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Ccid-5758-novel-topical-therapy-for-mild-to-moderate-plaque-psoriasis-Clinical, Cosmetic and Investigational Dermatology
open access to scientific and medical research Novel topical therapy for mild-to-moderate This article was published in the following Dove Press journal: Clinical, Cosmetic and Investigational Dermatology15 September 2009Number of times this article has been viewed Abstract: The benefits of vitamin D derivatives for the treatment of chronic plaque psoriasis
are well documented. Of importance is how compatible they are with, and how they compare to, other established treatments for psoriasis. This paper reviews 15 studies with calcitriol 3 µg g-1 ointment (Silkis®/Vectical™ ointment; Galderma Laboratories) applied twice daily for up to 52 weeks. The ointment was found to be effective and safe for the treatment of mild-to-moderate
plaque psoriasis including sensitive skin areas. Calcitriol 3 µg g-1 ointment was found to be as
effective as, or even superior to, other established treatment modalities and more highly tolerated
than other local treatment modalities in most studies’ comparisons. It could be combined with
other psoriasis treatment modalities such as ultraviolet B phototherapy or topical corticosteroids
in order to achieve a faster response and in order to reduce the risk of adverse events.
Keywords: 1,25-dihydroxyvitamin D , calcitriol, psoriasis, therapy
Psoriasis is a chronic inflammatory disease of the skin which affects about 2% to 3% of
the population. About 15% to 20% of these patients suffer from additional inflammatory
diseases of their joints. Some authors state that psoriatic arthritis is more common in
severe and advanced cases of skin psoriasis, but in up to 15% of cases it precedes the
skin disease and about 6% never develop skin lesions. Psoriasis of finger or toe nail
involvement is also observed in many cases. The most frequent clinical form of the
skin disease is plaque psoriasis with lesions preferentially located on the scalp, elbows,
knees and the sacral area. Established topical treatments of plaque psoriasis include
salicylic acid, corticosteroids, dithranol, tar, and both vitamin A and D derivatives.
In cases recalcitrant to topical therapy or extensive or with palmoplantar skin area
involvement additional ultraviolet phototherapy or, alternatively, systemic treatment
modalities including methotrexate, retinoids, cyclosporine, fumarates and biologics
could be administered.
The overall effectiveness of topical vitamin D derivatives in treating psoriasis is well documented. Generally, patients show good tolerance to these agents, with no marked disturbance in their calcium metabolism,1,2 although hypercalcemia does occur occasionally3,4 and some patients reported skin irritations5,6 The important consideration for vitamin D derivatives now is their comparability and compatibility, both in terms of effectiveness and tolerance, with other established treatments for psoriasis.
An ointment with 3 µg g-1 calcitriol (Silkis®/Vectical™ ointment; Galderma Laboratories) was approved in Europe about 10 years ago and recently in the US for the treatment of mild-to-moderate plaque psoriasis. This paper reviews a submit your manuscript
Clinical, Cosmetic and Investigational Dermatology 2009:2 153–159 2009 Kowalzick et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.
number of studies in order to explore the characteristics sensitizing, phototoxic or photoallergic potential of 3 µg g-1 of calcitriol and to establish its place in the armamen- calcitriol ointment could be detected in animal and human tarium available for the management of patients with Pharmacology, mode of action,
Clinical studies – general
Several separate studies designed to asses the efficacy,
The role of calcitriol (1,25-dihydroxyvitamin D ), a naturally tolerability, and safety of applying calcitriol 3 µg g-1 ointment occurring endogenous hormonally-active derivative of twice a day are reviewed here; two were comparisons vitamin D, in keratinocyte proliferation and differentiation, with an excipient, two were comparisons with other together with its effects on the immune response, are the reasons standard treatments for psoriasis, two were comparisons for the interest in its potential to control hyperproliferative, with calcipotriol, another vitamin D derivative, one was a inflammatory skin diseases such as psoriasis. Receptors comparison with tacrolimus, a drug not yet approved for for calcitriol are found on epidermal keratinocytes and psoriasis, four investigated the combination of calcitriol dermal fibroblasts.7 Furthermore, keratinocyte growth and with other therapies, and four were open, uncontrolled differentiation are regulated by calcium concentration,8 and investigations. Most of these studies have been reported in as calcitriol increases intracellular calcium concentration,9 these processes may be indirectly affected by calcitriol. All studies were conducted with adult patients of both In vitro physiological studies have revealed that calcitriol sexes with chronic plaque-type psoriasis. Unless otherwise inhibits the proliferation of human skin cells and induces specified, treatments were applied to all psoriatic lesions them to differentiate into squamous and denucleated horny (except the head) for the duration of the study or until the cells.10,11 Additionally, calcitriol enhances the expression lesions cleared up. Efficacy was mostly assessed in terms of of keratins K10 and K6 in the keratinocyte population in global improvement, with erythema, scaling, induration and psoriasis plaques in vivo, which correlates with their clinical pruritus being scored according to the scale of Fredriksson improvement.12 Furthermore, it has been shown that calcitriol and colleagues29 or global severity scores (GSS), physician’s acts as an immunomodulator in the skin as a potent inhibitor global assessment scores (PGA), and dermatological of T-cell proliferation and of several inflammatory mediators sum scores (DSS). In many studies the psoriasis area and including interleukins-1, -6, and -8.13,14 severity index (PASI) score was used as a secondary efficacy In preclinical and phase I to III studies it was demonstrated variable.30 In studies directed to treatment of special sensitive that 3 µg g-1 calcitriol ointment is the minimal optimal effective skin areas modified PASI or target area scores (TAS) were dose for treatment of psoriasis, had no systemic toxicity and employed. Some studies included an evaluation of patients’ was tolerated well in the locality of application.15 quality of life during treatment using the psoriasis disability In humans, following topical administration of 3 µg g-1 index (PDI) or quality of life (QOL) questionnaires about calcitriol ointment to about 15% of the body surface area for 12 hours, on average 7.5% of the calcitriol applied was Evaluations were performed at the beginning of each excreted mainly via feces over a 10-day period. The level of study, at regular intervals throughout the relevant study, and at serum calcitriol remained unchanged and traces of exogenous the end of each study. Blood chemistry parameters, including calcitriol were only detected in 25% of participants in the serum albumin, total and adjusted calcium, urea, phosphate, relevant study.15 The main concern about the use of vitamin D alkaline phosphatase, and creatinine were also measured at derivatives is their possible influence on calcium homeostasis. In animals treated with 3 µg g-1 calcitriol ointment (on 15% of the body surface for four consecutive days) no increase in Efficacy, safety, and patient
the urine calcium excretion could be observed as compared to animals treated with the excipient over 10 days.16 For health acceptance
and safety reasons, in Europe, the use of 3 µg g-1 calcitriol Comparison with excipientointment is only approved for treatment of up to 35% of the In two placebo-controlled multicenter randomized double- body surface area in psoriasis patients with a maximum of blind parallel group studies including 839 subjects, 3 µg g-1 30 g per day being the approved level in the US. No irritant, calcitriol ointment or its excipient was administered twice submit your manuscript |
Clinical, Cosmetic and Investigational Dermatology 2009:2 daily for up to eight weeks. In both studies the drug was endpoint showed statistically signif icant (P 0.05) shown to be significantly more effective (P = 0.005 and differences in favor of betamethasone dipropionate, P 0.001, respectively) according to the response rate, and however the absolute reduction in mean PASI was both according to GSS and DSS (P 0.01 to P 0.001, comparable between the groups. A significantly (P 0.01) respectively) in mild-to-moderate plaque psoriasis than its higher proportion of patients who responded remained excipient. Furthermore, itching was significantly reduced in remission during the eight-week observation period in the calcitriol-treated group in both studies (P 0.001). following the calcitriol treatment (48%) as compared to In both studies calcitriol ointment had no effect on calcium the betamethasone treatment (25%). Seven patients in homeostasis as well demonstrating a good systemic and each treatment group reported local skin irritations. Two local safety profile in comparison to the groups being treated patients treated with calcitriol exhibited slight, transient with the excipient. There was a higher occurrence of local asymptomatic hypercalcemia, whereas this observation was adverse events in the relevant locality where the excipient made in three cases of the betamethasone treated group. Patients’ overall opinion of both ointments was generally “good” or “acceptable” in 91% of the calcitriol and in 92% Comparison with short-contact dithranol of the betamethasone group, respectively.22In an open, parallel-group study patients were randomized to eight weeks’ treatment with either calcitriol 3 µg g-1 ointment Comparison with calcipotriolapplied twice daily or dithranol cream applied once daily. To compare the efficacy and safety of calcitriol 3 µg g-1 Dithranol cream had to be removed after 30 min by shower ointment and calcipotriol 50 µg g-1 ointment both were bath. Its concentration started at 0.25% for the first seven days, applied twice a day for 12 weeks, a multicenter, randomized and then increased to 0%, 1%, and 2% at seven-day intervals investigator-blind parallel group study including 250 patients according to local tolerance. The global improvement scores with mild-to-moderate plaque type psoriasis was performed. and PASI scores were very similar between the two treatments; At endpoint the mean score of global improvement (0 = no considerable or definite improvement, or total clearance of change or worsening, 3 = cleared or almost cleared) rated by lesions, was observed in 72% of 60 calcitriol-treated patients the physician was 2.27 for calcitriol and 2.22 for calcipitriol; and 70% of 54 dithranol-treated patients, respectively. At the such differences being statistically insignificant. The same end of the study the improvements measured against the parameter scored by the patients was 2.12 for calcitriol and start of the study in the PASI scores were 64% and 57%, 2.09 for calcipotriol; again showing statistically insignificant respectively. In addition to standard assessments, the effect of differences. Mild to moderate skin irritation was observed psoriasis on the patients’ quality of life was measured using in percent of the patients treated with calcitriol and in 11% the PDI questionnaire about daily activities. Patients were treated with calcipotriol. The mean worst score for the also asked to assess the acceptability of the two medications cutaneous safety assessment (0 = none, 4 = very severe) was in terms of staining, smell, ease of spreading and irritation. lower in the calcitriol group (0.1) compared to the calcipotriol Patients in the calcitriol group experienced a significantly group (0.3) according to the physician’s judgment. This higher quality of life during the study period, than those in difference was significant (P 0.005) in favor of a better the dithranol group (P 0.05) as determined using the PDI cutaneous safety profile for calcitriol. According to the questionnaire. There was also a significant difference in favor patients’ judgment, the mean worst score for the cutaneous of calcitriol ointment in the rating of staining and irritation discomfort was lower in the calcitriol group (0.2) compared (P 0.01) and a higher proportion in the calcitriol group to the calcipotriol group (0.4). This difference was significant rated the overall acceptability of treatment as good (47%) (P 0.05) in favor of a better acceptance for calcitriol.24 In another intra-individual, randomized, investigator- blinded left-right comparison study including 75 patients with symmetrical mild-to-moderate plaque psoriasis In a randomized multicenter trial with 258 patients affecting sensitive areas (face, hairline, retroauricular and with chronic plaque psoriasis either calcitriol 3 µg g-1 flexural areas) calcitriol 3 µg g-1 ointment was compared ointment or the topical corticosteroid betamethasone to calcipotriol 50 µg g-1 ointment both administered twice dipropionate were administered twice daily for six weeks. daily. Global assessment of improvements as compared to the Global improvement and global severity scores at treatment beginning of the study by the investigators was significantly Clinical, Cosmetic and Investigational Dermatology 2009:2 submit your manuscript
better for the calcitriol treated lesions and the subjects’ being significant (P 0.05) in all but one of the time points global preference was in favor of calcitriol (both P 0.05). starting from week 1. This clinical response was reflected Perilesional erythema, edema and stinging or burning were in a highly significant difference (P = 0.005) in the mean statistically significantly (P 0.05 to 0.001) less severe with percentage reduction in PASI score for patients treated with calcitriol compared to calcipotriol. The patients’ evaluation of calcitriol plus UVB (65%) compared with those receiving local tolerability in this study was significantly (P 0.0001) phototherapy alone (43%). By study endpoint considerable in favor of calcitriol, whereas there was no patient preference or definite improvement or clearance of lesions was seen in regarding both treatments according to efficacy.25 45% of patients treated with calcitriol plus UVB and in 20% of those receiving UVB alone. The mean cumulative UVB dose was 5,291 J cm-2 in the calcitriol and 8,668 J cm-2 in To compare the efficacy of calcitriol 3 µg g-1 ointment and of the excipient group, respectively. Thus, on average, a 34% the calcineurin antagonist tacrolimus in a 300 µg g-1 ointment lower dose of UVB was administered to calcitriol-treated either given twice daily for six weeks, a double-blind parallel patients than to those in the control group.
group study was performed including 50 patients with In another open intra-individual half-side manner study, chronic plaque psoriasis involving facial and genitofemoral ten patients with symmetrical plaque psoriasis were treated areas. At the end of the study significantly (P 0.05) more on one arm with calcitriol 3 µg g-1 ointment twice daily patients treated with tacrolimus (60%) achieved complete and on the other arm with dithranol ointment once daily. or almost complete clearance according physicians global Additionally, these patients received narrow-band (311 nm) assessment compared to calcitriol (33%). The same was true UVB phototherapy five times a week for at least four weeks. for a target area score which at the end of treatment decreased Both treatment modalities notably reduced the modified by 52% with calcitriol and 64% with tacrolimus, respectively. PASI score equally effectively. Three patients preferred After two weeks, both calcitriol (71%) and tacrolimus (48%) calcitriol rather than dithranol and one patient vice versa induced considerable rates (nonsignificant) of perilesional when both quality of life and treatment acceptability were erythema. After six weeks, calcitriol induced a statistically significant (P 0.005) higher rate (58%) compared to tacrolimus (16%). Nonsignificant differences were found for edema, stinging/burning, and hot sensations, which occurred In a small, double-blind, randomized study patients applied in very few cases. In regard to overall tolerance, both treat- either the potent topical corticosteroid betamethasone ments were judged as excellent by 92% of the patients.27 valerate 0.1% ointment in the morning and calcitriol 3 µg g-1 ointment in the evening (n = 9), or betamethasone valerate ointment in both the morning and the evening (n = 10). Treatment lasted for six weeks.33 The combination The efficacy of calcitriol 3 µg g-1 ointment in combination therapy was at least as effective as betamethasone alone, with ultraviolet (UV) B phototherapy was compared with as indicated by the three measures of efficacy that were phototherapy alone in an eight-week study.19 The research assessed. At study endpoint 78% of patients using calcitriol/ was a double-blind study done through the use of vehicle betamethasone and 60% of those using betamethasone daily ointment in the control group. Patients received three sessions showed considerable improvement, or better, according to per week of broad-band UVB phototherapy until endpoint; the mean global improvement score. Likewise, the global dosage followed a defined schedule depending on the patient’s severity score at endpoint was 1 (slight) for 78% of the skin type. The dose of UVB was reduced or interrupted as combination group and 50% of the betamethasone group. necessary in cases of local intolerance. Ointments were Finally, the mean PASI score for patients in the calcitriol/ applied after irradiation or at least six hours beforehand. The betamethasone group decreased over the course of the treatment groups were comparable at the start of the study; study by 81% compared to 75% for betamethasone-treated the mean PASI scores of 17.4 for 49 patients in the calcitriol patients. No statistical analyses were performed due to the group and 16.6 for 53 patients in the control group were not significantly different. Mean global improvement scores In another two-phase parallel-group study including increased throughout the study period, with the difference 125 patients with chronic plaque type psoriasis either between treatments in favor of calcitriol plus UVB therapy calcitriol 3 µg g-1 ointment or calcipotriol 50 µg g-1 submit your manuscript |
Clinical, Cosmetic and Investigational Dermatology 2009:2 ointment were administered in the morning and the topical To assess the long-term efficacy and safety of calcitriol, corticosteroid clobetasol in the evening for two weeks, an open-label multicenter study of 324 patients with mild-to- followed by monotherapy with either calcitriol or calcipotriol moderate plaque psoriasis were included. They received twice daily for another 10 weeks. At week 2 in both arms, calcitriol 3 µg g-1 ointment twice a day for up to 52 weeks. more than 50% of the patients showed at least a marked 233 of the patients completed 26 weeks and 136 completed improvement of their psoriasis and at week 12, 79% in the 52 weeks of treatment. Efficacy was demonstrated over the calcitriol and 88% in the calcipotriol group, respectively. course of the treatment assessed with an investigator-rated Least-square means analysis of the PASI indicated both severity score. This evaluation demonstrated no or minimal regimens to be equivalent. There were no differences between psoriasis symptoms in 11% of the treated patients after the groups with regards to cutaneous safety or to incidence 12 weeks, in 22% after 24 weeks, in 37% after 36 weeks, and in 47% after 52 weeks. The psoriasis involved body surface area decreased from 16% at the beginning to 11% at the endpoints of the study. Serious adverse effects were In three separate studies, calcitriol 3 µg g-1 ointment was reported in eight patients, all cases probably unrelated to the used to treat moderate or severe lesions of chronic plaque study medication (skin ulcer at distant site, joint disorder, psoriasis localized in sensitive skin areas. In an open, two cases of metorrhagia, heart failure, hospitalization due five-center study, treatment was applied for eight weeks by to arteriosclerosis, breast cancer, and an infection following 11 male and 20 female patients with a history of psoriasis a dog bite). Ten patients showed transient hypercalcemia lasting from one to 757 months (mean 198 months) but none was clinically significant or led to discontinuation involving the face, hairline, or retroauricular areas.34 of the treatment. Furthermore, no clinically significant other A good response to treatment, in terms of improvement laboratory test parameters occurred. The global assessment in scaling, erythema, induration, and pruritus, was seen of improvement was rated by the patients. After 26 weeks by week 4 which continued through to week 8. The global 53% and after 52 weeks 64% of the patients reported at least improvement score indicated that at study endpoint, 74% a marked improvement of their psoriasis while 4% had dis- of patients were classified as definitely improved, or better. continued the treatment due to lack of efficacy and 3% due Another group of patients (12 males, 8 females) applied calcitriol 3 µg g-1 ointment for 6 weeks to psoriatic plaques on the face, hairline or retroauricular areas in a single-center Conclusions: Place of calcitriol
study.17 The clinical outcome showed a similar pattern to the previous study, although a higher proportion of in therapy of mild-to-moderate
patients experienced clearing of their lesions.17 One patient psoriasis
discontinued therapy prematurely, after 33 days of twice- Twice-daily calcitriol 3 µg g-1 ointment was demonstrated daily applications, due to complete clearance of lesions. to be an effective and safe treatment for mild-to-moderate In these two studies the cosmetic acceptability of treatment plaque psoriasis,20 including sensitive skin areas.17,26,34 was judged as good by the vast majority of patients; only The same is true for long-term treatment during and up to one patient considered the medication to be cosmetically For chronic conditions such as psoriasis the availability In another study 60 patients with mild-to-moderate of a range of therapies allows treatment to be adapted to plaque psoriasis involving sensitive areas were treated with patients’ needs, clinical response, and tolerance. It is therefore calcitriol 3 µg g-1 ointment twice a day for 12 weeks. The important to determine the comparability and compatibility clinical remission rate progressively increased throughout of different treatments and thereby to establish their place in therapy from 11.6% at week 4 to 63.3% at week 12. No serious adverse events and clinically relevant changes of Investigation of the efficacy of twice-daily calcitriol 3 µg g-1 calcium homeostasis were observed. Six patients withdrew ointment shows it to be as effective as short contact dithranol, after four weeks of treatment because of increasing pruritus. a well-established treatment for chronic plaque psoriasis.35 Another 12 patients noted mild skin irritation or pruritus However, due to the much lower frequency of skin irritation which spontaneously disappeared in six patients during and staining, calcitriol was associated with significantly better overall patient acceptability than dithranol cream. Clinical, Cosmetic and Investigational Dermatology 2009:2 submit your manuscript
Topical betamethasone dipropinate, a corticosteroid, was References
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still going strong! Eur J Dermatol. 1991;1:79–89.
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Spliceosomal peptide p140 for immunotherapy of systemic lupus erythematosus: results of an early phase ii clinical trial
Vol. 58, No. 12, December 2008, pp 3873–3883© 2008, American College of RheumatologySpliceosomal Peptide P140 for Immunotherapy ofResults of an Early Phase II Clinical TrialSylviane Muller,1 Fanny Monneaux,1 Nicolas Schall,1 Rasho K. Rashkov,2Boycho A. Oparanov,3 Philippe Wiesel,4 Jean-Marie Geiger,5 and Robert Zimmer5 Objective. To assess the safety, tolerability, and double-stran