
of gastrointestinal complaints

Tack home message
• (FMF) is a hereditary autoinflammatory disorder
characterised by acute attacks of fever and serosal
inflammation.
• FMF primarily affects Jewish, Armenian, Turkish, and
Arab populations.
• The disease is accompanied by a marked decrease in
quality of life due to the effects of attacks and
subclinical inflammation in the attack-free periods.
• Untreated or inadequately treated patients run the risk
of amyloidosis, which is an important cause of morbidity
and mortality

Fmf tricks in 20 m

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