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TRIGGERS FOR ATTACKS IN FAMILIAL MEDITERRANEAN FEVER: ARE THERE ANY REGIONAL
OR ETHNIC DIFFERENCES?
CEBICCI HUSEYIN1, AYKAC CEBICCI M2, SAHAN M3, GURBUZ S1, KARACA B1, KARAKUS A3, TOMRUK SUTBEYAZ S2, SUNKAK S2
1Emergency Medicine Department of Kayseri Training and Research Hospital, Kayseri - 2Department of Physical Therapy and
Rehabilitation of Kayseri Training and Research Hospital, Kayseri - 3Department of Emergency Medicine of Medical Faculty of
Mustafa Kemal University, Hatay, Turkey
Introduction
Familial Mediterranean Fever (FMF) is an
autosomal recessive disorder which is characterized
by recurrent episodes of fever and inflammation
including peritonitis, synovitis and pleuritis accom-
panied by pain(1-8). The etiology of FMF has not been
fully elucidated(3-9). FMF mostly affects populations
of the Mediterranean basin and particularly
Armenians, Turks, Arabs and North African Jews(1-3,8).
FMF onset occurs at an early age and mani-
fests itself with pain in the abdomen or chest, joint
pain and fever episodes(9). The most common clini-
cal symptoms are fever and peritonitis(2,3,10).
Abdominal pain is the most prevalent clinical find-
ing which occurs in 95% of patients(3). Febrile,
inflammatory episodes are usually treated with non-
steroidal anti-inflammatory drugs(1). Colchicine is
used for prevention of FMF attacks(1,7,8,11).
The quality of life is diminished during attacks
due to pain and sleep deprivation. Between the
attacks patients seem perfectly healthy.
Unpredictable nature of attacks and variable dura-
tion and frequency of attacks suggest the presence
of some external factors(9). FMF attacks have been
associated with anxiety and depression(12). Exposure
to cold, excessive physical activity, stressful life
events, high-fat diet and menstrual periods were
reported to trigger the attacks(9,13). Exposure to cold,
emotional stress, fatigue and menstruation were
Acta Medica Mediterranea, 2014, 30: 1349
ABSTRACT
Introduction: Familial Mediterranean Fever (FMF) is an autosomal recessive disorder which is characterized by recurrent
episodes of fever and inflammation including peritonitis, synovitis and pleuritis accompanied by pain.The present study was conduc-
ted with the aim to determine the triggering factors of FMF and investigate whether there are any differences between two regions
with different geographical characteristics with respect to triggers of attacks in FMF patients admitting to the emergency room with
an episode of abdominal pain.
Materials and methods: The study was planned as a prospective, two-site study to be conducted in Kayseri and Hatay.
Triggers of attacks were investigated for patients previously diagnosed with FMF who admitted to the emergency room with an episo-
de of abdominal pain.
Results: A total of 75 patients were enrolled in the study including 40 in Kayseri group and 35 in Hatay group. Kayseri group
had a predominance of female patients and Hatay a predominance of male patients. Emotional stress, excessive physical activity,
menstruation and exposure to cold were found to trigger FMF-associated abdominal pain episodes in Kayseri group, whereas emo-
tional stress and excessive physical activity were predominant triggers of attacks in Hatay group.
Conclusion: FMF attacks were found to be associated with emotional stress and excessive physical activity in both study grou-
ps. Excessive physical activity, menstruation and exposure to cold were significantly more likely to trigger attacks in Kayseri group
compared to Hatay group.
Key words: Turks, Arabs, Familial Mediterranean Fever, precipitating factors, abdominal pain.
Received May 18, 2014; Accepted September 02, 2014
found to be triggering factors for serositis. In the
same study, prolonged standing, extended journey
and fatigue were found to trigger musculoskeletal
symptoms(13). There is one study which suggested
that menstrual periods alone do not trigger attacks
but other concurrent factors are also present(8). A
study by Akar et al. found that while menstrual
periods could trigger FMF attacks, pregnancy may
actually have a protective effect against develop-
ment of attacks(14).
A number of studies have been conducted
about the relationship between FMF attacks and
genetic background (eg., gene mutations) or labora-
tory parameters (eg., vitamin D, plasma serotonin,
serum soluble Fas ligand and Fetuin-A levels)(13,15-19).
The estimated prevelance of FMF in Turkey is
1/1000 according to the Turkish FMF study
group(20).
We planned the present study to determine the
triggering factors of FMF and investigate whether
there are any differences between two regions with
different geographical characteristics with respect
to triggers of attacks in FMF patients admitting to
the emergency room of Kayseri Trainingand
Research Hospital (KTRH) (in the central
Anatolian region) and Mustafa Kemal University
Medical Faculty Hospital (MKUMFH) (in the
Mediterranean region) with an episode of abdomi-
nal pain.
Materials and methods
This was a prospective, two-site study. KTRH
is located in the city of Kayseri in the central
Anatolian region. MKUMFH is located in the city
of Hatay in the Mediterranean region near the
Syrian border. The study was approved by the local
ethics committee and was in accordance with the
World Medical Association Declaration of Helsinki
(Seoul 2008). Informed consent forms were signed
by all the patients enrolled. Patients 18 years of age
and older who admitted to the emergency rooms of
KTRH and MKUMFH during 1-year period
(January 2013- December 2013) with an episode of
abdominal pain were enrolled in the study if they
had been previously diagnosed with FMF by
rheumatologists and physical therapy and medicine
specialists. The patients with acute gastroenteritis,
urinary tract infections, acute appendicitis and acute
cholecystitis were excluded.
Hereafter, patients recruited in KTRH will be
referred to as Kayseri group and those recruited in
MKUMFH as Hatay group. Age, gender, duration
of disease, family history of FMF, medication use
and frequency of attacks were recorded for all
patients. Patients were questioned for factors which
we considered as potential triggers of attacks
including excessive physical activity (sports, heavy
working conditions), emotional stress, menstrua-
tion, extended journey, high-fat diet, exposure to
cold, trauma (requiring use of analgesics), infection
(any infection that necessitated therapy) within the
previous week. Properties of potential triggering
factors shown in Table 1.
Data were analysed using International
Business Machines (IBM) Statistical Package for
the Social Sciences (SPSS) 21 software package
(This program is licensed from under KTRH net-
work). Unless stated otherwise, values were
expressed as mean ± standard deviation (x± sd),
mean (minimum-maximum) or percentage (%). For
comparisons of categorical variables between
groups, chi-square test was used for qualitative data
and independent-t test for quantitative data.
1350 Cebicci Husein, Aykac Cebicci et Al
Triggering factors* Properties For example
Excessive physical
activity
Prolonged activities (more
than 30 minutes) causing
excessive sweating
Jogging, brisk walking for
an extended period of time,
climbing stairs with a heavy
load, heavy household cho-
res, fast-paced dancing
Emotional stress
Loss of loved ones, job
change, financial problems,
job interviews, exams
Menstruation
Extended journey Nonstop journey for more
than 3 hours
High-fat diet Consumption of more than
3 servings
Beef, other meats, butter,
mayonnaise, eggs, cheese,
milk, popcorn, fried potato,
cream, ice cream, cakes
Exposure to cold
Having been exposed to 4
°C or colder temperatures
for more than 1 hour on 3
occasions during the last
week
Trauma Requiring use of analge-
sics
Infection Any infection that necessi-
tated therapy
Table 1: Properties of potential triggering factors of
attacks.
*within the previous week of attack.
Results
A total of 75 patients were recruited in the
study (n=40 in Kayseri group and n=35 in Hatay
group) who admitted to the emergency room with
an episode of abdominal pain.
The mean age of patients was 38.7 ± 12.6
years for Kayseri group and 33.1±12.1 years for
Hatay group. There was no statistically significant
difference between the two groups in age (t:1.95;
p=0.06). Kayseri group consisted of 27 (67.5%)
females and 13 (32.5%) males and Hatay group
consisted of 14 (40%) females and 21(60%) males.
With respect to gender, there were statistically sig-
nificantly more female patients in Kayseri group
and statistically significantly more male patients in
Hatay group (χ2:5.69; p=0.01). The mean duration
of disease was 6.25 years in Kayseri group and 5.34
years in Hatay group (the difference was not statis-
tically significant, p=0.16). When both groups were
compared for the frequency of attacks (number of
attacks per year), the mean number of attacks was
8(1-24) in Kayseri group and 7.4(1-24) in Hatay group
with no statistically significant difference (p=0.51).
When compared for family history of FMF (FMF in
the first-degree relatives ie., mother, father or sib-
ling), 25 (62.5%) patients in Kayseri group and 16
(45.7%) patients in Hatay group were found to have
family history of FMF (not statistically significant
different; p=0.14). Patients in both groups (n=38 in
Kayseri group (95%) and n=32 in Hatay group,
91.4%) had an episode of abdominal pain while
receiving colchicine therapy (not statistically signif-
icant different, p=0.53). Demographic data of
patients are shown in Table 2 for both groups.
Risk factors that triggered abdominal pain in
FMF patients were excessive physical activity
(n=27, 67.5%), emotional stress (n=30, 75%), men-
struation (n=17, 42.5%), extended journey (n=1,
2.5%), high-fat diet (n=1, 2.5%), exposure to cold
(n=19, 47.5%) and infection (n=1, 2.5%) in Kayseri
group. Triggering factors in Hatay group were
excessive physical activity (n=13, 37.1%), emotion-
al stress (n=24, 68.6%), menstruation (n=5, 14.3%),
high-fat diet (n=2, 5.7%), exposure to cold (n=1,
2.8%) and infection (n=1, 2.8%). When Kayseri
and Hatay groups were compared for risk factors
triggering the attacks, excessive physical activity
(χ2:6.91; p=0.009), menstruation (χ2:7.16;
p=0.007) and exposure to cold (χ2:19.02; p=0.001)
were statistically significantly more common in
Kayseri group. There was no statistical difference
between the two groups in other risk factors.
Greater occurrence of attacks triggered by menstru-
al periods in Kayseri group can be explained by the
higher number of female patients in that group.
Exposure to cold was a more common triggering
factor in Kayseri group compared to Hatay group
due to geographical and climate differences
between these two regions. The risk factors trigger-
ing the attacks are shown in Table 3 for study
groups.
There were a total of 41 (54.7%) female and
34 (45.3%) male patients. When risk factors were
analysed with respect to gender, excessive physical
activity was found to be a trigger in 22 females
(53.6%), emotional stress in 31 (%75.6), menstrua-
tion in 22 (53.6%), high-fat diet in 1 (2.4%) and
exposure to cold in 16 (39%) female patients.
Triggers for Attacks in Familial Mediterranean Fever: Are there any regional or ethnic differences? 1351
Kayseri
(n=40)
n(%), mean±sd,
mean (min-max)
Hatay
(n=35)
n (%), mean±sd,
mean (min-max)
P value
Age 38.7±12.6 33.1±12.1 0.06
Gender
Male 13(32.5) ‡ 21(60.0) † 0.01*
Female 27(67.5) ‡ 14(40.0) †
Duration of disease (years) 6.25(1-20) 5.34(1-27) 0.16
Frequency of attacks
(number of attacks/year) 8(1-24) 7.4(1-24) 0.51
Family history of FMF 25(62.5) 16(45.7) 0.14
Colchicine users 38(95.0) 32(91.4) 0.53
Table 2: Demographic data of patients by groups.
*Statistically significant, p value: <0.05; FMF: Familial
Mediterranean Fever; †: Indicates a statistical difference com-
pared to Kayseri group; ‡: Indicates a statistical difference
compared to Hatay group.
Kayseri
(n=40)
Hatay
(n=35) P value
Excessive physical activity 27 (67.5) ‡ 13 (37.1) † 0.009*
Emotional stress 30 (75) 24 (68.6) 0.53
Menstruation 17 (42.5) ‡ 5 (14.3) † 0.007*
Extended journey 1 (2.5) 0 0.34
High-fat diet 1 (2.5) 2 (5.7) 0.47
Exposure to cold 19 (47.5) ‡ 1 (2.8) † 0.001*
Trauma 0 0
Infection 1 (2.5) 1 (2.8) 0.92
Total 40 (100) 35 (100)
Table 3: Risk factors triggering the attacks by study
groups.
*Statistically significant, p value <0.05
†: Indicates a statistical difference compared to Kayseri group.
‡: Indicates a statistical difference compared to Hatay group.
Among male patients, excessive physical activity
was found to be a trigger in 18 (52.9%), emotional
stress in 23 (65.7%), extended journey in 1 (2.9%),
high-fat diet in 2 (5.9%), exposure to cold in 4
(11.7%) and infection in 2 (5.9%) males. When risk
factors were analysed with regard to gender, expo-
sure to cold was statistically significantly more
prevalent in the female gender (χ2:7.06; p= 0.008).
This may be explained by the greater number of
female patients in Kayseri group and also differ-
ences in climate and geographical conditions. There
was no statistically significant difference between
two genders in other risk factors. Menstruation was
not included in the risk factor analysis of two gen-
ders. Also, 17 out of 22 females who were menstru-
ating at the time of attacks had other concomitant
external triggers (particularly excessive physical
activity and emotional stress). The risk factors trig-
gering attacks are shown in Table 4 by gender.
Discussion
FMF is an autosomal recessive disorder which
is characterized by recurrent episodes of abdominal
or chest pain, arthralgia, and fever(1-4). FMF is
caused by mutations in FMF gene (MEFV), which
encodes pyrin. Mutations in the MEFV gene are
cause uncontrolled neutrophil activation and
inflammation(21). The most common clinical symp-
toms are fever and peritonitis(2,3,10). However it is
still unknown what triggers or ends periodical
attacks. Unpredictable nature of attacks and vari-
able duration and frequency of attacks suggest the
presence of some external factors(9).
In the present study, we aimed to determine
whether there are any differences between two
regions of the same country with different climate
conditions (central Anatolian and Mediterranean
regions) in the external triggers of FMF-associated
abdominal pain attacks.
Previous studies have found that FMF attacks
were associated with anxiety and depression(9,12,13).
In a study by Giese et al.(22) the prevalence of anxi-
ety among Turkish FMF patients residing in
Germany was found to be greater than that of
healthy Turkish people also residing in Germany
but there was no difference between Turkish FMF
patients living in Germany and Turkish FMF
patients living in Turkey in the prevalence of anxi-
ety. In the present study, attacks were highly associ-
ated with emotional stress in both groups but there
was no significant between-group difference.
As shown by several studies, excessive physi-
cal activity can also trigger FMF attacks(9,13).
Consistently, in the current study excessive physical
activity triggered FMF attacks. Additionally, exces-
sive physical activity was significantly more com-
monly triggered an FMF attack in Kayseri group
compared to Hatay group.
Exposure to cold triggers FMF attacks(9,13). In
the present study, we found that exposure to cold
more commonly triggered FMF attacks in Kayseri
group compared to Hatay group, particularly
because of different climate conditions (Kayseri is a
colder city than Hatay).
A number of studies reported that menstrual
attacks may trigger FMF attacks(9,13). But there is a
study which suggested that menstruation alone
might not be sufficient to trigger attacks and other
factors may be involved(8). In the current study,
menstrual period was found to be an external trig-
ger for an FMF attack. Also, similar to what was
found by Ben-Chetrit et al.(8), there was a coexis-
tence of menstrual periods with other external trig-
gering factors (emotional stress and excessive phys-
ical activity) in the present study.
Extended journeys and high-fat diets may trig-
ger FMF attacks(9,13). Contrastingly, in our study,
extended journey and high-fat diet triggered FMF
attacks in a small number of patients. Similar to
Karadag et al.’s study(13), trauma and infection were
questioned as potential triggering factors but while
infection was found to trigger attacks in a few
patients, none of the attacks were triggered by trau-
ma.
1352 Cebicci Husein, Aykac Cebicci et Al
Females
(n=41)
Males
(n=34)
P value
0.28
Excessive physical activity 22(53.6) 18(52.9) 0.95
Emotional stress 31(75.6) 23(65.7) 0.44
Menstruation§ 22(53.6) 0
Extended journey 0 1(2.9) 0.26
High-fat diet 1 (2.4) 2(5.9) 0.44
Exposure to cold 16 (39.0) ‡ 4(11.7) † 0.008*
Trauma 0 0
Infection 1 (2.4) 2 (5.9) 0.11
Total 41 (100) 34 (100)
Table 4: Risk factors triggering the attacks by gender.
*Statistically significant, p value <0.05
†: Indicates a statistical difference compared to females.
‡: Indicates a statistical difference compared to males.
§:Menstruation were not included in the gender-based analysis
as a risk factor.
Conclusion
FMF attacks were more prevalent among
females in Kayseri group and among males in
Hatay group. This may be explained by the gene
mutations or predominance of Turkish residents in
Kayseri and of Arab residents in Hatay. In both
groups, emotional stress was the most common
external trigger of attacks followed by excessive
physical activity. Also, menstruation and exposure
to cold were two additional prominent external trig-
gers of attacks in Kayseri group.
Excessive physical activity, menstruation and
exposure to cold were more likely to trigger attacks
in Kayseri group compared to Hatay group.
The major limitation of this study was the fail-
ure to evaluate patients for gene mutations.
Further multi-centre, large-scale studies with
greater numbers of patients involving gene muta-
tion analysis are needed to identify triggering fac-
tors for FMF attacks in populations with different
ethnic backgrounds and in different regions.
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_________
Correspoding author
CEBICCI HUSEYIN,MD
Emergency Medicine Specialist
Department of Emergency Medicine, Kayseri Training and
Research Hospital,
38010, Kayseri
(Turkey)
Triggers for Attacks in Familial Mediterranean Fever: Are there any regional or ethnic differences? 1353
