ARTICLE
FK506 (tacrolimus) is an effective immunosuppresant drug
for the prevention of rejection after organ transplantation [1]. This
agent has also been used for several autoimmune diseases including systemic
lupus erythematosus (SLE) [2-4]. Tacrolimus is the prototype of a class
of topical immunosuppressive agents with great potential for the treatment
of inflammatory skin diseases such as atopic dermatitis, contact dermatitis
and alopecia areata [5, 6]. Topical treatment has been reported to be
particularly effective for the facial erythematous lesions of atopic dermatitis
[7]. Recently, we encountered a case of SLE in which the erythematous
lesions were treated successfully with topical tacrolimus. From this experience,
we expanded our use of topical tacrolimus to cutaneous LE and dermatomyositis.
Based on its safety and effectiveness, topical tacrolimus will become
a new tool for managing the skin lesions of collagen diseases.
Case report
A 35 year-old Japanese woman visited the dermatology clinic of Numazu
Municipal Hospital, Shizuoka, Japan in June 1986 because of facial erythema,
photosensitivity and discoid skin lesions. Blood examinations revealed
the presence of anti-DNA antibodies and hypocomplementemia. These findings
satisfied the criteria of the American College of Rheumatology for SLE.
Oral prednisolone (initially 30 mg/day) therapy was started, and the dose
was gradually tapered. The disease activity improved with a good response
to the corticosteroid therapy. After that, the maintenance dose of prednisolone
was 10 mg/day for 14 years. In April 2000, the erythematous and telangiectatic
lesion on her face recurred, and spread over her entire face (Fig.
1). There were no changes in the laboratory test results, including
complement components, anti-DNA antibodies, anti-SS-A/Ro antibodies and
anti-SS-B/La antibodies. We therefore tried topical tacrolimus therapy
combined with the maintenance prednisolone (10 mg/day) therapy. Tacrolimus
ointment (0.1%) was applied once a day and the average dose (a day) was
approximately 0.2 g. One month later, the erythema had regressed markedly
(Fig. 1), with no adverse
effects induced by the tacrolimus. Topical tacrolimus has been effective
in the treatment of the present case through a follow-up period of 8 months.
Summary of clinical trials of topical
tacrolimus
Based on this effective case, topical tacrolimus therapy was used for
the facial skin lesions of 11 cases with cutaneous LE and dermatomyositis.
Table I shows the clinical
and pathological profiles of these 11 cases treated with topical tacrolimus.
Informed consent was received from all patients including the case described
above. The patients included 3 SLE patients, 4 DLE patients and 4 dermatomyositis
patients, who had visited the Wakayama Medical University in Wakayama,
the Fujieda Municipal Hospital or the Numazu Municipal Hospital in Shizuoka.
Biopsy specimens from facial erythematous lesions were obtained for light
microscopic and direct immunofluorescent studies. Tacrolimus ointment
(0.1%) was applied on the facial lesional site once a day. The average
dose a day in all cases was within 0.3 g. The same dose was applied for
4 weeks. Four weeks later, the efficacy and the safety were evaluated
by at least two physicians. In the cases with SLE, SLEDAI was used for
systemic evaluations [8]. Of these 11 patients, 6 (3 SLE, one DLE and
2 dermatomyositis) showed a marked regression of their skin lesions after
tacrolimus therapy, but 4 patients (3 DLE and one dermatomyositis) were
resistant to the therapy. A good response was found for erythematous lesions
with edematous or telangiectatic changes in SLE and dermatomyositis. In
these cases, within 2 weeks after the start, marked improvements were
found (Fig. 2). From the
histology [9], slight infiltrates, vasodilatation and edematous changes
were common characteristics for the effectiveness of tacrolimus, but hyperkeratosis
and moderate infiltrates were not (Table
I). After the 4 week trial, the topical dose was tapered from 0.3
g/day to 0.1 g/day. During 8 months observation, 2 out of 6 good responders
showed recurrence of facial erythematous lesions. In DLE with typical
discoid lesions, tacrolimus therapy resulted in no improvement. The additional
4-weeks topical therapy were applied to the patients who were resistant
to the topical tacrolimus but no marked changes were produced. Through
the follow-up periods, a few patients complained of pruritus and burning,
which were the most frequent adverse effects induced by topical tacrolimus
therapy [5, 6]. However, we did not observe the side effects of hypertension
and nephrotoxicity, which have been seen in patients undergoing oral tacrolimus
therapy [10].
Discussion
Tacrolimus is a water-insoluble, macrolide inducer of immunosuppression
produced by Streptomyces tsukubaensis [11]. In the dermatological
field, tacrolimus has been used for atopic dermatitis, pyoderma gangrenosum,
psoriasis, graft-versus-host disease, alopecia areata and Behcet
disease [5, 6]. We have previously demonstrated that tacrolimus was very
effective for skin lesions and other autoimmune traits in an SLE-prone
MRL/Mp-lpr/lpr mouse model [12].
This report describes the usefulness of topical tacrolimus for erythematous
lesions of SLE, DLE and dermatomyositis. In particular, tacrolimus was
effective for the initial skin lesions of SLE such as edematous or telangiectatic
erythematous eruptions. Topical tacrolimus also had a therapeutic effect
on some patients with dermatomyositis. In DLE, it was effective for the
erythematous lesions but not for the chronic or discoid lesions. Histologically,
slight infiltrates, vasodilatation and edematous changes were common characteristics
for the effectiveness of tacrolimus. It has been also suggested that topical
tacrolimus has little effect on hyperkeratotic and acanthotic changes.
In psoriasis, a lack of response has been reported, and this unresponsiveness
might be due to the low absorption of the drug through the thick psoriatic
scales [13, 14]. Recently, Yamamoto et al. [15] reported the effectiveness
of topical tacrolimus for facial lesions of psoriasis. Based on these
findings and reports, the resistance of topical tacrolimus for DLE skin
lesions might be explained as follows: 1) low absorption of drug due to
hyperkeratotic and acanthotic changes, 2) unresponsiveness of skin infiltrating
cells themselves to the drug in the chronic lesion, which implies that
in DLE, the infiltrating cells have different characteristics compared
to early lesions of the other diseases including SLE and dermatomyositis.
For the facial erythema lesions of SLE, DLE and dermatomyositis, topical
corticosteroid therapy has been widely used. However, topical corticosteroids
frequently induce adverse effects such as telangiectasia, rosacea changes,
skin atrophy and so on. With respect to these side effects, topical tacrolimus
is well known to cause few problems, and is generally regarded as being
safe. All things considered topical tacrolimus will become a new tool
for managing the skin lesions of collagen diseases.
Article accepted 10/9/01
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