Treatment of psoriasis with calcipotriol: time of onset and healing of relapses

ARTICLE

Psoriasis is a relapsing disease although patients not receiving specific therapy may enjoy long periods of remission, and even permanent healing [1]. The question of relapse remains particularly important for the dermatologist however, since it influences the therapeutic strategy and requires him to convince patients that their disease is not incurable so as to obtain optimal compliance [2]. The specialist must therefore be familiar with the potential of all available therapeutic tools, particularly as regards the incidence and time to relapse after treatment.

There are obviously other factors that the dermatologist has to consider when proposing treatments, such as the patient's life-style, age and concomitant pathologies, and all the aspects of safety on which an objective estimate of the benefit-to-risk ratio must be based.

Calcipotriol is a topical antipsoriasis agent. Its clinical activity in psoriasis vulgaris has been amply confirmed and its efficacy is comparable to that of betamethasone 17-valerate or clobetasol [3, 4], and better than that of dithranol [5], using conventional treatment schedules; it is extremely well tolerated when used for prolonged periods (one year) [6, 7].

Despite ample demonstration of the excellent therapeutic safety and ease of handling of calcipotriol, no trials have yet investigated aspects related to protection from relapse and the absence of tachyphylaxis. No methodologically, well-structured clinical observations have yet been published on relapse after single-drug treatment with calcipotriol, or on how the duration of this treatment influences the incidence and time of appearance of relapse.

The present clinical trial was therefore designed to verify the time needed to achieve healing, the time and incidence of relapse after calcipotriol treatment, and the time needed to cure the relapse using calcipotriol again.

Material and methods

Forty out-patients with psoriasis, of either sex, aged over 18 years, were included in the trial. The study had a controlled, within patients design (Table I). Patients were ineligible if they had pustular psoriasis, or if they were receiving systemic antipsoriasis treatment, calcium, or vitamin D at a dose over 400 U/day.

The trial was conducted in accordance with the Declaration of Helsinki and its amendments, each patient giving their informed consent.

Calcipotriol ointment (50 µg/g) was applied twice a day to the lesions, without any occlusive dressing (max 100 g/week). Patients using topical or systemic antipsoriasis treatments at enrolment were required to observe run-in periods of respectively two weeks and two months. The severity of psoriasis was assessed using the PASI ­ Psoriasis Area and Severity Index [8]. The first treatment period lasted from enrolment until cure, or until the best possible therapeutic result had been achieved, in the dermatologist's judgement. "Healing" was taken to mean the disappearance of the psoriatic lesion, even if residual skin discolouration persisted.

After lesions had healed patients were kept under observation, using no specific antipsoriatic treatments, until relapse of the disease. "Relapse" was defined as patients who during follow-up, reached a PASI of half the baseline score. Relapsing patients were again given two applications of calcipotriol/day, until healing or the best possible therapeutic result was achieved. Patients were seen fortnightly throughout the trial.

The frequency of healing at each visit during the first treatment period was calculated, then during treatment of relapses. The frequency of recurrence was calculated, the mean time to healing, the mean time to relapse and the mean time to cure after relapse were all expressed in days and calculated using the dates of the follow-up visits.

At the end of the study, on the basis of the time needed to heal, the sample was stratified into two groups: those who healed in less than eight weeks, and those who healed in more than eight weeks. For each group we calculated the mean time to relapse and the time to relapse healing in days, and changes in PASI were analysed. Further assessment included the dermatologist's opinion of efficacy expressed using a five-point, semiquantitative scale from ­ 1, for worsening, to 3 for healing.

Parametric variables such as time to cure, time to healing after relapse and PASI were analysed by ANOVA for repeated measurements, and linear correlation by the Mantel-Cox test. Time to relapse was analysed by ANOVA for independent groups. Non-parametric variables such as the physician's opinion of efficacy were analysed using Friedman's test.

Forty cases were included in the trial (26 males, 14 females), mean (± SD) age 48.0 ± 16.4 years. The mean duration of the disease was 14.8 ± 2.4 years, 35 patients had psoriasis vulgaris, three had psoriasis associated with arthritis and two had psoriasis palmaris et plantaris. Twelve patients discontinued the study, for the following reasons: eight were lost to follow-up (two after the first treatment and six after treatment but before relapse); three stopped because of treatment failure during the first treatment period; one stopped because of an adverse reaction. Two cases were not included in the overall assessment, one because an exclusion criterion arose, and one because of an adverse event.

Results

After two weeks of treatment, 5.3% of patients were either cured or stopped treatment as they had achieved the best possible therapeutic result; at four weeks, 26.3% of the patients had achieved healing, at six weeks 36.8%, at eight weeks 52.6% and at ten weeks 92.1%. At this last visit the 15 remaining patients stopped treatment and entered the observation phase of the study even though the PASI was not completely considered as zero (Fig. 1).

The residual score presented by this last group of patients was caused by a moderate erythema and slight infiltration, while desquamation was absent.

Thirty-five patients were included in the follow-up because 2 cases were excluded from analysis and 3 patients dropped out because of treatment failure during the first cycle.

The frequency of recurrence was 18.2% at two weeks, 36.7% at four and six, 77.8% at eight, 85.2% after ten, and 88.9% after 14 weeks. No relapse occurred in 11.1% of cases. The disease thus recurred in a total of 24 (60%) of the patients enrolled. Of those who repeated the treatment for the recurrence, 12.5% were healed after two weeks, 33.4% after four, 62.5% after six and 100% after eight weeks. Treatment was not continued beyond this time.

The mean time to heal during the first treatment period was 53.5 ± 2.9 days (range 14-78 days). The mean time to relapse was 43.3 ± 4.5 days (range 14-112 days). The mean time to healing of the relapse was 44.6 ± 2.9 days (range 14-57 days).

The mean baseline PASI score was 8.3 ± 0.9; this was statistically significantly lower after four weeks of treatment. PASI scores are shown in Figure 1.

The group of patients experiencing healing in less than eight weeks presented a mean time to heal of 40.6 ± 2.9 days (range 14-56), and those needing more than eight weeks 69.6 ± 0.8 days (range 63-78). Table II sets out mean times to relapse and mean times to heal after relapse for the two groups. Within this stratification, baseline PASI and PASI at relapse were homogeneous, and reductions in the score after the first treatment and after treatment for relapse were not different (NS, ANOVA, Table III). Time to heal after relapse correlated significantly with the time to heal during the first treatment period: in the group taking more than eight weeks (69.6 days), relapses were healed in a shorter time (50.3 days) (Fig. 2, A and B).

No linear correlation was found for the healing time between the first and the relapse treatment (p = 0.07, NS).

Figure 3 sets out the dermatologist's judgement of efficacy at each visit.

Only one patient complained of intense itching and worsening of the erythema. These moderately severe events appeared ten days after starting treatment and lasted for a week, and were, in the physician's opinion, almost certainly related to the use of the drug. The trial treatment was withdrawn and topical cortisone was given.

Discussion

The data provide interesting information concerning some practical aspects of calcipotriol therapy in psoriasis.

Success of particular treatment schedules in chronic pathologies could depend upon the attention dedicated to a treatment planning, taking into consideration, for instance, seasonal effects.

Our results may be useful because they provide an estimate of the average time to healing ­ 53 days (about eight weeks), time to relapse ­ 43 days and time to healing after relapse 44 days.

We observed two, as yet, unreported clinical findings concerning calcipotriol: (1) a time to healing after relapse significantly related to the time to healing with the initial treatment (69.9 days for the first treatment corresponding to 50.3 days for the second, versus 40.6 days corresponding to 39.3 days) (Table I); (2) a delayed onset of relapse in patients treated for longer (relapse-free time of 48 days versus 37 days) and a relapse-free interval long enough to show no rebound effect immediately after stopping calcipotriol.

No published data are available on similar studies with calcipotriol making it difficult to corroborate our results.

A possible interpretation of these findings is that a longer treatment period with calcipotriol might produce greater persistence of the drug in the dermal layer and this might have an affect on the longer duration of the relapse-free interval.

It would be interesting to investigate whether prolonged initial calcipotriol treatment corresponds to a reduced number of year therapy cycles.

However, these data may serve as encouragement for further clinical investigations to clarify the problem.

The optimal treatment duration with calcipotriol is still open to debate, but the recent finding of the successful, once a day regimen of calcipotriol [9] contributes to the debate from the cost aspect.

The question of relapse of mild to moderate psoriasis after topical calcipotriol treatment has only been tackled so far on the sidelines of open and controlled trials of treament efficacy and safety. Among the long-term trials, McPhee et al. [10] used a method and experimental design that comes quite close to the present study. In 235 psoriasis patients treated with calcipotriol (50 µg/g, two applications/day), 25% experienced clearing after eight weeks, and the mean time to clearing (defined as the time in which half the patients experienced clearing) was 16 weeks.

Such long healing times contrast not only with the findings of the present trial (52.6% clearing at eight weeks) but also with the results of all other clinical trials published so far.

In other long-term trials, the experimental protocol did not define the relapsing patient clearly, making it complicated to compare results with ours, but any flare-ups of the disease were immediately retreated [6, 7].

Except for one case of intolerance to calcipotriol, manifesting as worsening of the pathology, no local or systemic adverse reactions were reported. The excellent tolerance in this and earlier trials is a further guarantee of the safety and ease of use of calcipotriol even in long-term trials with cyclic dosage schedules.

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