Vitamin D analogue calcipotriol is currently used in the local treatment of psoriasis. However, it also has antiproliferative and anti-inflammatory effects in the cells of the joint - suggesting a possible benefit in local treatment of arthritis. In this study, calcipotriol was studied in different in vitro methods to find out its effect on synovial and mesenchymal stromal cells. Primary human cell lines of osteoarthritis or rheumatoid arthritis patients (five mesenchymal stromal cells, MSC, and four synovial stromal cells, SSC) were cultured to study migration and proliferation of the cells in a wound healing model. The media was supplemented with calcipotriol, 1,25(OH)2D3, dexamethasone, betamethasone, methylprednisolone or control solution in 1-100 nM concentrations. To see possible toxic effects of calcipotriol, concentrations up to 10 µM in SSCs and MSCs were studied in apoptosis and necrosis assays in four cell lines. Calcipotriol and 1,25(OH)2D3, as well as the three glucocorticoids, reduced the migration of both SSCs and MSCs. In SSCs, the effect of calcipotriol and 1,25(OH)2D3 was at least as effective as with glucocorticoids, while with MSCs, the glucocorticoids were stronger inhibitors of migration. The antimigratory of calcipotriol and 1,25(OH)2D3 was consistently maintained in 10 µM and 1 µM. Calcipotriol was not toxic to MSCs and SSCs up to concentrations of 10 µM. Calcipotriol, as well as 1,25(OH)2D3, exerts antimigratory and antiproliferative effects on human SSCs and MSCs of the joint. These effects are not caused by apoptosis or necrosis. Both calcipotriol and 1,25(OH)2D3 have similar effects as glucocorticoids without apparent toxicity, suggesting that calcipotriol might be an eligible candidate to the local treatment of arthritis with a broad therapeutic window.

Psoriasis Vulgaris is a common immune-mediated skin disease. Its high prevalence, disability, chronicity, disfiguration, and associated comorbidities make it a challenge for physicians. Topical agents remain the mainstay of treatment for patients with mild to moderate psoriasis.

To evaluate the efficacy and tolerability of topical methotrexate 1% gel (MTX) versus topical calcipotriol 0.005% cream (CPL) in the treatment of localized plaque psoriasis.

This prospective comparative study included 40 patients with localized plaque psoriasis instructed to apply MTX to one side (group A) and CPL to the other side lesions (group B) twice daily for 12 weeks. Clinical and dermoscopic evaluations before, weekly during and after 3 months of treatment were done. The immunohistopathological assessment was done for skin biopsies from 10 patients in each group before and after treatment.

At the end of 12 weeks, there was marked-complete improvement in 97.5% of group A lesions treated with MTX 1% gel compared with 37.5% of group B lesions treated with calcipotriol 0.005% cream (p < 0.001). There was a very high statistically significant improvement in erythema that was cleared totally in 67.5% vs 22.5%, scaling in 75% vs 17.5%, and infiltration in 72.5% vs 27.5% in group A vs B, respectively (p < 0.001). These results were confirmed by dermoscopic and immunohistopathological findings.

Methotrexate 1% gel is a marvelous promising well-tolerated effective topical agent that can be used safely in the treatment of localized plaque psoriasis.

To identify long-term efficacy evidence that supports use of topical therapies as regular maintenance therapy in the prevention of psoriasis relapse.

A systematic literature review identified clinical trials and observational studies that reported efficacy outcomes for topical psoriasis therapies with treatment durations of at least 12 weeks. For therapies with long-term data, the approved treatment schedules in product labels were reviewed.

Forty-six studies with at least 12-week efficacy outcomes were identified. Eight randomized controlled trials and six observational studies or single-arm open-label studies reported efficacy data for >12-week treatment periods. Most studies used treatment regimens that reflect current standard of care of repeated treatment of relapses. The PSO-LONG study is the only identified randomized controlled trial to have compared regular proactive maintenance use of a topical treatment (calcipotriol/betamethasone foam) with reactive management in response to psoriasis relapses.

Limited high-quality long-term efficacy data are available for topical psoriasis therapies. While some product labels mention clinical experience of up to 12 months, they do not provide specific recommendations on the optimal long-term regimen. Calcipotriol/betamethasone foam is the only treatment for which the approved label allows either reactive treatment of relapse or regular (twice weekly) maintenance use.

Current data from daily practice show that vitamin D₃ analogues, corticosteroids and their fixed combination products are used heterogeneously for topical long-term treatment of psoriasis.

To evaluate scientific evidence about topical long-term therapy with vitamin D3 analogues, corticosteroids and their two-compound-products in psoriasis vulgaris and scalp psoriasis and to develop daily practice recommendations.

Systematic literature review via PubMed and Embase and informal expert consensus.

The search strategy identified 21 relevant clinical trials. Best evidence regarding topical long term treatment was available for the two-compound-formulation containing calcipotriene and betamethasone. In a comparative trial in psoriasis vulgaris the two-compound-formulation showed superior tolerability and cost effectiveness compared to monotherapy. In scalp psoriasis the two-compound-gel was superior compared to calcipotriene monotherapy. Standardized and simplified treatment application modes resulted in a better clinical outcome comparing to on-demand therapies.

Patients should be proactively involved in the choice of treatment, formulation and mode of application. Besides long-term treatment with the two-compound-formulation other treatment regimens including calcipotriene monotherapy can also be considered. Due to a favorable risk-benefit ratio in maintenance trials and due to better cost-effectiveness the application of two-compound-products once or twice a week after initial therapy is recommended.

Chronic plaque psoriasis is the most common type of psoriasis, and it is characterised by redness, thickness, and scaling. First-line management of chronic plaque psoriasis is with topical treatments, including vitamin D analogues, topical corticosteroids, tar-based preparations, dithranol, salicylic acid, and topical retinoids.

To compare the effectiveness, tolerability, and safety of topical treatments for chronic plaque psoriasis, relative to placebo, and to similarly compare vitamin D analogues (used alone or in combination) with other topical treatments.

We updated our searches of the following databases to February 2011: the Cochrane Skin Group Specialised Register, CENTRAL in The Cochrane Library (2011, Issue 2), MEDLINE (from 1948), EMBASE (from 1980), Science Citation Index (from 2008), Conference Proceedings Citation Index - Science (from 2008), BIOSIS (from 1993), Dissertation Abstracts via DialogClassic (all publication years), and Inside Conferences (all publication years).We identified ongoing and unpublished studies from the UK Clinical Research Network Study Portfolio and the metaRegister of Controlled Trials. We checked the bibliographies of published studies and reviews for further references to relevant trials, and we contacted trialists and companies for information about newly published studies.A separate search for adverse effects was undertaken in February 2011 using MEDLINE and EMBASE (from 2005).Final update searches for both RCTs and adverse effects were undertaken in August 2012. Although it has not been possible to incorporate RCTs and adverse effects studies identified through these final searches within this review, we will incorporate these into the next update.

Randomised trials comparing active topical treatments against placebo or against vitamin D analogues (used alone or in combination) in people with chronic plaque psoriasis.

One author extracted study data and assessed study quality. A second author checked these data. We routinely contacted trialists and companies for missing data. We also extracted data on withdrawals and on local and systemic adverse events. We defined long-term trials as those with a duration of at least 24 weeks.

This update added 48 trials and provided evidence on 7 new active treatments. In total, the review included 177 randomised controlled trials, with 34,808 participants, including 26 trials of scalp psoriasis and 6 trials of inverse psoriasis, facial psoriasis, or both. The number of included studies counted by Review Manager (RevMan) is higher than these figures (190) because we entered each study reporting a placebo and an active comparison into the 'Characteristics of included studies' table as 2 studies.When used on the body, most vitamin D analogues were significantly more effective than placebo, with the standardised mean difference (SMD) ranging from -0.67 (95% CI -1.04 to -0.30; 1 study, 119 participants) for twice-daily becocalcidiol to SMD -1.66 (95% CI -2.66 to -0.67; 1 study, 11 participants) for once-daily paricalcitol. On a 6-point global improvement scale, these effects translate into 0.8 and 1.9 points, respectively. Most corticosteroids also performed better than placebo; potent corticosteroids (SMD -0.89; 95% CI -1.06 to -0.72; I² statistic = 65.1%; 14 studies, 2011 participants) had smaller benefits than very potent corticosteroids (SMD -1.56; 95% CI -1.87 to -1.26); I² statistic = 81.7%; 10 studies, 1264 participants). On a 6-point improvement scale, these benefits equate to 1.0 and 1.8 points, respectively. Dithranol, combined treatment with vitamin D/corticosteroid, and tazarotene all performed significantly better than placebo.Head-to-head comparisons of vitamin D for psoriasis of the body against potent or very potent corticosteroids had mixed findings. For both body and scalp psoriasis, combined treatment with vitamin D and corticosteroid performed significantly better than vitamin D alone or corticosteroid alone. Vitamin D generally performed better than coal tar, but findings relative to dithranol were mixed. When applied to psoriasis of the scalp, vitamin D was significantly less effective than both potent corticosteroids and very potent corticosteroids. Indirect evidence from placebo-controlled trials supported these findings.For both body and scalp psoriasis, potent corticosteroids were less likely than vitamin D to cause local adverse events, such as burning or irritation. Combined treatment with vitamin D/corticosteroid on either the body or the scalp was tolerated as well as potent corticosteroids, and significantly better than vitamin D alone. Only 25 trials assessed clinical cutaneous dermal atrophy; few cases were detected, but trials reported insufficient information to determine whether assessment methods were robust. Clinical measurements of dermal atrophy are insensitive and detect only the most severe cases. No comparison of topical agents found a significant difference in systemic adverse effects.

Corticosteroids perform at least as well as vitamin D analogues, and they are associated with a lower incidence of local adverse events. However, for people with chronic plaque psoriasis receiving long-term treatment with corticosteroids, there remains a lack of evidence about the risk of skin dermal atrophy. Further research is required to inform long-term maintenance treatment and provide appropriate safety data.

Published data are reviewed on the pharmacology, efficacy, tolerability, and pleasantness of the vitamin D(3) analogue calcipotriol in a cream formulation (Daivonex/Dovonex cream; LEO Pharma AS, Denmark) in the treatment of psoriasis. Calcipotriol cream monotherapy is more effective than placebo, and as effective as betamethasone valerate cream and coal tar in psoriasis. A regimen of morning-cream and evening-ointment is equally effective as twice-daily calcipotriol ointment and is preferred by patients. Calcipotriol cream is also a highly efficacious maintenance treatment used alone or in an alternating regimen with calcipotriol/betamethasone dipropionate ointment. Short- and long-term trials have demonstrated that calcipotriol cream is well tolerated by patients with psoriasis. Irritation is observed less frequently than with calcipotriol ointment, making the cream very suitable for children and thin or sensitive areas, such as flexures or (off-label use) the face. Calcipotriol cream is generally preferred to the ointment formulation, as shown by preference testing, and leads to improved patient compliance. In conclusion, calcipotriol cream is not only an effective treatment for psoriasis but is pleasant to use and well tolerated even in sensitive areas. Therefore, calcipotriol cream is particularly useful for the maintenance treatment of psoriasis, after induction therapy with a fast-acting vitamin D/steroid two-compound product.

Chronic plaque psoriasis is the most common type of psoriasis and is characterised by redness, thickness and scaling. First line management of chronic plaque psoriasis is with topical treatments, including vitamin D analogues, topical corticosteroids, tar-based preparations, dithranol, salicylic acid and topical retinoids.

To compare the effectiveness, tolerability and safety of topical treatments for chronic plaque psoriasis with placebo; to compare vitamin D analogues with other topical treatments.

The Cochrane Skin Group's Trials Register was searched (2004/12). To update an unpublished 2002 review we also searched CENTRAL in The Cochrane Library (Issue 1,2005); MEDLINE (to 2005/02); EMBASE (to 2005/08); Science Citation Index (to 2005); Biosis (to 2005); Dissertation Abstracts (all publication years); Inside Conferences (all publication years); SIGLE (to 2005); National Research Register (all projects with a start date of 2001 to 2005); metaRegister of Current Controlled Trials.

Randomised trials comparing treatments against placebo or against vitamin D analogues in people with chronic plaque psoriasis.

One author extracted study data and assessed study quality. A second author checked these data. We routinely contacted triallists and companies for missing data. We extracted data on withdrawals and adverse events.

The review included 131 RCTs with 21,448 participants. Vitamin D was significantly more effective than placebo, although there was a wide variation in effect size with the standardised mean difference (SMD) ranging from -0.82 (95% CI -1.34 to -0.29) to -1.90 (95% CI -2.09 to -1.71). With one exception, all corticosteroids performed better than placebo, with potent corticosteroids (SMD: -0.95 (95% CI: -1.11 to -0.80; I(2): 61.1%; 17 studies; 2386 participants)) having smaller benefits than very potent corticosteroids (SMD: -1.29 (95% CI: -1.45 to -1.13; I(2): 53.2%; 11 studies; 1571 participants)). Dithranol and tazarotene performed better than placebo. Head-to-head comparisons of vitamin D against potent or very potent corticosteroids found no significant differences. However, combined treatment with vitamin D /corticosteroid performed significantly better than either vitamin D alone or corticosteroid alone. Vitamin D performed better than coal tar, but findings relative to dithranol were mixed. Potent corticosteroids were less likely than vitamin D to cause local adverse events. No comparison of topical agents found a significant difference in systemic adverse effects.

Corticosteroids perform as well as vitamin D analogues and are associated with a lower incidence of local adverse events. Further research is required to inform long-term maintenance treatment.

Vitamin D has pleiotropic effects that go beyond its traditional role in calcium homeostasis. Hundreds of genes with vitamin D receptor response elements directly or indirectly influence cell cycling and proliferation, differentiation, and apoptosis. Vitamin D compounds also have effects on cell function that are nongenomic. The noncalcemic actions of vitamin D influence normal and pathological cell growth, carcinogenesis, immune function, and cardiovascular physiology. This review examines many of the various mechanisms by which vitamin D alters cellular growth and differentiation and explores cell-specific factors that influence responsiveness to vitamin D.

There is a need for new treatments for scalp psoriasis, as many topical treatments are cosmetically unacceptable and difficult to apply, resulting in poor compliance.

To compare the efficacy and safety of a new, once-daily, two-compound scalp formulation (Xamiol; LEO Pharma A/S, Ballerup, Denmark) containing calcipotriol 50 microg g(-1) plus betamethasone 0.5 mg g(-1) (as dipropionate), with the active ingredients as single compounds in the same vehicle.

This 8-week, multicentre, double-blind, parallel-group study, randomized adult patients with scalp psoriasis involving > 10% of the scalp to the two-compound scalp formulation (n = 568), betamethasone dipropionate 0.5 mg g(-1) (n = 563), or calcipotriol 50 microg g(-1) (n = 286). The primary efficacy measure was the proportion of patients with 'absence of disease' or 'very mild disease' according to investigators' assessments at week 8.

The proportion of patients with 'absence of disease' or 'very mild disease' at week 8 was significantly higher in the two-compound group (68.4%) than the betamethasone dipropionate (61.0%, P = 0.0079) or calcipotriol (43.4%, P < 0.0001) groups. The proportion of patients rating their scalp psoriasis as 'clear' or 'almost clear' was significantly higher for the two-compound scalp formulation (69.6%) than for betamethasone dipropionate (59.9%, P = 0.0006) or calcipotriol (44.7%, P < 0.0001). The incidence of lesional/perilesional adverse events was lower in the two-compound and betamethasone dipropionate groups than the calcipotriol group.

The two-compound scalp formulation was well tolerated and more effective in the treatment of scalp psoriasis than either of its individual components in the same vehicle.

There is a need for more effective therapy for scalp psoriasis.

To assess the efficacy and safety of a 2-compound scalp formulation including calcipotriol and betamethasone dipropionate in the treatment of scalp psoriasis.

Patients (n = 218) with scalp psoriasis were randomized to treatment with the 2-compound scalp formulation (n = 108) or betamethasone dipropionate in the same vehicle (n = 110). The treatments were applied once daily on the scalp for up to 8 weeks.

The 2-compound scalp formulation showed a significantly higher efficacy than betamethasone dipropionate on the total sign score at the end of treatment (p = 0.042) and after 2 weeks (p = 0.005).

The calcipotriol plus betamethasone dipropionate scalp formulation was superior to betamethasone dipropionate in the same vehicle when used once daily for up to 8 weeks in the treatment of scalp psoriasis.

The scalp is the most common site of disease involvement at the onset and throughout the course of psoriasis. For many patients, psoriasis of the scalp is the most difficult aspect of their disease; yet, despite a wide range of therapy options and an extensive literature base, scalp psoriasis remains difficult to treat, highlighting a long-standing unmet need for the effective treatment of scalp psoriasis. A review of past and current medical literature reveals that a number of interesting therapeutic approaches have been used in the treatment of scalp psoriasis. The diverse and sometimes extreme therapeutic approaches, the marginal benefit of many topical agents, the paucity of controlled studies evaluating the efficacy of topical agents in the treatment of scalp psoriasis and the high level of patient dissatisfaction with currently available treatments for psoriasis all support the need for new, effective and well-tolerated treatment options for scalp psoriasis.

Psoriasis vulgaris requires lifelong treatment associated with considerable health cost. Studies showed that a combination of a steroid and a vitamin D(3) analogue is more effective than both compounds in monotherapy.

To determine the cost-effectiveness of a fix calcipotriol/betamethasone combination (Daivobet/Dovobet/Taclonex) compared to a morning/evening non-fix calcipotriol/betamethasone combination in psoriasis treatment.

A Markov model (discrete-time stochastic process based on transitions between health states) with 2 treatment arms (Daivobet/Dovobet/Taclonex vs. non-fix calcipotriol/betamethasone) over a 48-week time period was developed. The effectiveness criterion was the number of days with clearance or marked improvement. Clinical and health resource utilisation data were derived from randomised studies.

Treatment with Daivobet/Dovobet/Taclonex showed a higher cost-effectiveness compared to the non-fix combination, even when assuming a maximum compliance for the twice daily non-fix combination and varying the effectiveness of Daivobet/Dovobet/Taclonex by 10%.

Psoriasis treatment with a fix calcipotriol/betamethasone combination is more cost-effective than a non-fix morning/evening combination.

Management of psoriasis begins with identification of the extent of cutaneous disease. However, a holistic, contractual approach to treatment is encouraged, with particular reference to psychosocial disability and quality-of-life issues. The presence of psoriasis on palms, soles, body folds, genitals, face, or nails, and concomitant joint disease, are also important when considering treatment options. An evidence-based approach is essential in delineating differences between the many available treatments. However, archaic approaches, especially combinational ones, are routinely used by some clinicians, with inadequate prospective or comparative evidence. Treatments currently available are: topical agents used predominantly for mild disease and for recalcitrant lesions in more severe disease; phototherapy for moderate disease; and systemic agents including photochemotherapy, oral agents, and newer injectable biological agents, which have revolutionised the management of severe psoriasis. Other innovative treatments are undergoing clinical studies, with the aim of maintaining safe, long-term control of the condition.

The calcipotriol/betamethasone dipropionate two-compound product is safe and effective in the short-term treatment of psoriasis.

The primary objective was to investigate the safety of two treatment regimens involving use of the two-compound product over 52 weeks. The efficacy results are presented here.

Six hundred and thirty-four patients were randomised double-blind to treatment (once daily, when required) with either: 52 weeks of two-compound product (two-compound group), 52 weeks of alternating 4-week periods of two-compound product and calcipotriol (alternating group), or 4 weeks of two-compound product followed by 48 weeks of calcipotriol (calcipotriol group).

There was a trend towards a difference between treatments from the overall treatment effect for the percentage of satisfactory responses for each patient during the study (p = 0.071). This appeared to be due to the comparison of the two-compound and calcipotriol groups (p = 0.025).

There was a trend towards the efficacy of the two-compound product used for up to 52 weeks being better than that of 4 weeks of the two-compound product followed by 48 weeks of calcipotriol.

The two-compound product calcipotriol/betamethasone dipropionate is arising as a first-line treatment for mild-to-moderate plaque psoriasis. Its beneficial action is attributed to the synergistic effect of its components on keratinocyte proliferation and differentiation, and on inflammation. The good tolerability of the two-compound product is thought to be due to the anti-inflammatory effect of betamethasone. Evidence from short-term (4-12 weeks) and long-term use (> 1 year) has shown a good safety profile. Areas such as the face or skin folds, which are sensitive to the components of the combination, should be avoided. Finally, it is unsuitable for use in unstable psoriasis, in which potent steroids may lead to an increased inflammatory response.

Calcipotriol has become a first-line treatment for psoriasis. Its efficacy and safety have been shown in many comparative clinical trials carried out in outpatients. In a comparative study in patients visiting the outpatient department once every 14 days, it was shown that calcipotriol was more effective and better tolerated compared with dithranol.

To compare the clinical efficacy of calcipotriol ointment with that of dithranol cream in a supervised treatment regimen.

In a multicentre randomized controlled trial in six centres in the Netherlands, 106 patients with chronic plaque psoriasis were included, 54 receiving calcipotriol ointment twice daily and 52 dithranol cream once daily. Patients were treated at the day-care centre, using the care instruction principle of daily visits during the first week and twice-weekly visits subsequently for up to 12 weeks.

This study failed to prove that calcipotriol is as efficacious as dithranol when used in a day-care setting (noninferiority test). The mean percentage reduction in Psoriasis Area and Severity Index from baseline to end of treatment was 57.0% in the calcipotriol group vs. 63.6% in the dithranol group. However, the two-sided test for superiority indicated no statistically significant difference between the treatment groups (P = 0.39). At the end of treatment, 15% of the patients treated with calcipotriol ointment and 25% of those treated with dithranol cream did not require any further treatment. Although calcipotriol ointment appeared to be more effective during the first 8 weeks, a difference was no longer apparent at 12 weeks. In comparison with the high number of drop-outs due to cutaneous side-effects in the calcipotriol group, the frequency of a tolerable degree of irritation appeared to be higher in patients treated with dithranol. However, concomitant corticosteroid treatment of dithranol irritation in seven patients may have contributed to this difference between both treatments. Moreover, patients receiving therapy with calcipotriol ointment experienced fewer application-related skin and subcutaneous tissue disorders than patients treated with dithranol cream: 21 of 53 (40%) and 37 of 52 (71%), respectively. This difference is statistically significant (P = 0.001).

The hypothesis that calcipotriol ointment might be at least as effective as dithranol cream in the day-care setting could not be proven in the present study. Whereas calcipotriol has become a mainstay in the routine outpatient treatment of psoriasis not requiring a day-care setting, dithranol treatment, being difficult as a routine outpatient therapy, has increased efficacy and improved tolerability if the treatment is carried out in a day-care setting.

The calcipotriol/betamethasone dipropionate two-compound product Dovobet/Daivobet/Taclonex(LEO Pharma A/S, Ballerup, Denmark) has been shown to be safe and effective in the treatment of psoriasis for up to 8 weeks. As psoriasis is a chronic disease, long-term treatment may be required, so there is a need to investigate the safety of its use over a longer period of time.

To investigate the safety of two treatment regimens involving use of the two-compound product over 52 weeks in the treatment of patients with psoriasis.

Patients (n = 634) were randomized double-blind to treatment with: (i) 52 weeks of the two-compound product (two-compound group); (ii) 52 weeks of alternating 4-week periods of the two-compound product and calcipotriol (alternating group); or (iii) 4 weeks of the two-compound product followed by 48 weeks of calcipotriol (calcipotriol group). Treatments in all groups were used once daily when required.

Adverse drug reactions (ADRs) occurred in 45 (21.7%) patients in the two-compound group, 63 (29.6%) in the alternating group and 78 (37.9%) in the calcipotriol group. The odds ratio for an ADR in the two-compound group relative to the calcipotriol group was 0.46 (95% confidence interval 0.30-0.70; P < 0.001). ADRs of concern associated with long-term topical corticosteroid use occurred in 10 (4.8%) patients in the two-compound group, six (2.8%) in the alternating group and six (2.9%) in the calcipotriol group; those with the highest incidence were skin atrophy, occurring in four (1.9%), one (0.5%) and two (1.0%) patients, respectively, and folliculitis, in three (1.4%), one (0.5%) and no patients, respectively.

Treatment with the two-compound product for up to 52 weeks appears to be safe and well tolerated whether used on its own or alternating every 4 weeks with calcipotriol treatment.

1alpha,25-Dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], the active metabolite of vitamin D(3), is known for the maintenance of mineral homeostasis and normal skeletal architecture. However, apart from these traditional calcium-related actions, 1,25-(OH)(2)D(3) and its synthetic analogs are being increasingly recognized for their potent antiproliferative, prodifferentiative, and immunomodulatory activities. These actions of 1,25-(OH)(2)D(3) are mediated through vitamin D receptor (VDR), which belongs to the superfamily of steroid/thyroid hormone nuclear receptors. Physiological and pharmacological actions of 1,25-(OH)(2)D(3) in various systems, along with the detection of VDR in target cells, have indicated potential therapeutic applications of VDR ligands in inflammation (rheumatoid arthritis, psoriatic arthritis), dermatological indications (psoriasis, actinic keratosis, seborrheic dermatitis, photoaging), osteoporosis (postmenopausal and steroid-induced osteoporosis), cancers (prostate, colon, breast, myelodysplasia, leukemia, head and neck squamous cell carcinoma, and basal cell carcinoma), secondary hyperparathyroidism, and autoimmune diseases (systemic lupus erythematosus, type I diabetes, multiple sclerosis, and organ transplantation). As a result, VDR ligands have been developed for the treatment of psoriasis, osteoporosis, and secondary hyperparathyroidism. Furthermore, encouraging results have been obtained with VDR ligands in clinical trials of prostate cancer and hepatocellular carcinoma. This review deals with the molecular aspects of noncalcemic actions of vitamin D analogs that account for the efficacy of VDR ligands in the above-mentioned indications.

Several topical treatments are available for patients with psoriasis. Although individualization of the treatment remains important, there is a need for treatment recommendations to identify the best treatment out of the available treatments and to help with improvement in treatment compliance. In this communication we give our views on the assessment of severity of psoriasis. We provide recommendations for selection of treatments, reconciling the clearance phase and the long-term management. Finally, we provide recommendations for the treatment of particular localizations: the scalp and psoriasis at sensitive sites.

The goals of the experiments reported in this paper were to explore skin bioavailability and cell growth inhibitory activity of new vitamin D3-based conjugates studied as a potential drug complex for psoriasis.

Conjugation was made between polyunsaturated fatty acids (PUFAs), such as linolenic acid or gamma-linolenic acid, and calcipotriol--a vitamin D3 analogue clinically used for topical treatment of psoriasis. These complexes were prepared by coupling the corresponding fatty acid with calcipotriol in the presence of dicyclohexyl-carbodiimide (DCC) and 4-(dimethylamino)-pyridine (DMAP) to obtain an ester bond.

The conjugates were capable of enhancing the penetration of the vitamin into the skin as well as inhibiting proliferation of keratinocytes in cultures. The antiproliferative activity even increased after simulating the full hydrolysis of the conjugates. In vitro skin penetration studies revealed that the conjugates penetrated into the skin at higher levels relative to calcipotriol alone. It was also demonstrated that the conjugate containing n-3 fatty acid penetrated into the skin at higher levels as compared to the conjugate containing n-6 PUFA. High-performance liquid chromatography analysis has shown that after penetration, a major portion of calcipotriol-PUFA conjugate was first converted mainly into another isomer form, presumably by transesterification, and only then it was hydrolyzed to form apparently high local concentrations of both calcipotriol and PUFA.

The unique biotransformation that occurred after penetration into the skin indicates that these conjugates are mutual prodrugs that are able to be bioprocessed in the skin and fully converted to the parent therapeutic agents.

This article discusses the prebiologic armamentarium, which continues to play a significant role in certain patients for the treatment of psoriasis. With the creation of the newer"biologics," however, the treatment of psoriasis is being re-evaluated.

A two-compound ointment containing calcipotriol 50 micro g g-1 and betamethasone dipropionate 0.5 mg g-1 has recently been shown to be an effective treatment for psoriasis.

This study was designed to investigate efficacy and safety of different treatment regimens with the two-compound product (Daivobet/Dovobet; LEO Pharma, Ballerup, Denmark) and calcipotriol 50 micro g g-1 ointment (Daivonex/Dovonex; LEO Pharma).

In total, 972 patients with psoriasis vulgaris were randomized to one of three treatment regimens: group 1, the two-compound product once daily for 8 weeks followed by calcipotriol ointment once daily for 4 weeks; group 2, the two-compound product once daily for 4 weeks followed by 8 weeks of treatment with calcipotriol ointment once daily on weekdays and the two-compound product once daily at weekends; and group 3, calcipotriol ointment twice daily for 12 weeks. The efficacy was evaluated by Psoriasis Area and Severity Index (PASI) and investigators' global assessments of disease severity. The primary response criteria were percentage reduction in PASI and proportion of patients with absent/very mild disease according to the investigators' global assessments after 8 weeks of treatment.

The mean reduction in PASI from baseline to the end of 8 weeks of treatment was 73.3% for group 1, 68.2% for group 2 and 64.1% for group 3. The proportion of patients with absent/very mild disease at the end of 8 weeks of treatment was 55.3% for group 1, 47.7% for group 2 and 40.7% for group 3. For both primary response criteria, group 1 was statistically superior to group 3 (P < 0.001), whereas group 2 did not differ significantly from group 3. The difference between group 1 and group 2 was statistically significant with regard to PASI but not regarding the proportion of patients with absent/very mild disease. Patients receiving initial therapy with the two-compound product achieved the fastest treatment response, and the maximum treatment effect for these patients was seen after 5 weeks. This effect was maintained with continued treatment with the two-compound product for up to 8 weeks. After 12 weeks of treatment, no significant differences were seen between the three groups with regard to reduction in PASI, whereas the proportion of patients with absent/very mild disease in group 2 was superior to that in group 3. Patients receiving therapy with the two-compound product experienced fewer lesional/perilesional adverse drug reactions than the calcipotriol-treated patients (P < 0.001): 10.9% in group 1, 11.5% in group 2 and 22.3% in group 3.

Two different short-term treatment regimens employing a recently developed two-compound product (calcipotriol/betamethasone dipropionate) provided rapid and marked clinical efficacy and were shown to be safe therapies for psoriasis vulgaris.

Calcipotriene and betamethasone dipropionate are topical treatments for psoriasis vulgaris. Their mode of action is different. Improved risk/benefit may result with concomitant use of the two compounds together. A new vehicle has been created with the objective of obtaining optimal stability of both calcipotriene and betamethasone dipropionate in the combination product.

We compared the clinical efficacy of a fixed combination of calcipotriene and betamethasone dipropionate in a new vehicle to calcipotriene in the new vehicle, betamethasone in the new vehicle, and the new vehicle alone.

This was an international, multicenter, prospective, randomized, double-blind, parallel-group, 4-week study in patients with psoriasis vulgaris amenable to topical treatment.

The mean percentage reduction in PASI from baseline to end of treatment was 73.2% in the combination group (n = 301), 48.8% in the calcipotriene group (n = 308), 63.1% in the betamethasone dipropionate group (n = 312) and 28.8% in the new vehicle group (n = 107), (P < .001). The mean percentage reduction in PASI during the first week was 48.1%, 28.4%, 41.4%, and 21.5%, respectively (P < .001).

A combination product of calcipotriene 50 microg/g and betamethasone dipropionate 0.5 mg/g in the new vehicle shows superior efficacy with a more rapid onset of action than the new vehicle containing either constituent alone in the treatment of psoriasis vulgaris.

There is clinical uncertainty about the appropriate use of first-line topical treatments for psoriasis.

To assess the relative effectiveness and tolerability of topical treatments for psoriasis suitable for use both in primary and secondary care.

All major medical databases of published literature were searched electronically; references of trial reports and recent reviews were searched; authors and companies were contacted for missing data from published reports. The study selection comprised: (1) randomized placebo-controlled trials of topical treatments for psoriasis; and (2) randomized head-to-head studies of the new vitamin D3 derivative treatments for psoriasis that reported clinical outcome using a Total Severity Score (TSS), Psoriasis Area Severity Index or Investigator Assessment of Global Improvement. Eligibility and validity were assessed and data extracted independently by two authors. Clinical outcomes were pooled using a random effect standardized weighted mean difference (SWMD) metric, including 3380 patients randomized in 41 placebo (vehicle)-controlled trials and 4898 patients randomized in 28 head-to-head studies.

There was a significant benefit in favour of active treatments against vehicle, SWMD: -1.06 (95% confidence interval [CI]: -1.26 to -0.86), approximately a 2-point improvement on a 12-point TSS after 6-8 weeks of treatment. The only significantly different benefit was for very potent corticosteroids: SWMD: -1.51 (95% CI: -1.76 to -1.25), approximately a 3-point improvement on a 12-point TSS. Head-to-head studies support these findings, except that calcipotriol was estimated to be more effective than dithranol, coal tar and other vitamin D3 derivatives. Polytherapy, using a potent steroid and calcipotriol, was more effective than calcipotriol alone: SWMD 0.42 (95% CI: 0.12-0.72 ) approximately a 0.8-point improvement on a 12-point TSS. No important differences in withdrawal or reporting of adverse events were identified.

Trials of short duration neither adequately inform the management of chronic disease nor describe the sequelae of treatment. The evidence base for long-term care, reflecting the disease pathway, should be improved. Combination therapy with topical vitamin D analogues and steroids, and maintenance therapy following treatment response merit further investigation.