Combination of calcipotriol and clobetasol propionate as a premixed ointment for the treatment of psoriasis

ARTICLE

Auteur(s) : Norito KATOH, Saburo KISHIMOTO

Department of Dermatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan

Article accepted on 14/4/2003

Calcipotriol has emerged as a new topical therapy for psoriasis with a different mode of action from topical steroids during recent decades. Calcipotriol has been shown to be significantly superior to betamethasone valerate [1] and fluocinonide [2], and has become one of the most prescribed treatments for psoriasis. In addition to its superb efficacy, calcipotriol does not pose the same risk of skin atrophy and tachyphylaxis as steroids in the long-term [3]. The effect of calcipotriol, however, is seen more slowly than that of steroids. Also, there is a 30% risk of developing transient lesional irritation with this agent [4]. To maximize the speed of initial improvement and to minimize the risk of long-term treatment, topical sequential therapy with a superpotent steroid and calcipotriol was introduced [5]. The regimen is comprised of three steps in total of which the topical application of these ointments twice-per-day is recommended: the steroid in the morning and calcipotriol in the evening (Step 1), calcipotriol on weekdays and the steroid on weekends (Step 2), and calcipotriol alone (Step 3). However, patients with psoriasis are unwilling to apply topical greasy ointments twice-per-day, particularly in the morning, to their whole body for a long period. In addition, it is difficult for some patients to decide when they should switch to the other treatments or whether the agents they are applying are adequate or not.
In this study, we compared the efficacy and adverse effects of monotherapy with calcipotriol and combination therapy with calcipotriol plus the superpotent steroid, clobetasol propionate applied once per day. To reduce the burden on patients, we prescribed calcipotriol and clobetasol propionate in a single container as a premixed ointment. Additionally we evaluated the efficacy of a corresponding two-step regimen which consisted in initial calcipotriol/clobetasol combination therapy (Step 1), followed by calcipotriol monotherapy (Step 2).

Patients and methods

Patients

Sixty-one Japanese adult outpatients with stable plaque psoriasis were randomly assigned to one of the two treatments. Patients with psoriasis requiring systemic therapy and having had any treatment in the previous month were excluded. Informed consent was obtained from all participants and the procedures were in accordance with the Helsinki Declaration of 1975, as amended in 1983.

Treatment and evaluations

One of the following treatments was started within a day of patient selection. One group received monotherapy with 0.005% calcipotriol ointment (Dovonex^TM, Fujisawa Phrmaceutical, Osaka, Japan) once per day after bathing. The other group was treated with a combination of 0.004% calcipotriol and 0.01% clobetasol propionate ointment (Dermovate^TM, Glaxo Smith Kline, Tokyo, Japan) in a single container as premixed ointment using commercially available 0.005% calcipotriol and 0.05% clobetasol propionate (mix formulation = 4:1) once a day after bathing. This ointment was mixed by a pharmacist in our hospital on the first day of treatment for each patient and a fresh batch was prescribed each visit. The severity of the psoriasis eruptions was evaluated biweekly for 12 weeks by means of eruption points of truncal involvement, calculated as the sum of severity of erythema, scaling and induration on a 5-point scale (0 to 4). In addition, the Psoriasis Area and Severity Index (PASI) was scored as previously described [6] to evaluate the difference in clinical characteristics between the two groups. Patients whose eruption score reduced by 50% or greater from the baseline score after 12 weeks of combination therapy were instructed to apply 0.005% calcipotriol ointment alone once a day for another 12 weeks. Those on monotherapy were instructed to continue it for another 12 weeks. Patients whose eruption score did not reduce less than 50% from the baseline score after 12 weeks of each therapy were started other on treatments such as phototherapy and anthralin.

Statistics

To detect the differences between the two groups at the baseline we used the unpaired-t test (age, age at onset of psoriasis, PASI and the eruption score) and chi-square test (gender). The 2 groups were compared for the proportion of patients showing any adverse effects and at least 50% reduction in eruption score from the baseline score after 2 weeks of treatment using the chi-square test. The eruption score each assessment week was compared between the groups by means of the unpaired-t test. All the analyses were carried out using StatView Ver.5 (SAS Institute Inc. NC) on a Macintosh computer. P values were 2-sided and those less than 5% were regarded as significant.

Results

Patient characteristics

The 2 treatment groups were not significantly different with regard to pertinent clinical variables at baseline (Table I).

Table I. Data are mean ± SD. All variables except gender ratio were compared using unpaired-t-test; gender ratio was compared by means of chi-square test. Patients in the monotherapy group received calcipotriol ointment once daily; those in the combination therapy group received a premixed ointment of 0.004% calcipotriol and 0.01% clobetasol propionate once per day

Adverse effects

Of 32 patients, 9 (28.1%) in the monotherapy with calcipotriol experienced local irritation such as a burning sensation, itching and exacerbation of the eruption. For 7 of these patients (77.8%), the irritation was transient and could be overcome by reducing the frequency of application or diluting the ointment with petrolatum. Two patients developed persistent lesional irritation and were withdrawn from the treatment. The combination therapy with calcipotriol and clobetasol propionate as a premixed ointment produced local and transient irritation in one among 29 patients (0.03%). Adverse effects occurred less frequently in the combination group (P < 0.0001).

Proportion of patients with at least 50% reduction in eruption score two weeks after treatment

The monotherapy with calcipotriol resulted in at least 50% reduction of eruption points in 9 of 30 patients (30%) at 2 weeks of treatment. The same degree of reduction occurred in 18 of 29 patients (62.1%) in the combination therapy. The above proportions were significantly different (P = 0.0268).

Eruption score on different assessment days

Of the 61 patients enlisted, 59 patients completed 12 weeks of the protocol. Eruption scores were significantly lower in the combination therapy group than in the control group at different time points except in weeks 2 and 4 (Fig. 1).

Switching from combination therapy to monotherapy

Patients in the combination group whose eruption score reduced by 50% or greater from the baseline score after 12 weeks of therapy were instructed to apply calcipotriol ointment alone once a day. Of 28 patients, 15 (54%) were able to maintain their clinical remission with calcipotriol alone for another 12 weeks. The other 13 patients experienced exacerbations of their eruptions 4.3 ± 1.7 days (mean ± SD) after switching from combination therapy to monotherapy as assessed by the patients. In these patients, restart of the combination therapy lead to the second remission. Some, but not all, patients who were able to maintain their remission for another 12 weeks agreed to stop the treatments with 0.005% calcipotriol for 2 weeks to observe remission duration and relapse rate. Two of 9 patients in the monotherapy group and 3 of 11 patients in the combined therapy followed by monotherapy group maintained their remission. The other 7 and 8 patients in each group experienced exacerbations of their eruptions after 4.8 ± 1.9 and 5.0 ± 2.2 days, respectively.

Discussion

Since patients with psoriasis have to apply topical agents often for a long period, it is important for clinicians to consider improved compliance with the treatment. Some patients mix calcipotriol, steroids and other agents by themselves to facilitate application without regard for the compatibility of these agents. Calcipotriol is relatively unstable and is inactivated by acidic pH, including salicylic acid and hydrocortisone-17-valerate [8]. The high-performance liquid chromatography analysis demonstrated that calcipotriol was stable in a mixed form with clobetasol propionate at room temperature for at least 2 weeks (unpublished observation) as were as calcipotriol and halobetasol propionate as was reported by Patel et al. [7]. They also showed that halobetasol propionate ointment was stable for at least 13 days when it was mixed with calcipotriol [7]. It is known that 17 ester and 21 hydrate of corticosteroid mainly contribute its stability [8]. Both halobetasol propionate and clobetasol propionate have the same 17 ester and 21 chloride instead of hydrate, suggesting that clobetasol propionate is expected to be stable in a mixed form with calcipotriol as halobetasol propionate. In this study, therefore, we used a combination regimen in a single container as a premixed ointment for better patient compliance.
Lebwohl et al. reported that the mean overall severity index was significantly lower in the calcipotriol/halobetasol treatment group than in either the calcipotriol group or the halobetasol group in their multicenter trial [9]. In this study, to simplify the treatment regimen and to reduce the amount of topical steroid, we selected transition phase therapy in the original sequential therapy [5] as a first step treatment by using premixed 0.004% calcipotriol and 0.01% clobetasol propionate ointment in a single container. More patients exhibited at least moderate (50% or greater) improvement in the combination group than in the monotherapy group after 2 weeks of therapy. A greater reduction in eruption score was also demonstrated with the combination regimen after 6 weeks and later. This result indicates that a combination regimen with 0.004% calcipotriol/0.01% clobetasol propionate as a premixed ointment is still more effective than monotherapy with calcipotriol. An early double-blind clinical study showed no statistical significance between 0.025% clobetasol propionate and 0.1% betamethasone valerate in their effect on psoriasis [10]. It is therefore supposed that the effect of 0.01% clobetasol propionate alone on psoriasis should be mild. A recent report demonstrated that the immunosuppressive effect of 1,25-dihydroxyvitamin D3 on T helper type 1 cells was augmented when it was used with corticosteroids [11], suggesting that the combination of 0.004% calcipotriol and 0.01% clobetasol propionate has additive or synergistic effects in those patients who do not respond to calcipotriol or clobetasol propionate alone.
To maximize the effect of topical steroids while minimizing their long-term toxicity, a superpotent steroid is considered optimum as the initial steroid regimen [12]. In this study, 62% of patients exhibited 50% or greater reduction in eruption score after 2 weeks of our combination therapy, whereas 91% of those showed a similar improvement with the application of calcipotriol AM and halobetasol PM [13]. About half of the patients were able to maintain remission after switching from combination therapy to calcipotriol alone in this study, although little information is available about the proportion of such patients from “step 2” to “step 3” in the original sequential therapy [5]. It may be more effective to maintain remission in addition to rapid resolution when using these agents by initially using 0.0025% calcipotriol/0.025% clobetasol propionate formula. A pilot study of sequential therapy for psoriasis using the combination of 0.0025% calcipotriol/0.025% clobetasol propionate (Step 1) and 0.004% calcipotriol/0.01% clobetasol propionate (Step 2) as premixed ointments and calcipotriol alone (Step 3) exhibits a preferable response in our institute (unpublished observation). It is necessary to compare the prognosis of eruptions, compliance of the patients, and amounts of steroids in long-term treatment among various regimens. It is also important to observe whether there is any difference in the relapse rate and remission duration between combination therapy and monotherapy after stopping treatment because the use of steroids improves psoriasis but may also induce relapses that become hard to treat.
Local and transient irritation from calcipotriol was significantly reduced in our combination therapy as previously reported [9]. We believe that the combined once-per-day application of 0.004% calcipotriol/0.01% clobetasol propionate as premixed ointments for psoriasis is a promising regimen because of better compliance than the original sequential therapy and improved efficacy with, if any, fewer adverse effects than those of calcipotriol.

Acknowledgements. This work was supported in part by a grant from the Japanese Ministry of Education, Science, Sports and Culture. < 

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