ARTICLE
Auteur(s) : Toshiyuki YAMAMOTO, Kiyoshi NISHIOKA
Department of Dermatology, Tokyo Medical and Dental University,
School of Medicine, 1‐5‐45 Yushima, Bunkyo‐ku, Tokyo 113‐8519,
Japan
Reprints: T. Yamamoto Fax: (+ 81) 3 5803 0143
E‐mail: yamamoto.dermmed.tmd.ac.jp
Article accepted on 14\7\03
Tacrolimus (FK 506) is an immunosuppressive agent isolated from the
fermentation broth of Streptomyces tsukubaensis [1].
Tacrolimus easily penetrates the epidermis because of its smaller
molecular weight [2]. Tacrolimus binds to immunophilin proteins in
the cytoplasm of lymphocytes, and the binding creates a complex
that inactivates the calcium‐dependent calcineurin‐phosphatase.
Calcineurin is needed for interleukin‐2 (IL‐2) transcription by
T‐lymphocytes. Since IL‐2 is an autocrine growth factor for
T‐lymphocytes, tacrolimus suppresses the activation and
proliferation of T‐lymphocytes. Both systemic and topical
tacrolimus have been shown to be effective for several inflammatory
skin disorders [3‐5]. Psoriasis is a chronic inflammatory skin
disorder characterized by scaly, thickened erythematous plaques.
Although the precise etiology of psoriasis still remains unknown,
its pathogenesis is immunologically mediated by activation of
skin‐directed T‐lymphocytes. The efficacy of topical tacrolimus
ointment for chronic psoriatic plaques is controversial [6, 7]. We
have recently reported that topical application of tacrolimus
ointment is effective for facial psoriasis [8]. Here we further
evaluated the effect of topical tacrolimus for facial lesions in
21 cases of psoriasis vulgaris.
Patients and methods
Twenty‐one cases of psoriasis vulgaris (15 males and
6 females; 23‐76 years of age; mean 51.1 years old)
were evaluated. The diagnosis was confirmed by clinical and
histopathological examination. Mean disease duration was
10.1 years. All of the patients had typical extra‐facial
psoriasis. The PASI score ranged from 2.4 to 16.6, with a mean of
8.1. The extra‐facial lesions had been treated with topical
steroids (strong or very strong class) or vitamin D3 ointments,
which were unchanged during the trial. None of the patients
received any systemic treatment within 4 weeks before the
trial start or during the therapy. After receiving informed
consent, 0.1% tacrolimus ointment (Protopic; Fujisawa
Pharmaceutical Co. Ltd., Tokyo, Japan) was applied twice a day
without occlusion. The disease severity (degree of erythema,
infiltration and desquamation) of the facial lesions was assessed
by PASI score both initially as well as after 4 weeks of
treatment, which was tested for significance by the Wilcoxon
matched‐pairs test. The degrees were as follows; 0, absent; 1,
slight; 2, moderate; 3, striking; and 4, exceptionally striking.
Laboratory examination, including liver and renal function tests,
was carried out before and after treatment. The therapeutic
response was globally evaluated as complete response, partial
response and resistant after 4 weeks.
Results
After 4 weeks, 19 cases showed improvement. The mean
score of erythema decreased from 1.76 to
0.62 (P <.0001), that of infiltration decreased
from 1.33 to 0.43 (P <.0005), and that of
desquamation decreased from 0.95 to 0.24 (P <.001).
A complete or partial response was obtained in 10 (47.6%) and 9
(42.9%) patients, respectively. A typical response to topical
tacrolimus treatment is shown in Figures 1 and 2. Two
patients were resistant to topical tacrolimus. The therapeutic
response is shown in Figure 3. The therapeutic
response was not apparently influenced by the duration of the
disease. The maximum amount of tacrolimus ointment used during the
4‐week trial did not exceed 5g in total. Routine laboratory tests
for renal and liver function were always negative or within normal
limits. Recurrences were observed in 5 patients among
10 patients with complete clearance during 1 month of
follow‐up after treatment, which, however responded again to the
tacrolimus ointment. As side effects, slight skin tingling was
noted in 4 cases when they started, but the feeling was
transient. None of the patients had any signs of skin atrophy or
telangiectasia during the clinical trial.
.
.
.
Discussion
Topical application of tacrolimus has recently been shown to be
effective in the treatment of several inflammatory skin disorders,
including atopic dermatitis [9‐12], chronic cutaneous
graft‐versus‐host disease [13], mucosal lichen planus [14‐17],
steroid‐induced rosacea [18], ichthyosis linearis circumflexa [19],
pyoderma gangrenosum [20, 21], leg ulcers in rheumatoid arthritis
[22], and malar rash in systemic lupus erythematosus [23]. On the
contrary, it is recommended that patients with Netherton‘s
syndrome, who have a skin barrier dysfunction, do not use
tacrolimus ointment because of the potential for increased systemic
absorption [24].
As for chronic plaque type psoriasis, no significant difference
was found in the effect between topical tacrolimus ointment and
placebo, although 0.3% topical tacrolimus was applied only once
daily in a pilot study [6]. On the other hand, Remitz et al.
[7] demonstrated that application of 0.3% tacrolimus ointment
resulted in a significant reduction in erythema, infiltration,
superficial blood flow, and epidermal thickness compared with the
control vehicle. Ointments were applied under occlusion every
2‐3 days. The lack of effect may be due to low absorption of
the drug through thick psoriatic scales.
In the present study, our data showed an improvement in erythema,
infiltration and desquamation of the facial psoriasis by 4‐weeks
topical tacrolimus therapy, although this study was a small,
open‐labeled, uncontrolled trial. A complete clearance was noted in
10 patients (47.6%). In the study population, total PASI
scores of 17 patients were less than 10, indicating that the
body surface areas applied with topical steroid is not diffuse. And
the steroid ointments used were of a very strong class, and were
unchanged before and during the trial. We thus consider that an
improvement of facial psoriasis is not affected by systemic effect
of steroids. Until now, topical corticosteroid or vitamin D3
therapy has been used for facial psoriasis. Long‐term topical
corticosteroid application can cause skin atrophy, telangiectasia,
rosacea‐like or perioral eruption. Our present study showed that
topical tacrolimus treatment may be one of the useful therapies for
facial lesions of psoriasis without occlusion. Usually, facial
psoriasis lesions are not covered with thick scales, which may
block the penetration of the ointments, resulting in
ineffectiveness. During preparation of this manuscript, a similar
report has just been published [25], which is consistent with our
results. In their study, 0.1% tacrolimus ointment was applied twice
daily for 8 weeks for the facial or intertriginous areas in
21 patients with psoriasis. A total of 81% of patients
(17 of 21) showed complete clearance at day 57.
The most common adverse effects of topical tacrolimus therapy were
sensation of skin burning, pruritus, flu‐like symptoms, skin
erythema, and headache [26]. In this study, 4 patients
experienced slight skin tingling within the first few days of
application, which, however, was local and soon disappeared during
the treatment.
In conclusion, we propose that topical tacrolimus may be a useful
therapy for facial psoriasis lesions.
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