High-concentration (20 mug/g) tacalcitol ointment therapy on refractory psoriasis vulgaris with low response to topical corticosteroids

ARTICLE

Psoriasis is one of the chronic inflammatory skin diseases. It is characterized by reddening and thickening of the skin, and the psoriatic lesions are usually covered with silver scales. Although the pathophysiology of psoriasis is diverse, it is characterized by hyperproliferation of the epidermis associated with abnormal differentiation, and by migration of leukocytes from the dermis to the epidermis.

Phototherapy and systemic therapy are currently available as effective treatments for moderate to severe psoriasis vulgaris, while topical corticosteroids and active vitamin D₃ are usually selected for mild to moderate disease.

Topical corticosteroids possess an anti-inflammatory activity that is evaluated by vasoconstrictor assay. This activity is correlated with their clinical efficacy, and they are classified into several groups based on the potency of their clinical effects [1, 2]. Dermatologists choose a corticosteroid for protracted treatment of psoriasis vulgaris under the consideration of possible occurrence of undesirable side effects such as cutaneous atrophy, teleangiectasia, rosacea, etc. However, adequate efficacy is sometimes not achieved even after topical corticosteroid therapy. Tacalcitol is one of the active vitamin D₃ analogs and has been shown to be effective in the treatment of psoriasis vulgaris [3-5]. Conventional preparations of tacalcitol were 2 mug/g of ointment, cream and scalp solution in Japan and 4 mug/g of ointment in European countries. High-concentration (20 mug/g) tacalcitol ointment is presently under clinical trials for the treatment of refractory psoriasis. A double-blind, left-right comparative study has already demonstrated that 20 mug/g tacalcitol ointment was significantly more effective than 2 mug/g tacalcitol ointment, for the psoriatic lesions that had not been sufficiently improved with the 2 mug/g ointment [6].

In addition, since tacalcitol possesses inhibitory activity against inflammation in in vitro studies [7, 8], in addition to having higher potency in terms of its conventional pharmacological actions, it is expected to be effective against psoriasis vulgaris lesions which show a low response to topical corticosteroids.

This study was conducted for the purpose of assessing the efficacy and safety of high-concentration (20 mug/g) tacalcitol ointment for the treatment of psoriasis vulgaris which showed no adequate improvement in response to topical corticosteroids.

Materials and methods

Study design

This study was conducted as a prospective, multicenter, open-label, non-controlled study.

Subjects

The subjects were psoriasis vulgaris patients ranging in age from 16 to 79 years old, irrespective of inpatient or outpatient status or sex. Pregnant and breast-feeding women were excluded from this study. Patients with significant heart or liver disease, impaired renal function, or hypercalcemia were also excluded. Systemic anti-psoriatic drug therapy, super-potent topical corticosteroids (clobetasol propionate, diflorasone diacetate), drugs affecting calcium metabolism, and concomitant PUVA or UVB were prohibited within 2 weeks before the start of the treatment and throughout the duration of the treatment.

Psoriasis vulgaris lesions, which showed low response to potent (difluprednate, mometasone furoate, betamethasone dipropionate, fluocinonide, etc.) or mid-strength (dexamethasone valerate, betamethasone valerate, prednisolone valerate acetate, hydrocortisone butyrate propionate, etc.) topical corticosteroids for at least 3 weeks before the start of the treatment and whose severity of erythema or thickness was rated "severe" or "very severe", were selected on the basis of the patient's clinical chart.

Treatment

Ointment containing tacalcitol 20 mug/g was kindly provided by Teijin Limited, Japan. The test ointment was applied once daily for 12 weeks, and the maximum daily dose was limited to 4 g. The use of drugs other than the test drug at the test sites and the use of super-potent or potent topical corticosteroids at other sites were prohibited. The application of the drugs was monitored at each visit, and the amounts of the drugs used were recorded.

Assessment

Clinical evaluations were made every 2 weeks for 12 weeks. At each visit the severity of the erythema, thickness, and scaling at the test sites were rated on a 5-point scale: 0, absent; 1, slight; 2, moderate; 3, severe; 4, very severe.

Global improvement at each point in comparison with the day on which treatment was started, considering the severity of each of the signs at the test sites and the surface area of the lesions, was rated on a 6-point scale: - 1, worse; 0, no change; + 1, slight improvement; + 2, moderate improvement; + 3, marked improvement; + 4, cured. Adverse events were monitored at each visit.

Hematological studies (erythrocyte, leukocyte, platelet count, hemoglobin, hematocrit), blood biochemical studies (calcium, inorganic phosphate, albumin, total protein, total bilirubin, urea nitrogen, creatinine, AST, ALT, alkaline phosphatase, lactate dehydrogenase), and urinalysis (glucose and protein) were performed at the start of the treatment and at 4, 8, and 12 weeks.

Statistics

The efficacy rate based on the number of cases graded "moderate improvement" or better in the final global improvement rating and the 95% confidence interval were calculated. Changes in clinical parameters and changes in laboratory test results were tested for significance by the 1-sample Wilcoxon test, with the data on the day on which treatment was started as the criteria.

Ethics

The study protocol was approved by all of the institutional review boards. Written informed consent was obtained from all the patients before participating in the study. The study was conducted in accordance with Good Clinical Practices (GCP).

Results

Study cohort

The study was conducted from August 1998 to September 1999, with 82 patients in 31 hospitals in Japan. Two patients were excluded from all of the analysis because of inappropriate use of the test drug. Of the 80 remaining patients, 26 were excluded from the analysis of efficacy because of protocol violations. The reasons for exclusion were violations of the inclusion or exclusion criteria (2 patients), dosage/administration errors (10 patients), and missing observations during the treatment period (14 patients). As a result, 54 patients (38 males, 16 females) were included in the efficacy analysis. Their age (mean (S.D.) was 57.4 (14.4) years (25-77 years), and the duration fo their psoriasis (mean (S.D.)) was 119.1 (99.4) months (4-408 months).

Efficacy

The severities of the erythema, thickness, and scaling are shown in Figure 1. All three skin manifestations were significantly improved from 2 weeks onward after the start of treatment with tacalcitol 20 mug/g ointment (p < 0.001). The efficacy rate based on the final global improvement ratings of "moderate improvement" or better was 88.9% (48/54; 95% CI: 77.4-95.8%). The final global improvement rating is shown in Figure 2. The efficacy rates based on global improvement ratings of "moderate improvement" or better at 2-week intervals, beginning 2 weeks after the start of the treatment were 22.2%, 42.6%, 68.5%, 74.1%, 83.3%, and 88.9%, respectively, and increased every 2 weeks (Figure 3).

The "moderate improvement" or better efficacy rates in the final global improvement ratings according to test site were: head, 100% (1/1); trunk 92.9% (13/14); upper extremities, 80.0% (4/5); lower extremities, 83.3% (15/18), and other sites (sites that involved more than one test site), 93.8% (15/16). Global improvement according to the classification of corticosteroid used before the start of the study was: potent corticosteroids, 83.9% (26/31); mid-strength corticosteroids, 95.7% (22/23) (Figure 4). Photographs of the improvement in skin manifestation are shown in Figure 5.

Safety

A total of 32 adverse events were observed in 26 of the 80 patients included in the safety analysis, and 5 of the events were graded as probably related to the test drug. They were all local adverse reactions (2 events of application site-irritation, 2 events of itching, and 1 event of application site-redness) and are summarized in Table I. Only one serious adverse event, cerebral infarction, was reported, but it was judged to be unrelated to the test drug.

No changes in mean serum calcium values were seen at any time during the study period (Figure 6). Monitoring of the hematological and biochemical parameters did not show any abnormal findings regarded as "probably", "possibly", or "definitely" related to the test drug.

Among the abnormal changes in clinical test values, one event of positive urinary protein was regarded as possibly related to the test drug.

Discussion

In view of the fact that the occurrence of local adverse reactions, such as cutaneous atrophy and teleangiectasia, increase according to the potency of the clinical effects of topical corticosteroids and that tachyphylaxis occasionally occurs during the treatment [9], dermatologists have been prescribing potent or mid-strength topical corticosteroids, restricting the super-potent steroids only to short-term use. However, psoriasis vulgaris lesions of low response to topical corticosteroids are known to exist.

Tacalcitol is one of the active vitamin D₃ analogs, and in Japan a 2 mug/g preparation has been used since 1993 as a safe and an effective drug for the treatment of psoriasis. In addition to having more potent conventional pharmacological actions [10-12] the tacalcitol 20 mug/g ointment assessed in the present study has been shown to possess anti-inflammatory activity in in vitro studies [7, 8]. Using tacalcitol 20 mug/g ointment to treat refractory lesions of low response to topical corticosteroids may further expand the range of treatment with tacalcitol preparations.

In this study we selected refractory lesions based on the patient's chart and assessed the therapeutic effect of tacalcitol 20 mug/g ointment for 12 weeks.

The evaluation of global improvement in response to tacalcitol 20 mug/g ointment consistently increased from 2 weeks onward after the start of treatment. All of the skin manifestations, erythema, thickness, and scaling, improved from 2 weeks after the start of treatment onward. The patients' test sites were selected from their clinical charts, and target lesions were selected from the whole body. Global improvement stratified by lesion site showed efficacy rates of 80% or more at all sites. Regardless of the potency of the steroid drug used before the start of the study, the global improvement rating also showed efficacy rates of 80% or more. The results of this study showed that switching to tacalcitol 20 mug/g ointment resulted in efficacy against the lesions chosen as the targets of this study, that is the lesion in which no adequate improvement with topical corticosteroids seemed to be obtained.

Adverse reactions consisted of only irritation, itching, and redness at the sites of application, and no serious manifestations or systemic adverse reactions were seen. Moreover, the local adverse reaction rate of 3.8% was almost the same as the rate of occurrence with the 2 mug/g tacalcitol topical preparation, and no increases in the incidence of adverse reactions or development of new adverse reactions was observed as a result of increasing the tacalcitol concentration. No increase in serum calcium concentration was observed at any time during the study period. This study confirmed the safety of the test drug at a maximum application of 4 g per day for 12 weeks. The safety of high-concentration tacalcitol ointment was also supported even in a long-term study, in which no serious or late adverse reactions were seen when 10 g per day of the ointment was applied for a maximum of 54 week [13].

The results of this study showed that tacalcitol 20 mug/g ointment is effective against lesions in which topical corticosteroids are ineffective and that it can be used safely.

Since tacalcitol 20 mug/g ointment retains the same safety as the 2 mug/g preparation and is highly effective, it is recommended to switch topical corticosteroids to tacalcitol 20 mug/g ointment in psoriatic lesions which are refractory to treatment.

High-concentration (20 mug/g) tacalcitol ointment is concluded to be effective and safe for the treatment of refractory psoriasis with low response to topical corticosteroids therapy.

CONCLUSION

Acknowledgements

The following investigators also participated in the study: H. Shimizu,
H. Kobayashi, T. Matsumura, T. Akasaka, Y. Mitsuhashi, M. Kawaguchi, F. Ohtsuka, H. Fujisawa, T. Morishima, Z. Yamaguchi, H. Suzuki,
M. Tan, M. Endo, S. Watanabe, T. Nakagomi, H. Mori, S. Kawana,
E. Aoki, T. Nishikawa, M. Tanaka, T. Murata, M. Koga, T. Ohi, Y. Umezawa, M. Niimura, A. Kitada, M. Iijima, T. Nakada, T. Eto, Y. Todoroki, M. Mizoguchi, M. Ito, S. Ohhashi, H. Ishizaki, M. Yanagihara, T. Mochizuki, T. Tsuji, A. Morita, M. Uehara, K. Danno, Y. Miyachi, K. Toda,
T. Horio, H. Okamoto, M. Ishii, H. Kobayashi, K. Fukai, T. Tezuka,
Y. Sakamoto, M. Kitano, M. Natsuaki, S. Minami, H. Ueki, S. Arase,
Y. Nameta, K. Hashimoto, K. Sayama, Y. Kubota, T. Moriue, J. Katsuura, J. Nakayama, Y. Egami, T. Hashimoto, N. Yamamoto, M. Watanabe, N. Tsukazaki, T. Ono, Y. Inoue, K. Nishioka, K. Otoyama.

Article accepted on 29/7/02

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