Clinical report Eur J Dermatol 2008; 18 (4): 452-6

Zeynep DEMIRCAY1 Predictive factors for acne flare during

Sadiye KUS2
Haydar SUR3
1
Department of Dermatology, Marmara
University School of Medicine, Istanbul,
Turkey
2
Department of Dermatology,
Acibadem Hospital, Istanbul, Turkey
3
Department of Health Management,
Marmara University Health Education
Faculty, Istanbul, Turkey
Reprints: S. Kus
<sadiye.kus@anadolusaglik.org>
Article accepted on 27/2/2008
isotretinoin treatment
Flare of acne is common at the beginning of isotretinoin treatment.
However, severe flare is rare. Multiple comedones, male gender and
young age are reported as promoting factors. However, detailed infor-
mation is still limited. Our aim was to investigate the incidence, types
and course of acne flare and the predictive factors for its occurrence. 244
patients were enrolled. Acne grade was defined according to global acne
grading system (GAGS) score. Flare was classified according to the
increase in number of inflammatory nodules and treatment requirements
of the patients. Risk factors (age, sex, duration of acne, basal acne grade,
baseline numbers of comedones, papule-pustules, nodules, hyperandro-
genism, and presence of sinuses) were investigated. 161 patients com-
pleted the study. 79 patients (32%) had facial and/or truncal flare. Flare
was mild in 18% (n = 44), moderate in 10% (n = 24), and severe in 4.5%
(n = 11) of the patients. For severe flare, male sex, severe acne, GAGS
cut-off score greater than 28, presence of more than 44 facial comedones
and 2 facial nodules and presence of truncal nodules were found to be
predictive. Recognizing predictive factors for severe flare may help to
take early precautions and to prevent severe flares which may result with
permanent scars.
Key words: acne, isotretinoin, flare, acne fulminans, deterioration,
predictive factors

I Material and methods

sotretinoin is an effective agent for the treatment of
acne and has been widely used since it was first intro-
duced in 1979 [1]. Most of the adverse effects due to
isotretinoin are tolerable, treatable, dose dependent and
self-limited [2]. Flare of acne is an expected event at the
beginning of isotretinoin treatment. However, severe flare,
which necessitates treatment with systemic steroids or dis-
continuation of the drug, is rare [3-5]. In fact severe flare
has been reported in less than 6% of the acne patients
treated with isotretinoin [2, 6].
Acne is a distressing condition which may lead to psycho-
social problems such as depression, anxiety and social
inhibition [7-11]. During exacerbations, the inflammatory
acne lesions may become suppurative or ulcerative and
result in permanent scars [4, 12]. Solid facial edema of
acne, an uncommon skin condition, may also occur as a
complication of acne vulgaris [13]. These painful and dis-
figuring lesions of severe flare not only increase the psy-
chosocial impact of acne, but also impair our relationship
with patients. Therefore, it is important to recognize the
predictive factors to be able to introduce early interventions
and to prevent severe flares.
Two hundred forty-four acne patients attending our acne
outpatient clinics between 2003 and 2005 were enrolled to
this prospective study. The study was approved by ethics
committee of Marmara University School of Medicine.
Patients
Patients with moderate to very severe acne, acne with
scarring, acne unresponsive to conventional therapy and
acne associated with significant psychological distress
were included in the study. Patients with symptoms of
hyperandrogenism (menstrual irregularity, hirsutism, an-
drogenetic alopecia, seborrhea and acne with a distribution
on the lower face, mandibular region, or neck) were evalu-
ated for hormonal parameters (free and total testosterone,
luteinizing hormone (LH), follicle stimulating hormone
(FSH), (dehydroepiandrosterone sulfate) (DHEA SO4),
17-0H progesterone, cortisole) and polycycstic ovary on
ultrasound.
Treatment and evaluations
doi: 10.1684/ejd.2008.0441

The presence of multiple large comedones, male gender
and young age are reported to be promoting factors for flare
[4-6]. However, detailed information regarding flare of
acne during isotretinoin treatment is still limited. Conse-
quently, the target of this study was to investigate the
incidence, types and course of acne flare and the predictive
factors for its occurrence during isotretinoin treatment.
The initial dose of isotretinoin was 0.5 mg/kg. At the end of
the first month, the dose was increased to 1 mg/kg. The
dose was reduced in patients who experienced moderate or
severe flare during treatment. Anti-androgen therapy (oral
contraceptives, cyproterone acetate or spironolactone) was
given to female patients who had evident signs of hyperan-
drogenism.

452 EJD, vol. 18, n° 4, July-August 2008

Table 1. Global acne grading system (GAGS) [12]
Location Factor × Grade (0-4)*=
Local score
I) Forehead 2
II) Right cheek 2 Statistical analysis
III) Left cheek 2 Based on the assumptions of the prevalence of flare being
IV) Nose 1 0.06 and the desired half-width 95% confidence interval
V) Chin 1 being 0.03 and estimated power of the study being 90%, the
VII) Chest and upper back 3 sample size was revealed as 242 patients. The analysis was
Global score
0: None
1-18: Mild
19-30: Moderate
31-38: Severe
> 39: Very severe
*0, no lesions; 1, ≥ one comedone; 2 ≥ one papule; 3, ≥ one pustule;
4, ≥ one nodule.
Patients were evaluated by the same investigator (ZD) at the
baseline, at weeks 2 and 4 and then once in every four
weeks until the completion of cumulative dose of isotretin-
oin (120-150 mg/kg). The grading of acne was defined
according to global acne grading system (GAGS) score
(table 1) [14]. Based on GAGS, “0” was considered none,
“1-18” as mild, “19-30” as moderate and “≥ 31” as severe
acne. At each visit, comedones and inflammatory lesions
(papules, pustules and nodules) were also counted on the
forehead, right cheek, left cheek, nose, chin, chest and
upper back.
Flare was classified according to the increase in number of
inflammatory nodules when compared to the previous visit
and treatment requirements of the patients. Flare was
graded as mild, when there were less than 5 new nodules
that resolved without any change in the treatment; moderate
when the number of new nodules was between 5 and 10 and
necessitated dose reduction and/or addition of oral antibi-
otics (azithromycin or clindamycin); severe, when there
were 10 or more new nodules and besides dose reduction or
cessation of isotretinoin, addition of oral steroids were
required (figure 2).
In patients with mild flare no additional treatment was
required and the lesions resolved within four weeks. In
patients with moderate flare the dose of isotretinoin was
reduced to 0.1 mg/kg and an oral antibiotic was added until
the flare subsided. Azithromycin was preferred in majority
of the patients. As previously described in a report on the
treatment of acne [15], the dose of azithromycin was
500 mg/day for three consecutive days (days 1, 2, and 3) for
the first week, two consecutive days (days 1, 2) for the
second week and 500 mg/week (day 1) for the following
2-4 weeks until the flare subsided. In agreement with the
previous reports, our treatment approach in severe flare was
to start systemic steroids and to reduce the dose of isotret-
inoin to 0.1 mg/kg [4-7]. In our patients prednisone was
given at a dose of 0.5-1 mg/kg for two weeks and then
gradually tapered. It was generally continued for two
months until the flare subsided. During this period the dose
of isotretinoin was cautiously increased. Our experience
was that flare frequently relapsed especially if the steroid
dose was reduced or stopped quickly.
Remission has been defined as total clearance of inflamma-
tory acne lesions. The duration of flare was recorded for
EJD, vol. 18, n° 4, July-August 2008
each patient. All of the possible risk factors for flare such as;
age, sex, duration of acne, basal acne grade, baseline num-
bers of comedones, papule-pustules, nodules, hyperandro-
genism, and presence of sinuses were all investigated.
conducted using an intent-to-treat approach including 244
patients who were initially assigned to treatment. All grades
of flare (mild, moderate, severe) and severe flare were taken
into consideration separately for the statistical the evalua-
tion.
The distribution of quantitative data did not generally
match with the normal distribution rules. Thus, the distri-
butions were summarized in terms of median and range
scales rather than mean and standard deviations. Chi square
tests were carried out for proportion comparisons.
Cut off values for age, comedones, papules, pustules and
nodule counts were determined as median values of the
variables. For truncal comedones and nodules, the median
was < 1, so the presence or absence of nodules was used as
a criteria.
Statistical analysis was performed using the SPSS 11.5
software.
Results
There were 136 (56%) female and 108 (44%) male patients.
The median age was 21 (range between 14-46); the median
for GAGS score was 28 (range: 12-43). Thirty-seven (27%)
female patients had hyperandrogenism. 77 (32%) patients
had facial macrocomedones.
From a total of 244 patients, 161 patients completed the
study. Ten patients had side effects that required stopping
isotretinoin (elevated blood liver enzymes in five patients,
elevated blood lipid levels in three patients, headache in one
patient and arthralgia in one patient). The study flow chart is
given in figure 1.
n=244
Patients enrolled to the study
n=161 n=73
Treatment completed Treatment not completed
Lost to follow-up: 54*
Adverse event: 10
Flare: 6
Patient's request: 2
Surgical operation: 1
*19 patients at week 4, 5 patients at week 8, 24 patients at week
12, 3 patients at week 16, 3 patients at week 20
Figure 1. Study flow chart.
453
 Seventy nine patients (32%) had facial and/or truncal flare
(including the patients who left the study due to flare). Flare
was mild in 18% (n = 44), moderate in 10% (n = 24), and
severe in 4.5% (n = 11) of the patients. The distribution of
patients who experienced flare in terms of severity and
location is indicated in table 2.
Severe flare with systemic signs and symptoms was present
in only one male patient.
The median time to flare was 4 weeks (range: 2-16). The
median duration of flare was 5 weeks (range: 2-20). For
severe flare, the median time to flare was 2 weeks (range:
2-12), and the median duration of flare was 8 weeks (range:
2-20) under treatment. The percentage of completion of
treatment was significantly higher (p < 0.05) in patients
who had flare.
Predictive factors for acne flare (mild, moderate, severe) is
Figure 2. Severe flare with inflamed nodules and crusting given in table 3 and table 4 (severe flare). The presence of
papulopustular lesions. severe acne, macrocomedones, truncal nodules and facial
comedones counted as greater than 44 were determined as
the statistically significant patient characteristics that were
Table 2. The distribution of patients who experienced flare in predictive for flare (mild to severe).
terms of severity and location (facial or truncal) For severe flare, male sex, severe acne, GAGS cut-off score
greater than 28, presence of more than 44 facial comedones
Flare Mild Moderate Severe and 2 facial nodules and presence of truncal nodules were
location n (%) n (%) n (%)
found to be the predictive factors.
Facial 42 (18) 21 (9) 6 (3)
Truncal 8 (3) 8 (3) 7 (3) The rate of flare in patients with hyperandrogenism and
without hyperandrogenism was 35.1% and 28.3%, respec-

Table 3. Predictive factors for acne flare (n = 244)

Independent variable Incidence of flare (%) p-value

Sex Female 30 p = 0.899
Male 31
Age < 20 31 p = 0.899
≥ 21 30
Sinus Absent 30 *
Present 80
Acne severity Moderate 7 p = 0.000
Severe 56
Hyperandrogenism Absent 28 p = 0.52
Present 35
Adequately treated hyperandrogenism Absent 29 p = 0.384
Present 40
Macrocomedone Absent 23 p = 0.000
Present 48
Truncal comedone Absent 28 p = 0.405
Present 34
Truncal nodule Absent 24 p = 0.000
Present 53
GAGS score** < 28 17 *
≥ 29 45
Facial comedone count** < 44 27 p = 0.016
≥ 44 47
Facial papule-pustule count** < 20 29 p = 0.489
≥ 20 34
Facial nodule count** <2 26 p = 0.07
≥2 37
Truncal papule-pustule count** <7 29 p = 0.582
≥7 32
*Sinus status and GAGS score cut-off value could not be evaluated due to inadequate distribution.
**Cut-off values.

454 EJD, vol. 18, n° 4, July-August 2008

Table 4. Predictive factors for severe acne flare (n = 244)

Independent variable Incidence of flare (%) p-value

Present
Sex Female 2 p = 0.013
Male 8
Age < 20 3 p = 0.481
≥ 21 5
*
Sinus Absent 3
Present 60
Acne severity Moderate 1 p = 0.005
Severe 12
*
Hyperandrogenism Absent 0
Present 5
*
Adequately treated hyperandrogenism Absent 5
Present 0
Macrocomedone Absent 2 p = 0.40
Present 9
Truncal comedone Absent 2 p = 0.216
Present 7
Truncal nodule Absent 2 p = 0.001
Present 14
GAGS score** < 28 1 p = 0.005
≥ 29 8
Facial comedone count** < 44 1 p=0
≥ 44 19
Facial papule-pustule count** < 20 5 p = 1.00
≥ 20 4
Facial nodule count** <2 1 p = 0.003
≥2 9
Truncal papule-pustule count** <7 3 p = 0.225
≥7 6
*Sinus, hyperandrogenism and adequately treated hyperandrogenism status could not be evaluated due to inadequate distribution.
**Cut-off value.

tively (p > 0.05). Severe flare was only seen in 2 females,
who both had untreated hyperandrogenism.
Discussion
Deterioration of acne at the beginning of oral isotretinoin
treatment is a well known event. Severity of flare varies
among patients [4, 16]. Chivot summarized the flare of acne
as follows [4, 16]:
1. Inflammatory attacks which resolve spontaneously at the
end of the first month.
2. Recurring inflammatory attacks in the following months
that may show a progressive course, especially if the dose
of isotretinoin is increased.
3. Explosive inflammatory attacks seen in the second and
third months in which the clinical picture is similar to acne
fulminans, with or without systemic signs. Such a flare
requires 0.5-1 mg/kg of prednisolone daily for two or three
weeks with gradual tapering thereafter [2, 6].
In our study, we graded flare according to the number of
new inflammatory nodules and the treatment requirements
of the patients, to be able to classify patients more accu-
rately. Regarding the clinical course of patients with differ-
ent grades of flare, our grading system was comparable
with the one defined by Chivot [4, 16].
In the present study, 32% of the patients experienced flare,
beginning at week four and lasting for 5 weeks. Flare was
mild in 18% (n: 44), moderate in 10% (n: 24), and severe in
4.5% (n: 11) of the patients. In most of the patients, flare
was mild and localized on the face. We observed that the
occurrence of flare was related to the presence of severe
acne, macrocomedones, sinus and a high total number of
comedones and nodules.
In the present study, we especially focused on defining the
predictive factors for severe flare, which may be disfiguring
and lead to permanent scars. Severe flare is reported in 3 to
6% of acne patients treated with isotretinoin [2, 6]. Simi-
larly, severe flare was seen in 4.5% of our acne patients.
Clark et al. observed that severe flare developed within the
first 3 to 5 weeks of isotretinoin treatment, while Chivot et
al. reported that it usually had occurred in the second or
third months of the treatment [4, 6]. In our study, despite
treatment, severe flare appeared at week 2 and continued for
8 weeks which is a longer duration than milder intensities
of flare.
The presence of macrocomedones and male sex are re-
ported to be related to severity of flares [4-6]. In our study,
male sex was also an important predictive factor for severe
flare. In fact, severe flare was only observed in two female
patients with untreated hyperandrogenism. According to

EJD, vol. 18, n° 4, July-August 2008 455

our results, the presence of facial macrocomedones and
truncal comedones, severe acne, a high number of facial
comedones and presence of more than 2 facial nodules
were other risk factors for severe flare. Although we could
not find a statistically significant relationship between pres-
ence of sinus and severe flare, we observed that 4 of 5
patients with sinus had flare, three of whom were severe.
Rarely, severe flare with systemic signs simulating acne
fulminans may be observed in association with isotretinoin
treatment [17-20]. Leyden reported that this clinical picture
generally develops in male patients with crusted lesions on
the chest prior to treatment [5]. We had only one male
patient who experienced acne fulminans with fever and
joint pain. His symptoms were managed by reduction the
dose of isotretinoin to 0.1 mg/kg and the addition of sys-
temic antibiotics and 1 mg/kg prednisolone. Prior to
therapy, he had multiple macrocomedones and severe cys-
tic acne.
Severe flare is reported to be more frequent at a dose of
1 mg/kg [5]. We could not evaluate the role of isotretinoin
dose on acne flare because we started with a standard dose
of 0.5 mg/kg in all patients. The pathogenesis of acne flare
during isotretinoin treatment is unknown. Recent data sug-
gests that the mechanism of the inflammatory effect is
complex. It has an anti-inflammatory action by inhibition of
inflammatory cytokines, and a pro-inflammatory action,
probably related to a release of P acnes antigens and/or
antigens of the pilosebaceous follicle. These antigens could
induce intense inflammation, notably by a mechanism
involving super antigens and/or Toll-like receptors. It may
also have a modulating effect on many inflammation factors
[21, 22]. The study of Perkins et al. supported that isotret-
inoin may enhance neutrophil responses to pro-
inflammatory stimuli [23].
Surprisingly, we observed that in patients who experienced
flare, adherence to treatment was better. Since they had
more severe acne, this result was probably due to these
patients’ belief in the necessity of an ongoing treatment.
Conclusion
The results of our study are consistent with the results of the
previous reports in which male sex and macrocomedones
were found to be related with severe flare [3, 5, 6]. In
addition, we observed that presence of truncal comedones,
severe acne, a high number of facial comedones and the
presence of more than 2 facial nodules were the other risk
factors. Recognizing these predictive factors for severe
flare may help us to take early precautions such as the
mechanical extraction of comedones before starting isotre-
tinoin, pretreatment or concomitant treatment with oral
antibiotics or steroids and introduction of isotretinoin in
low doses [2]. These measures would not only increase our
treatment success but also improve patient satisfaction in
those suffering from acne. j
456
Acknowledgements. Financial support: none. Conflict of
interest: none.
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