Contact Lens and Anterior Eye 39 (2016) 431–434

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Contact Lens and Anterior Eye

journal homepage: www.elsevier.com/locate/clae

Effects of topical acne treatment on the ocular surface in patients with

acne vulgaris$
Seray Aslan Bayhana,* , Hasan Ali Bayhana , Emine Çölgeçenb , Canan Gürdala
a
Bozok University Faculty of Medicine, Ophthalmology Department, Yozgat, Turkey
b
Bozok University Faculty of Medicine, Dermatology Department, Yozgat, Turkey

A R T I C L E I N F O A B S T R A C T

Article history: Purpose: To assess the ocular side effects during topical retinoid-antibiotic combination treatment in
Received 28 March 2016 patients with facial acne vulgaris.
Received in revised form 27 May 2016 Methods: Forty-three patients applying topical isotretinoin + erythromycin combination (isotrexin gel,
Accepted 27 June 2016
GlaxoSmithKline) once daily for the treatment of acne vulgaris were enrolled. Full ophthalmologic
examination, Schirmer test (with topical anesthesia), fluorescein break-up time (BUT), corneal
Keywords: fluorescein staining and tear osmolarity measurement with the TearLab system (TearLab Corporation)
Topical treatment
were carried out before and at the end of the first month of the treatment. For evaluation of symptoms
Dry eye
Acne vulgaris
participants completed the ocular surface disease index (OSDI) questionnaire at each visit.
Results: The mean age of the patients was 23.16  3.03 (18–30) years. Mean tear osmolarity increased
significantly from 282.09  8.95 mOsm/L at baseline to 300.39  16.65 mOsm/L after the treatment
(p < 0.001). BUT decreased from an average of 11.93  1.12 s at baseline to 6.65  3.03 s at the end of the
first month (p < 0.001). The OSDI score worsened significantly (5.41  3.65 vs 21.53  12.95, p < 0.001)
and punctate epitheliopathy was seen in 51% of eyes after the treatment. The average Schirmer values
were 13.09  1.90 and 12.41  2.44 mm/5 min before and at the end of the first month of the treatment,
respectively (p = 0.117).
Conclusions: The findings of this study indicate that topical retinoid-antibiotic combination treatment
causes significant signs and symptoms of dry eye. Patients receiving topical treatment for acne should be
evaluated regularly to ensure the timely detection and treatment of pathologic signs on the ocular
surface.
ã 2016 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

1. Introduction treatment regimens with these targets are composed of retinoids

Acne vulgaris is a chronic inflammatory disease of the
pilosebaceous unit resulting from several interacting pathophysi-
ologic factors [1]. Among these, sebaceous gland hyperplasia with
hyperseborrhea, abnormal keratinization with subsequent block-
age of pilosebaceous ducts, bacterial colonisation of hair follicles
by Propionibacterium acnes and inflammation are the most
notable factors that contribute to acne development [2].
The available topical and systemic treatment options (medical
treatment, lasers, light therapy) aim to interrupt the formation of
the non-inflammatory lesions, inflammation, bacterial coloniza-
tion and prevent complications including acne scars. Medical
$
None of the authors has a financial and proprietary interest in any material or
method mentioned and there is no public or private support.
* Corresponding author at: Adnan Menderes Bulvarı, Bozok University Medicine
Faculty, Ophthalmolgy Department, Yozgat, Turkey.
E-mail address: seraybayhan@Hotmail.com (S. Aslan Bayhan).
and antibiotics. Retinoids are important tools in the management
of acne because they act against all major etiologic factors
implicated in acne including abnormal keratinisation, the micro-
comedones (the earliest clinical lesions evolving into either non-
inflammatory comedones or inflammatory papules and pustules)
and are also antiinflammatory [2–4]. Besides this, antibiotics are
known to be the most effective therapy for inflammatory type of
acne but due to potential for bacterial resistance, side effects and to
increase efficacy usually combined therapy with retinoids is
recommended [5].
However, it is certain that some acne vulgaris patients stop
using systemic and/or topical treatment regimens because of the
side effects and due to teratogenicity, caution is advised during
systemic and even topical use of isotretinoin in women of
childbearing age [6,7]. The most common adverse reactions
observed during systemic acne treatment are mucocutaneous
and ophthalmological [8]. Ocular side effects associated with
systemic acne treatment particularly with oral isotretinoin usage

http://dx.doi.org/10.1016/j.clae.2016.06.009
1367-0484/ã 2016 British Contact Lens Association. Published by Elsevier Ltd. All rights reserved.

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432 S. Aslan Bayhan et al. / Contact Lens & Anterior Eye 39 (2016) 431–434
were investigated many times. These undesired ocular side effects
include dry eye, blepharoconjunctivitis, corneal opacities, abnor-
mal meibomian gland secretion, conjunctival epitheliopathy,
photophobia, and teratogenic ocular abnormalities [6–10].
Despite ocular adverse reactions associated with systemic acne
treatment having been evaluated in detail, to our knowledge there
is no study evaluating the effects of topical acne treatment on the
ocular surface. This study was carried out to investigate possible
side effects of a common topical retinoid-antibiotic combination
(isotrexin gel, GlaxoSmithKline) on the ocular surface and to assess
patient symptoms with this treatment.
2. Materials and methods
This prospective study comprised young subjects (aged 18–30
years) who applied to dermatology out-patient department of our
university hospital with facial acne vulgaris. Patients with a
diagnosis of mild to moderate acne, defined as those having 2 and
30 inflammatory and/or noninflammatory lesions with an
Investigator’s Global Assessment score of 2 or 3 were included
after receiving thorough information about the study aim and
procedure and providing their written informed consent.
The study was approved by the local ethical committee and was
performed in accordance with the ethical principles described in
the Declaration of Helsinki.
Patients were excluded if they had nodulocystic lesions,
secondary acne (e.g., chloracne, drug-induced acne), pathological
findings in biomicroscopical examination (e.g., eyelid margin
crusting, eyelid margin thickening, eyelid margin erythema,
conjunctival injection, conjunctival chemosis, filaments on the
cornea, corneal scar), history of refractive surgery, ocular or
systemic disease other than acne, or had hypersensitivity or a
previous allergic reaction to any of the components of the study
drug. Pregnancy was also an exclusion criterion.
Patients in the study applied topical isotretinoin 0.05% + eryth-
romycin 2% combination (isotrexin gel, GlaxoSmithKline) once
daily for the treatment of their facial acne vulgaris. To minimize the
potential risk for overdose subjects were instructed to apply the
assigned study drug using a sufficient quantity (recommended
volume: 2 finger-tip units per application) to cover the entire face
[11].
Full ophthalmologic examination, Schirmer test (with topical
anesthesia), fluorescein break-up time (BUT), corneal fluorescein
staining and tear osmolarity measurement with the TearLab
system (TearLab Corporation) were carried out before and at the
end of the first month of the treatment. BUT was measured using a
sterile fluorescein paper diluted with a nonpreserved, balanced salt
solution. While the patients were looking upward, the fluorescein
paper was touched to the inferior fornix conjunctiva, and the
patients were directed to blink three times. Then the patients look
straight forward without blinking. The tear film was observed
under cobalt blue filtered light of the slit-lamp biomicroscope, the
time elapsed between the last blink and appearence of first break
in the tear film was recorded. Also, slit-lamp examination of
conjunctiva and cornea (which were now stained by fluorescein)
using cobalt blue light was performed to look for signs of dry eye.
To perform Schirmer test and measure the basal tear secretion,
a drop of topical anesthetic agent (0.5% proparacaine hydrochlo-
ride) was instilled to the inferior fornix and excess moisture on the
eyelid margin was dried with a cotton tip applicator. A Schirmer
test strip was placed at the inferotemporal conjunctival fornix after
a few minutes. The amount of wetting was recorded after 5 min.
For evaluation of symptoms participants completed the ocular
surface disease index (OSDI) questionnaire before and at the end of
the first month of the treatment. The OSDI is a questionnaire
including 12 questions, which are subdivided into three groups.
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The first group contains questions about the ocular symptoms of
dry eye syndrome, the second about the ocular symptoms while
watching television or reading a book, and the third group contains
the questions about ocular symptoms induced by environmental
factors.
2.1. Statistical analysis
All data were analyzed using SPSS software (version 16.0 SPSS,
Inc, Chicago). The descriptive statistics were presented as mean
 standard deviation (SD). Only the results from the right eyes
were used for statistical analysis. The paired samples t-test was
used for the comparison between baseline values and the
measurements performed at the end of the first month of the
treatment. A P value less than 0.05 was considered statistically
significant.
3. Results
The study comprised 43 eyes of 43 patients. The mean age of the
patients was 23.16  3.03 (18–30) years. Table 1 summarizes
demographic characteristics of the subjects.
Mean tear osmolarity increased significantly from
282.09  8.95 mOsm/L at baseline to 300.39  16.65 mOsm/L after
the treatment (p < 0.001). At the end of the first month of the
treatment 13 patients (30.2%) had a tear osmolarity spike more
than 305 mOsm/L cut-off value, and 11 of them (25%) also had a
tear osmolarity spike more than 308 mOsm/L cut-off value for dry
eye.
BUT decreased from an average of 11.93  1.12 s at baseline to
6.65  3.03 s at the end of the first month. The OSDI score worsened
significantly (5.41  3.65 vs 21.53  12.95, p < 0.001) and punctate
epitheliopathy was seen in 22 eyes (51%) after the treatment. The
average Schirmer values were 12.84  5.13 and 11.61  4.90 mm/
5 min before and at the end of the first month of the treatment,
respectively (Table 2).
One patient had blepharitis and hyperemia of the lid margin at
the end of the first month of the treatment.
4. Discussion
Topical therapeutic agents are commonly used as the first-line
therapy for the management of mild to moderate acne vulgaris [3].
There is increased evidence supporting the recommendation of a
combination of a topical retinoid plus an antimicrobial agent as
first-line therapy for most patients with acne as a means of
targeting multiple pathogenic features and both inflammatory and
noninflammatory acne lesions [12]. Thus, knowledge of, and
warning of, a common topical retinoid-antibiotic combination
induced side effects is fundamental. In this study, we have
demonstrated for the first time that topical antiacne treatment
induces significant signs and symptoms of dry eye.
Of the ocular side effects associated with systemic isotretinoin
(an ingredient of our study drug), signs and symptoms of ocular
surface alterations are common and up to 30% of patients treated
with this drug complain about dry eyes [13]. Animal data of
histopathological changes in the eyelids caused by systemic
Table 1
Demographic characteristics of the subjects.
Age (years) 23.16  3.03
Sex (female/male) 28/15
Refractive error 0.075  0.84
 S. Aslan Bayhan et al. / Contact Lens & Anterior Eye 39 (2016) 431–434
Table 2
Results of the tear function tests and OSDI scores of the patients.
Parameter Before treatment After treatment
BUT (seconds) 11.93  1.12 6.65  3.03
Schirmer (mm/5 min) 13.09  1.90 12.41  2.44
Tear osmolarity (mOsm/L) 282.09  8.95 300.39  16.65
OSDI score 5.41  3.65 21.53  12.95
BUT, fluorescein break-up time; OSDI, ocular surface disease index.
treatment with isotretinoin includes degenerative changes in the
meibomian gland acini, leading to cell necrosis and a decrease in
the basaloid cells lining the acini walls [14]. It is known that
meibomian gland function depression induces increased evapora-
tion and tear film instability, causing drying and secondary
irritation of the conjunctiva and cornea [15]. In addition, the
lacrimal gland was shown to secrete isotretinoin and that in
patients treated systemically with isotretinoin, the ocular surface
is exposed to the drug via the tear film [16]. Thus, the presence of
isotretinoin and its metabolites in the tear film may also directly
irritate the ocular surface and lead to dry eye.
Although isotretinoin is commonly thought to be a synthetic
retinoid, it is actually a natural derivative of retinoic acid that is
normally present in the human body in small amounts [17].
Previous human percutaneous absorption studies have indicated
that retinoids are minimally absorbed after topical application,
even after multiple applications at doses approximately 12 times
greater than normal daily use, regardless of combination with
chemical sunscreens [18–20]. We also know from the previous
studies that during systemic isotretinoin treatment, eye dryness
was related to the dose used and low-dose treatment reduces both
systemic adverse effects and adverse ocular effects [21]. These are
especially important while interpreting our results because our
patients were using only topical therapy and with topical agents
low systemic absorption which reduces the potential for the
development of ocular adverse effects is expected. But our results
indicate that topical treatment regimen induced tear film
instability and hence dry eye in acne vulgaris patients.
Interestingly, despite such reassuring percutaneous absorption
studies, several published case reports described structural
abnormalities consistent with retinoic acid embryopathy in infants
who exposed to topical retinoids in utero [22,23]. So, some
systemic absorption may also be expected in some circumstances
during topical treatment. Structural differences in skin barrier are
likely to be responsible for the patient’s variable response to
topical therapy [24,25]. Our patients had acne vulgaris, thus their
diseased skin might have been the reason for the potential of
increased systemic absorption and development of ocular adverse
effects. Furthermore, topical retinoid-antibiotic combination
present in sweat running down to the eyelids could contaminate
the conjunctival sac and irritate the ocular surface. Also, absorption
from spills of retinoid-antibiotic gel over the lid margin seems
more likely, because bits of cosmetics can be observed in women’s
tear film.
In this study, we evaluated the effects of a combination drug. A
combination drug was chosed because while prescribing anti-acne
medications, polypharmacy is preferred up to 90–95% [26]. On the
other hand, the antibiotic side of our study drug, erythromycin is
not expected to be responsible from dry eye. Macrolide antibiotics
are also used for the treatment of meibomian gland dysfunction
[27]. However, in recent years it is hypothesized that tetracyclines
and erythromycin exert their anti-acne effects by inhibition of
retinoic acid metabolism in the skin and thus mimic therapeutic
action of retinoic acid [28]. Therefore, application of isotretinoin in
combination with erythromycin may have enhanced skin pene-
tration of isotretinoin.
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433
In the current study, we found a statistically significant
reduction in tear break up time values of the patients and punctate
P value epitheliopathy was seen in 51% of eyes during treatment. There are
<0.001 controversial reports on the effects of isotretinoin on break up
0.117 time. Karalezli et al. and Cumurcu et al. reported a decesead tear
<0.001 break up time, whereas Milson et al. found a normal tear break up
<0.001
time during systemic isotretinoin treatment [10,21,29]. It is known
that individuals with acne vulgaris experience more ocular
diseases and are reported to have instability of tear film as
reflected by a decrease in break up time [30]. To exclude the
baseline dry eye syndrome on tear film changes in our acne
vulgaris patients, we used strict inclusion criteria to enroll patients
with normal tear film function. But, usage of topical antiacne
medication in our inherently susceptible acne patients unbalanced
and destabilized the tear film that in turn caused formation of dry
spots.
Diagnosis of dry eye begins with patient history and the OSDI is
one of the best-validated questionnaires for the evaluation of the
symptoms objectively. Özcura et al. reported that there was a
significant inverse correlation between the OSDI and tear break up
scores [31]. Similarly, though the correlation was not evaluated in
our study, the mean OSDI scores of the patients increased
significantly while break up time values decreased at the end of
the first month of the treatment.
Mathers et al. suggested that clinical symptoms during
isotretinoin therapy are related to decreased meibomian gland
function and consequent increased tear evaporation and tear
osmolarity [32]. Their study was the only study evaluating tear
osmolarity in patients using isotretinoin. The analysis of tear
osmolarity is a valuable objective tool for evaluating the dry eye. In
this study, we used the TearLab osmolarity system which is a
nanotechnology-based, point-of-care testing diagnostic instru-
ment measuring tear osmolarity noninvasively. The most sensitive
tear osmolarity value reported for distinguishing dry eye from
normal is 305 mOsm/L, whereas another more recent study
suggests 308mOsm/L using TearLab Osmolarity system [33,34].
Tear osmolarity measurements of our patients were also increased
significantly during topical antiacne treatment, though the mean
values not reached to dry eye levels.
In the current study, though BUT decreased and tear osmolarity
increased during treatment, there was no significant change in
Schirmer test results. This finding is compatible with those by
Mathers et al. and Bozkurt et al., who also found no significant
changes in Schirmer’s test during systemic antiacne treatment,
hence, an absence of any associated aqueous deficiency [32,35].
The limitations of this study are, first, its short duration of
follow-up. Second, patients’ reports are lacking after discontinua-
tion of treatment, thus our study could not inform us about
reversibility of the signs and symptoms of dry eye. On the other
hand, it has been already reported that all ocular complications
associated with isotretinoin usage manifested within the first 4
weeks of therapy and turned out to be fully reversible after
discontinuation of treatment [10,36]. Third, in addition to active
ingredients (isotretinoin and erythromycin), isotrexin gel also
contains excipients including hydroxypropylcellulose, butylated
hydroxytoluene and anhydrous ethanol. In this study, we only
demonstrated dry eye signs and symptoms induced by isotrexin
gel, and could not clarify which ingredient is responsible from
these signs and symptoms.
5. Conclusion
While limited in size and scope, our study demonstrates for the
first time that topical retinoid-antibiotic combination induces
significant signs and symptoms of dry eye in acne vulgaris patients.
Thus, due to incomplete reporting of adverse effects, patients using
434 S. Aslan Bayhan et al. / Contact Lens & Anterior Eye 39 (2016) 431–434
even topical antiacne treatment should be asked carefully about
dry eye symptoms to protect ocular surface. Based on the effects
showed in our results, larger-scale and longer-term confirmatory
studies seem to be justified.
Conflict of interest
None of the authors has a financial and proprietary interest in
any material or method mentioned and there is no public or private
support
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