ARTICLE
Seborrhoeic dermatitis is a benign chronic dermatitis affecting 3 to
10% of the general population [1], which mainly affects young male adults.
Its symptoms associate at various levels erythema, desquamation, pruritus,
burning and stretching. Because of a predominant localisation to the face
and scalp, it may have an important psychological impact. Moreover, stress
often increases the lesions.
The main topical treatments of seborrhoeic dermatitis are corticosteroids
and antifungals. But there is concern about their long-term safety, corticosteroids
inducing frequent relapses when stopped and antifungals being irritant
for the face when used for a long period or on severe dermatitis. The
efficacy of lithium treatment, first observed in psychotic patients [2],
has been investigated in several placebo-controlled trials [3-6], which
mainly showed a significant improvement of erythema and desquamation after
4 weeks of treatment. However, the majority of these studies have been
performed on a limited number of patients and give a response rate including
partial and complete remissions indiscriminately, without the possibility
of evaluating the percentage of complete remission alone, which is the
effective goal of the treatment. In order to answer this question, we
performed a multicenter, double-blind, randomised study comparing the
efficacy and safety of 8% lithium gluconate ointment with placebo in moderate
to severe seborrhoeic dermatitis.
Methods
Patients
Patients aged between 18 and 65 years with a facial seborrhoeic dermatitis
for at least two months and presenting at inclusion both a moderate or
severe erythema and desquamation were eligible, providing they gave their
written inform consent. Exclusion criteria were any cutaneous diseases
requiring a specific topical treatment of the face (atopic dermatitis,
psoriasis...), general or local lithium therapy, facial topical or oral
immediate release corticosteroids since less than 2 weeks and slow release
corticosteroids since less than 2 months.
Method
This multicenter, randomised, double-blind, placebo-control, study had
an eight-week duration. At inclusion (D0), patients were randomly allocated
to either 8% lithium gluconate ointment or to a matching placebo, which
was the vehicle, to be applied twice a day for 8 weeks (D0 to D56), after
facial wash with a neutral liquid soap provided with the trial treatment.
Assessments, performed at inclusion (D0) and after 4 (D28) and 8 (D56)
weeks, included a quotation of the objective dermatitis symptoms, erythema
and desquamation, a counting of comedones and microcysts, an evaluation
of the skin oiliness and an evaluation by the patient of functional signs
like pruritus, stretching and burning. The clinical and functional symptoms
were rated by the investigator as absent (0), slight (1), moderate (2)
or severe (3). Each patient was always evaluated at each visit by the
same investigator. The opinion of the patients was required with a similar
rating for functional symptoms. Skin sampling was performed at inclusion
to assess Malassezia furfur presence and at the end of the treatment
in parasitology by scraping. And a blood sampling to assess creatinine
(13 patients in each group) and lithium levels (45 patients in each group)
was performed at all visits in several centres. Additionally, at D28 and
D56, the patients were to assess the trial treatment efficacy and cosmetic
properties on 100 mm Visual Analogue Scales (VAS).
Compliance was assessed by questioning the patient. The study was conducted
according to the Helsinki Declaration (Hong Kong revision 1989) and to
the rules of European Good Clinical Practices. The protocol and consent
form were approved by a National Ethics Committee.
The main efficacy criterion was the rate of patients showing a complete
remission of erythema and desquamation at D28 and D56. Complete remission
was defined as complete disappearance of both erythema and desquamation;
partial remission was defined as the persistence of slight (score 1) erythema
and/or desquamation, all other cases were considered as no response to
treatment. Secondary efficacy criteria included rating of objective and
functional symptoms, evaluation of treatment effect and cosmetic properties
by the patient on VAS. Safety was assessed on adverse event monitoring.
The sample size calculation for this study was based on an expected
success rate of 25% in the placebo group and an expected difference of
25% in success rates between the two treatment groups, with a two-sided
* level of 0.05 and a power of 0.80, which gives a sample size of 57 evaluable
patients per group. Efficacy was assessed on the intent-to-treat (ITT)
population, which included all randomised patients who had the disease
under study, applied the treatment at least once and had at least one
efficacy evaluation after baseline. There was no per-protocol analysis
scheduled. Safety was assessed on all patients who took at least one dose
of the study treatment.
All categorical variables were compared between groups for each time-point
using the Fisher's exact test. Continuous variables were analysed at each
time-point using Student's T tests for treatment effect comparison.
Results
Patients
Of 129 patients who entered the study, 66 were randomised to lithium
gluconate and 63 to placebo. Twenty-two patients did not complete the
study, 10 in the lithium group and 12 in the placebo group. Six patients
were lost to follow-up (4 allocated to lithium and 2 to placebo). Six
patients, 3 in each group, discontinued for adverse event. Five patients
discontinued for treatment failure (2 allocated to lithium and 3 to placebo),
3 for protocol violation (1 allocated to lithium and 2 to placebo) and
2 placebo patients withdrew their consent. Drop-out rates did not differ
among treatment groups.
Out of the 129 enrolled patients, 5 (3 allocated to lithium and 2 to
placebo) had no data available after D0 and were excluded from all efficacy
analyses. Another patient allocated to lithium did not have the correct
inclusion criteria and was excluded from the efficacy analyses. Finally,
123 patients were taken into account for the efficacy analyses, 62 patients
allocated to lithium and 61 to placebo.
As expected, the majority of patients were male, and rather young. There
were no significant differences in demography, baseline characteristics,
medical history and clinical examination among the 2 treatment groups
(Table I).
Figure 1 show the results
of the study. The comparison between treatments was consistently and significantly
in favour of 8% lithium gluconate ointment, with a rate of complete remission
of 11% and 29.1% and an overall remission rate (complete and partial)
of 74% and 90.9% after respectively 4 and 8 weeks. In the placebo group,
only 5.1% and 3.8% of complete remission were noted after 4 and 8 weeks
of treatment with a global response of respectively 47.4% and 54.7%.
The secondary efficacy criteria analyses confirmed these findings (Fig.
2): with a significant improvement of erythema, desquamation and burning
in the lithium group as compared to placebo as of the 4th week of treatment.
For pruritus and stretching, the difference was significant only after
8 weeks of treatment. The skin oiliness similarly improved in the two
treatment groups without any difference.
The compliance to treatment was good and similar in the 2 groups.
As shown in Figure 3,
the treatment efficacy assessed by the patient on a VAS was also in favour
of lithium with a satisfaction reaching 65.8 ± 26.6 mm after 4 weeks
and 75.1 ± 23.6 mm after 8 weeks for lithium group and respectively
52.1 ± 30.7 mm and 56.5 ± 31.6 for the placebo group. The quality
of application was assessed as significantly better in the placebo group,
with a constant satisfaction of average 80 mm as compared to 65 mm in
the control group. After 8 weeks, Malassezia furfur was still present
in the 2 groups without any significant difference with 30% positive samples
in the lithium group and 40% in the placebo group, compared to 41% and
57% respectively at inclusion.
No serious adverse event was reported during the study. Nineteen patients
reported adverse events, 8 (12%) allocated to lithium and 11 (17.5%) allocated
to placebo. Except for two patients from the placebo group, who reported
headaches for one and lombalgia for the other one, not related to the
treatment, all reported events concerned the skin. In the lithium and
placebo groups, burning was reported by respectively 4 (6%) and 5 (8%)
patients, erythema by 2 (3%) and 3 (5%) patients and pruritus by 1 patient
in each group. Six patients prematurely withdrew for these cutaneous adverse
events: 3 in the lithium group (1 patient experienced erythema, another
had new lesions appearing and a third had a suspected erythematous lupus
not confirmed) and 3 in the placebo group (1 patient reported erythema
and burning, another reported itching and erythema and a third reported
burning).
There was no comedogenic effect noted with lithium salts.
Serum lithium level, measured in an average of 45 patients in each group,
significantly increased from 2.76 µg/l at baseline to 4.48 µg/l
at D28 and 4.15 µg/l at D56 in the lithium group and remained unchanged
at 2.6 µg/l in the placebo group. Creatininaemia, measured in 13
patients in each group, remained unchanged.
Discussion
This study shows that lithium gluconate ointment is an effective and
safe therapy for seborrhoeic dermatitis, with 29.1% of complete remission
after 8 weeks of treatment and a global score including partial remission
of 90%. To our knowledge, this is the second [7] published
study taking into account the complete remission of erythema and desquamation.
This point appears of interest, because it allows us to appreciate the
real efficiency of the molecule and to answer the hopes of the patient
which are not a partial remission.
The tolerance of the product was good, stretching and pruritus which
were the most frequent adverse events were mainly mild to moderate. No
cutaneous side effects as reported with the use of systemic lithium in
psychiatric disorders were noted: mainly papulo squamous changes, induction
of psoriasisform lesions, acne or pustulous lesions. The exact mechanism
of action of lithium gluconate in seborrhoeic dermatitis still remains
unknown. Interestingly, it appears different from systemic lithium which
has been shown in psychiatric patients [8] to increase the production
of inflammatory cytokines (TNF* and IL6). Indeed, with the topical application
of lithium, an anti-inflammatory effect is noted. Some hypotheses can
be put foward. It could act by inhibiting Malasezzia furfur which
colonizes the cutaneous lesions. Indeed, in vitro [9,
10] it has been shown that lithium salt could inhibit the proliferation
of Malassezia furfur at concentrations similar to those used in
seborrhoeic dermatitis. This inhibiting effect on Malassezia furfur
would be mainly related to an inhibition by lithium salts of
the production of free fatty acids necessary to the growth of Malassezia
furfur [11]. However, in this study, the percentage of positive samplings
remains similar both before and after treatment in both the lithium group
and in the placebo group. Lithium gluconate could also act by an anti-inflammatory
activity by inhibiting the production of arachidonic acid [12]
which is the first step inducing the production of leucotrienes and prostaglandines.
In vitro [13, 14], it has been shown that lithium salts inhibited
the production of prostaglandins E1, E2 and thromboxane B2. Concerning
the increase of lithium serum after 1 month of treatment in our study,
remaining stable after 2 months of treatment, it indicates that 8% lithium
gluconate ointment is able to go through the skin, however the increase
to 4.4 µg/l remains very far from the toxic level which is 9000 µg/l
and finally remains very low compared with patients treated by systemic
lithium.
CONCLUSION
This study confirms the benefit of 8% gluconate lithium ointment in the
treatment of seborrhoeic dermatitis of the face. In the future, the next
step will be to compare this treatment with a topical treatment usually
used in this affection, that is corticosteroids or topical antifungals.
Acknowledgements
Participating investigators: J.-.J Guilhou, N. Basset-Seguin, O. Dereure,
CHU Montpellier; O. Bayrou, Hôpital Rothschild (Paris); C. Beylot,
CHU Bordeaux; J.-M. Bonnetblanc, CHU Limoges; P. Celerier, CHU Le Mans;
G. Guillet, B. Sassolas, CHU Brest; B. Guillot, CHU Nîmes; P. Humbert,
Hôpital St-Jacques, Besançon; D. Lambert, C. Morvan, CHU
Dijon; P. Lauret, X. Balguerie, Hôpital Charles-Nicolle, Rouen;
D. Leroy, L. Machet, CHU Tours; P. Plantin, CH Quimper.
This work has been supported by Labcatal (Montrouge, France).
Article accepted on 30/7/02
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