ARTICLE
Effective medications are available for treatment of acne, but tolerance
problems may preclude adequate treatment regimens, altering the compliance
of patients. A prime example of this is treatment with topical retinoic
acid which often causes skin irritation [1-3]. An attempt to obtain better
compliance would be to reduce erythema and scaling, as well as to reduce
associated subjective signs such as burning, itching and stinging. A classic
means of achieving this is to combine the retinoid treatment with a moisturizer;
another would be to hydrate the skin directly, by applying water to the
treated sites.
A medical spring water (Avène), which has a low salt content
and an anti-inflammatory activity, has been beneficially used in various
inflammatory dermatoses such as atopic dermatitis [4]. Especially, the
sensorial properties induced by Avène water when applied onto the
skin have been compared favourably with more mineralised waters [5]. It
was therefore hypothesized that topical water might be helpful in amending
retinoic acid-induced irritation in acne patients.
Patients and methods
This was an exploratory, controlled, open labelled, randomised, multicentric
(4 well-trained centers) and two parallel group study, that was performed
during winter time (January to April). The study population included out-patients
with moderate to severe acne, i.e. justifying the use of topical
retinoic acid treatment. Selected patients were male or female, of at
least 12 years of age. Pregnant and lactating women were excluded from
the study. Patients who had been treated with systemic retinoids within
the last 3 months, as well as topical retinoids within the last month
were also excluded. Informed consent was obtained from all patients, and
the project was approved by the ethic committee of one participating medical
center.
According to a computerised randomisation system, one group (control
group) was instructed to apply a 0.05% retinoic acid cream (Retin-A®,
Johnson and Johnson Laboratories, Raritan, New-Jersey) each evening for
28 days on all facial acne lesions. The second group (water group), received
similar instructions to apply retinoic acid cream, but in addition was
asked to spray Avène medical spring water on the entire face ad
libitum, with a recommendation of 4 times a day. All patients were
also given a cleansing bar adapted to acne patients (Ultra-Rich Soap-free
Cleansing Bar, Avène Laboratories, Boulogne, France). At the beginning
of the study, they were informed that if a local tolerance problem occurred,
they should request an extra visit to the investigator, and not reduce
or stop the retinoic acid treatment themselves. The investigator then
could decide either to withdraw the patient if local side effects were
severe, or instead to prescribe an adjuvant non comedogenic moisturiser
(Moisturising Emulsion®, Galénic Laboratories, Boulogne,
France). Tubes and sprays given at the previous visit, were returned to
the investigator. Adverse events were reported during the entire study
period.
Patients were examined on the day of the study inclusion (baseline),
then on day 7 and day 28 (end of treatment). At each of these visits,
signs of local intolerance (scaling, erythema, burning and itching) on
the test areas were scored blindly by the investigators, according to
the following 4-point scale: absent, mild, moderate and severe. Investigators
were requested to report the number of patients who required the adjuvant
emollient moisturiser and the number of days of use, with the help of
the patient diaries. The number of days of actual application of the retinoic
acid cream was counted as a measure of compliance, according to the diaries.
Investigators were also requested to evaluate globally the tolerance of
treatment of each patient, according to a defined 4-point scale (very
good = no sign of irritation during the study; good = mild irritation
for less than 8 days; poor = irritation of moderate severity, or of mild
severity for 8 days or more; very poor = irritation leading to treatment
interruption). Finally, a global evaluation for the evolution of acneic
lesions (papules and pustules, nodules and cysts, comedones and microcysts,
inflammatory scars) was performed, based on a 4-point scale established
on the number of lesions: absent (0), mild (1-9), moderate (10-19), and
severe (20-40+).
Local tolerance between the two groups of patients was analysed using
the Wilcoxon's test. Changes from baseline of acne lesions and treatment
comparison were evaluated by a McNemar test and a Wilcoxon's test, respectively.
This study was investigated under Good Clinical Practise standards.
Results
A total of 70 patients were originally included in the study, as follows:
36 in the water group and 34 in the control group. One patient was lost
to follow up for a study-unrelated reason. Five other patients were withdrawn
on the day 7 visit because of intolerance to treatment; four of these
were in the control group and one in the water group. Data from these
five patients could still be analysed by the LOCF (last observation carried
forward) technique [6]. Compliance with the treatment until the end of
the study was achieved in the remaining 64 patients. Accordingly, 69 patients
were appraisable for analysis and constituted the study population, i.e.
35 patients in the water group and 34 patients in the control group. Baseline
characteristics of the two treatment groups were comparable, as shown
in Table 1. No differences
on baseline as well as end-point values were observed between investigating
centers.
Signs of local irritation in both groups are illustrated in Table
2. Indeed, the water showed a more prominent effect on reducing
scaling from the first week of treatment (p = 0.02, between-group analysis),
and this was maintained through to the end of treatment (p = 0.0002, Table
2A). A beneficial effect of the water was also noted on erythema,
but only in terms of tendency (non significant between the groups at any
of the assessment points, Table
2B). No modulating effects on burning or itching could be observed
with the water in the study (Table
2C and D).
The number of patients that necessitated the adjuvant emollient tended
to be less numerous in the water group, i.e. 15 (43%), compared
to the control group, i.e. 22 (65%, p = 0.07, not significant).
Similarly, the mean number of daily applications (± SEM) of retinoic
acid was 28.97 (± 0.97) days with the water, and 26.03 (± 1.48)
days without (p = 0.16, not significant), and premature withdrawals to
local irritation were lower in the water group (1 patient) than the control
group (4 patients). The overall tolerance observed clinically by the investigators
supported this by demonstrating that the water group showed a better tolerance
profile than that of the control group (p = 0.04, Table
3). Finally, the severity of acne lesions in both groups after
the 28 days of treatment (end of the study) showed a significant improvement
in some components of acne (comedones/mycrocysts, and papules/pustules),
but with no significant difference between the two study groups (Table
4). No systemic adverse effects were reported in the two treatment
groups, during the study.
Discussion
Our findings showed that simple application of a water on acne-involved
skin is able to prevent or reduce scaling that often occurs during facial
retinoic acid treatment. Patient-perceived signs such as burning or itching
appeared to be more resistant to the adjuvant treatment with water. Because
frequent failure of topical therapy of acne often results from local intolerance
to the treatment and in loss of patient compliance, the association of
a topical retinoid with water spray might enhance the efficacy/tolerability
ratio of a topical retinoid alone.
Water is able to amend skin dryness by having a rapid hydration capacity
on the superficial layers of the skin. It increases softness and suppleness
of the skin, in a manner that is dependent on its mineral concentration
[5]. Avène water, which has a low mineral content, has also been
shown to be effective in relieving inflammatory intestinal mucosa in some
atopic patients, when taken orally [4]. In the present study, water treatment
was found to have protecting effects against some irritant activity of
retinoids in acne patients. This beneficial activity was significant in
scaling problems produced by retinoid treatment, and not significant on
erythema, burning and itching. The water effect enabled patients to avoid
the need for adjuvant moisturising emollients in some instances. Furthermore,
in this short-term study (4 weeks), water does not appear to alter the
therapeutic action of retinoic acid in acne. However, whether its significant
preventive effect on retinoic acid-induced scaling is due primarily to
its specific properties (i.e. Avène properties), or a non
specific action (i.e. properties of all waters) remains to be determined.
Also, further studies must be undertaken to verify the clinical advantage
of the water from the physician's point of view as well from the patient's
point of view, especially in comparison to waters with other characteristics.
In conclusion, skin hydration seems to be a promising adjuvant to retinoic
acid treatment of acne, in conjunction with or without an emollient.
Article accepted on 27/4/00
CONCLUSION Acknowledgements
We would like to thank Dr. N. Bizouard and members of the Association
de Recherche en Dermatologie.
This study has been sponsored by the Pierre-Fabre Research Institute.
Two of the authors (K. Vie and P. Dupuy) are employees of this institute.
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