Vectical^® Ointment 3 mcg/g

BACKGROUND: Psoriasis is a hyperproliferative and inflammatory skin disorder that affects roughly 2 percent of the worldwide population. Clobetasol propionate is the most common corticosteroid used to treat moderate-to-severe psoriasis but the potential for side effects limits its long-term use. Topical vitamin D, which is used to treat mild-to-moderate psoriasis, has been shown to be safe when used daily for up to 52 weeks. To date, very few studies exist evaluating the use of clobetasol propionate in a regimen with calcitriol to manage moderate-to-severe disease over time. OBJECTIVES: To evaluate the efficacy and assess safety of a regimen of sequential topical treatments with clobetasol propionate 0.05% spray for up to four weeks followed by calcitriol 3 µg/g ointment for eight weeks in the management of moderate-to-severe plaque psoriasis. METHODS: This was a multi-center, open-label study in subjects aged 18-80 years with moderate-to-severe plaque psoriasis at baseline. Subjects applied clobetasol propionate 0.05% spray twice daily for up to four weeks. At the end of four weeks, if the subject’s overall disease severity (ODS) was assessed as clear, almost clear, mild or moderate, subjects started treatment with calcitriol 3 µg/g ointment twice daily. Twice-daily treatment with calcitriol 3 µg/g ointment continued for eight weeks (until week 12) or unless the subject’s ODS was assessed as severe or returned to the baseline score, at which time it was discontinued. Subjects were evaluated at baseline and at weeks 2, 4, 8 and 12. RESULTS: Of the 305 subjects enrolled, 170 subjects completed the full 12-week study with no major protocol deviations andcomprised the per-protocol (PP) study population. Treatment success, defined as at least one grade improvement in ODS at week 12 compared to baseline, was achieved in 84.1 percent of subjects. The percent body surface area affected (% BSA) decreased from 7.1 percent at baseline to 3.9 percent at week 12 (P<0.001). The sequential treatment regimen was well tolerated with no unexpected adverse events. Most reported adverse events and cutaneous irritations were mild in severity. CONCLUSIONS: The results of this study indicate that the 12-week regimen of clobetasol propionate 0.05% spray treatment for four weeks immediately followed by an eight-week treatment phase with calcitriol 3 µg/g ointment is efficacious and safe for the management of moderate-to-severe plaque psoriasis.

Topical vitamin D3 agents have emerged as important options for the treatment of psoriasis. Calcitriol, a naturally occurring and biologically active form of vitamin D3, has been developed in an ointment formulation for topical psoriasis therapy in the United States. The product has been used outside of the United States for years. Several short-term (<6 months) clinical trials have demonstrated that calcitriol ointment 3 µg/g improves symptoms of psoriasis in participants with mild to moderate plaque psoriasis without demonstrating clinical evidence of alterations in calcium homeostasis, but little information has been available about the safety and effectiveness of continuous long-term use of calcitriol ointment. In this open-label, multicenter study, 324 participants with primarily mild to moderate chronic plaque psoriasis were treated with calcitriol ointment 3 µg/g twice daily for up to 52 weeks. A total of 136 participants completed 52 weeks of treatment. Serious adverse events (AEs) (reported by 1 participant each unless otherwise noted) included a pretibial skin ulcer (study drug was used only on the upper body), a joint disorder, metrorrhagia (2 participants), heart failure, hospitalization due to arteriosclerosis, breast carcinoma, and an infection (due to a dog bite). Clinical improvement in psoriasis symptoms was assessed by an investigator-rated global severity score (GSS) and participant-rated global assessment of improvement in psoriasis symptoms from baseline. Improvements in GSS were seen over the course of treatment. Calcitriol ointment 3 µg/g is a safe, effective, and well-tolerated option for the long-term treatment of chronic plaque psoriasis. Clinical improvement was maintained for up to 52 weeks, with no clinical effect on calcium homeostasis or other relevant laboratory test parameters.

BACKGROUND: Psoriasis is a chronic skin disorder affecting approximately 2% of the US population. Psoriasis may occur anywhere on the body with initial presentation usually seen between 15 and 30 years of age. Calcitriol 3 µg/g ointment has demonstrated good clinical efficacy as well as topical and systemic safety when used to treat psoriasis. OBJECTIVES: To confirm the efficacy and safety of calcitriol 3 µg/g ointment versus its vehicle in the treatment of subjects with mild to moderate chronic plaque psoriasis. METHODS: Suitable subjects were randomized to receive either calcitriol 3 µg/g ointment or its vehicle twice daily for up to 8 weeks in 2 multicenter, randomized, vehicle-controlled, double-blind parallel group studies. Efficacy was evaluated through a Global Severity Score dichotomized in success (clear and minimal) or failure. Erythema, plaque elevation, scaling and dermatologic sum score (sum of the scores for erythema, plaque elevation, and scaling), pruritus, and global improvement were also assessed. Routine safety and clinical laboratory parameters, including calcium homeostasis, were evaluated throughout the study. RESULTS: In total, 839 subjects were included in the 2 studies: 419 patients received calcitriol 3 µg/g ointment and 420 received the vehicle. In both studies, calcitriol 3 µg/g ointment was shown to be significantly more effective than its vehicle, with onset of therapeutic effect seen as early as week 2 and sustained at all subsequent visits. Calcitriol 3 µg/g ointment demonstrated good systemic and local safety profile comparable to its vehicle with no effect on calcium homeostasis. CONCLUSION: Calcitriol 3 µg/g ointment applied for 8 weeks is effective and safe in the treatment of mild to moderate psoriasis.

BACKGROUND: Calcitriol and calcipotriol, two vitamin D derivatives, are available for topical treatment of psoriasis and have been shown to be effective. AIM: To compare the efficacy and safety of calcitriol 3 µg/g and calcipotriol 50 µg/g. METHODS: This was a multicentre, randomized, investigator-masked, and parallel comparison in subjects with mild to moderate chronic plaque-type psoriasis receiving either calcitriol or calcipotriol ointment twice daily for 12 weeks. Efficacy evaluations comprised global improvement (on a 4-point scale from 0: no change or worse, to 3: clear or almost clear) assessed by the investigator and by the subject. Efficacy further included the ‘dermatological sum score’ at each study visit. Safety evaluations included adverse event reporting, cutaneous safety assessed by the investigator and cutaneous discomfort assessment by the subject (both on a 5-point scale from 0: none, to 4: very severe). RESULTS: A total of 250 subjects of both gender were recruited. At week 12, the LS mean score of global improvement rated by the investigator was 2.27 for calcitriol and 2.22 for calcipotriol. This difference was not statistically significant, with calcitriol demonstrating to be non-inferior to calcipotriol for global improvement. This same parameter was scored by the subject, with a mean of 2.12 for calcitriol and 2.09 for calcipotriol. The percentage of patients with at least marked improvement tended to be in favour of calcitriol (95.7% vs. 85% for calcipotriol). However, differences were not statistically significant. The mean worst score for the cutaneous safety assessment was higher in the calcipotriol group (0.3 vs. 0.1 and 0.4 vs. 0.2, by the investigator and the patient, respectively). These differences were statistically significant in favour of a better safety profile for calcitriol (P = 0.0035). Fourteen dermatological and treatment-related adverse events were reported with calcipotriol vs. only five with calcitriol for a total of 22 adverse events reported throughout the study. CONCLUSION: Calcitriol administered twice daily over a 12-week treatment period demonstrated similar efficacy to calcipotriol, while showing a significantly better safety profile.

BACKGROUND: Ointments, classically used for the treatment of dermatological diseases, are monophasic viscous semisolid formulations. According to the proportion of their compounds, they have physicochemical and organoleptic properties and when applied on skin show a specific behaviour allowing to be spread more or less easily. OBJECTIVE: To measure in vitro rheological characteristics of three vitamin D derivative ointments prescribed for the treatment of psoriasis, and to compare their viscosity and clinical acceptability when applied on the diseased skin. METHODS: Rheological characteristics of tacalcitol 4 µg/g, calcipotriol 50 µg/g and calcitriol 3 µg/g ointments were assessed by measuring the oscillatory viscoelastic parameters and the permanent flow analysis. Clinical acceptability was studied in 20 psoriatic male or female subjects, aged 18 years or older. A survey evaluated the acceptability of calcitriol vs. tacalcitol and calcipotriol. Questions included information about fluidity, spreading capacity and stickiness after application. RESULTS: We demonstrated that viscoelastic parameters were four times higher for ointment tacalcitol than for calcipotriol and calcitriol, corresponding to a higher consistency of ointment tacalcitol compared to calcipotriol and calcitriol showing both similar results; better fluidity was demonstrated by calcitriol than by tacalcitol andcalcipotriol. Comparable results were obtained for the quality to be spread. The sensation of stickiness, significantly different between tacalcitol and calcitriol, was not different between calcipotriol and calcitriol. CONCLUSION: The above results confirm the relationship between rheological in vitro and sensorial in vivo results: variations between different formulations may have an important influence on non-adherence and treatment failure.

BACKGROUND: Calcitriol is the active metabolite and hormonal analogue of vitamin D3. It is widely used for the topical treatment of psoriasis showing good tolerability and effectiveness. OBJECTIVES: To assess the efficacy, tolerability and safety of calcitriol 3 µg/g ointment in mild to moderate plaque psoriasis involving sensitive areas. METHODS: Sixty patients with a body surface area < 35% were enrolled into a prospective open label clinical study. Patients were treated for 12 weeks with a twice daily calcitriol 3 µg/g topical ointment application. Efficacy and safety were assessed during the therapy and during a 6-month follow-up period. RESULTS: The study demonstrated a high clinical remission rate which progressively increased throughout therapy (11.6% at week 4, 28.3% at week 8 and 63.3% at week 12). No serious adverse events and clinically relevant changes of calcium/phosphorus homeostasis were reported. CONCLUSIONS: The study suggests that calcitriol 3 µg/g ointment, applied twice daily, is an effective topical treatment for chronic psoriatic plaques involving less than 35% of the body surface and sensitive areas.

For psoriasis therapy, topical derivatives of vitamin D3 represent a versatile option: they can be used either alone or in combination with other agents such as topical corticosteroids. In this two-phase parallel-group study, the naturally occurring vitamin D3 analogue, calcitriol, was compared with the vitamin D analogue calcipotriol in 125 patients with chronic plaque-type psoriasis. The proposed treatment regimen was an initial bitherapy for 2 or 4 weeks, with clobetasol propionate 0.05% cream, a super potent topical corticosteroid applied in the morning and either calcitriol 3 mug/g ointment or calcipotriol 50 mug/g ointment applied in the evening, followed by monotherapy with either calcitriol or calcipotriol applied twice daily until endpoint week 12. Efficacy evaluations (global assessment of improvement, PASI and body surface area (BSA) affected) showed no significant differences between the two regimen groups at the primary endpoints (week 2 and week 12) or at any interim points. At week 2 the investigator’s global assessment showed clinical success (psoriasis markedly improved, almost clear or clear) for more than 50% of the patients in both groups and for 48 (79%) and 56 (88%) patients, respectively in the calcitriol and calcipotriol regimen group at week 12. Least-square means analysis of PASI indicated the calcitriol regimen to be equivalent to the calcipotriol regimen. There were no significant differences between the two groups with regards to cutaneous safety or to incidence of adverse events. The present study shows that for the treatment of mild to moderate plaque psoriasis calcitriol 3 mug/g ointment can provide a safe and effective alternative to calcipotriol 50 mug/g ointment while being administered within a regimen based on a bitherapy with corticosteroids followed by a vitamin D3 maintenance monotherapy.

BACKGROUND: Psoriasis involving sensitive skin areas remains difficult to treat because of the side-effects of topical corticosteroids and the irritancy potential of vitamin D3 derivatives. Several clinical trials have demonstrated that calcitriol, the naturally occurring and hormonally active form of vitamin D3, is effective and safe at the dose of 3 µg g^-1 for the treatment of psoriasis affecting the trunk and limbs. METHODS: We compared the safety and efficacy of calcitriol 3 µg g^-1 ointment and calcipotriol 50 µg g^-1 ointment in a multicentre, randomized, investigator-blinded, left-right comparison in mild to moderate chronic plaquepsoriasis affecting sensitive areas, defined as being the face, hairline, retroauricular and flexural areas. One pair of symmetrical and bilateral target lesions was selected from each area and assessed for perilesional erythema, oedema, and stinging/burning. Global assessment of local tolerability and global improvement were rated by the investigator, and the subjects were asked to evaluate the tolerability and efficacy of each product and to express their global preference. RESULTS: In the 75 subjects, calcitriol and calcipotriol both led to clearing of at least one target lesion in 21 (28%) of the subjects each. Perilesional erythema (P < 0.001), perilesional oedema (P < 0.02) and stinging/burning (P < 0.001) were all significantly less severe with calcitriol than with calcipotriol. The subjects’ evaluation of local tolerability was significantly (P < 0.0001) in favour of calcitriol. Ten treatment-related dermatological events occurred in eight subjects, including one subject who experienced skin discomfort on both sides. All other events occurred only on the calcipotriol-treated side (irritant dermatitis, six subjects; contact dermatitis, one subject). Global assessment of improvement from baseline by the investigators was significantly greater for the calcitriol-treated lesions (P < 0.02). The subjects’ global preference was significantly in favour of calcitriol (P < 0.02). CONCLUSIONS: In the present study, calcitriol ointment was found to be better tolerated and would appear to be more effective than calcipotriol ointment in the treatment of psoriasis in sensitive areas.

A randomized, double-blind, left-right, vehicle-controlled study to assess the therapeutic efficacy and safety of twice daily application of 15 µg/g calcitriol ointment for a period of 6 weeks was performed in 32 patients suffering from bilateral, symmetrical, severe chronic plaque psoriasis. Twice daily 15 µg/g calcitriol ointment significantly improved erythema, induration, scaling and global severity of psoriatic plaques, and was much more effective than vehicle ointment. The difference in overall clinical efficacy between calcitriol and vehicle was statistically significant from week 1 onwards, and was maintained over the entire study. On completion of the study, clearance of psoriatic lesions was found in 47% of calcitriol-treated sides and in 13% of vehicle-treated sides. Skin histopathology of calcitriol-treated sides revealed a return to normal keratinization, with decreased inflammatory cell infiltration in the dermis and disappearance of the inflammatory infiltrate from the epidermis. Three patients had asymptomatic hypercalcaemia during the study. Mean serum levels of total calcium, albumin-adjusted total calcium, phosphorus, 25-hydroxyvitamin D and calcitriol did not show statistically significant changes in the baseline/end-point comparisons.

Constant exposure to a wide variety of microbial pathogens represents a major challenge for our skin. Antimicrobial peptides (AMPs) are mediators of cutaneous innate immunity and protect primarily against microbial infections. Cathelicidins were among the first AMPs identified in human skin and recent evidence suggests that they exert a dual role in innate immune defense: At first, due to their antimicrobial activity they kill pathogens directly. In addition, these peptides initiate a potent host response to infection resulting in cytokine release, inflammation and a cellular response. Disturbed cathelicidin expression and function was observed in several common inflammatory skin diseases, such as psoriasis where cathelicidin peptide converts inert self-DNA and self-RNA into an autoimmune stimulus. In atopic dermatitis decreased levels of cathelicidin facilitating microbial superinfections have been discussed. Furthermore, abnormally processed cathelicidin peptides induce inflammation and a vascular response in rosacea. Until recently, the molecular mechanisms underlying cathelicidin regulation were unknown. Recently, the vitamin D3 pathway was identified as the major regulator of cathelicidin expression. Consequently, vitamin D3 entered the spotlight as an immune modulator with impact on both innate and adaptive immunity. Therapies targeting vitamin D3 signaling may provide new approaches for infectious and inflammatory skin diseases by affecting both innate and adaptive immune functions.

Antimicrobial peptides (AMPs) are strongly expressed in lesional skin in psoriasis and play an important role as proinflammatory "alarmins" in this chronic skin disease. Vitamin D analogs like calcipotriol have antipsoriatic effects and might mediate this effect by changing AMP expression. In this study, keratinocytes in lesional psoriatic plaques showed decreased expression of the AMPs beta-defensin (HBD) 2 and HBD3 after topical treatment with calcipotriol. At the same time, calcipotriol normalized the proinflammatory cytokine milieu and decreased interleukin (IL)-17A, IL-17F and IL-8 transcript abundance in lesional psoriatic skin. In contrast, cathelicidin antimicrobial peptide expression was increased by calcipotriol while psoriasin expression remained unchanged. In cultured human epidermal keratinocytes the effect of different vitamin D analogs on the expression of AMPs was further analyzed. All vitamin D analogs tested blocked IL-17A induced HBD2 expression by increasing IkappaB-alpha protein and inhibition of NF-kappaB signaling. At the same time vitamin D analogs induced cathelicidin through activation of the vitamin D receptor and MEK/ERK signaling. These studies suggest that vitamin D analogs differentially alter AMP expression in lesional psoriatic skin and cultured keratinocytes. Balancing AMP "alarmin" expression might be a novel goal in treatment of chronic inflammatory skin diseases.

Toll-like receptor (TLR)-mediated detection of viral nucleic acids and production of type I interferons (IFNs) by plasmacytoid dendritic cells (pDCs) are key elements of antiviral defense. By contrast, inappropriate recognition of self-nucleic acids with induction of IFN responses in pDCs can lead to autoimmunity. In this review we describe how pDC responses to self-DNA are normally avoided and focus on our recent finding that in psoriasis, a common autoimmune disease of the skin, these barriers can be breached by the cationic antimicrobial peptide LL37. LL37 binds extracellular self-DNA fragments into aggregated particles that enter pDCs and trigger robust IFN responses by activating endosomal TLR9 as if they were viruses. We also describe the mechanisms that normally control production and activity of LL37 in human skin and propose that the persistent overexpression of LL37 in psoriasis leads to uncontrolled IFN responses that drive autoimmune skin inflammation.

The innate immune system of mammals provides a rapid response to repel assaults from numerous infectious agents including bacteria, viruses, fungi, and parasites. A major component of this system is a diverse combination of cationic antimicrobial peptides that include the α- and β-defensins and cathelicidins. In this study, we show that 1,25-dihydroxyvitamin D3 and three of its analogs induced expression of the human cathelicidin antimicrobial peptide (CAMP) gene. This induction was observed in acute myeloid leukemia (AML), immortalized keratinocyte, and colon cancer cell lines, as well as normal human bone marrow (BM)-derived macrophages and fresh BM cells from two normal individuals and one AML patient. The induction occurred via a consensus vitamin D response element (VDRE) in the CAMP promoter that was bound by the vitamin D receptor (VDR). Induction of CAMP in murine cells was not observed and expression of CAMP mRNA in murine VDR-deficient bone marrow was similar to wild-type levels. Comparison of mammalian genomes revealed evolutionary conservation of the VDRE in a short interspersed nuclear element or SINE in the CAMP promoter of primates that was absent in the mouse, rat, and canine genomes. Our findings reveal a novel activity of 1,25-dihydroxyvitamin D3 and the VDR in regulation of primate innate immunity.

Vitamin D3 analogues are a first-line treatment of chronic plaque psoriasis, but so far, comparative clinical studies on calcipotriol and calcitriol ointment are sparse, and in particular no comparative studies are available on cell biological effects of these compounds in vivo. Using flow cytometric assessment, we investigated whether these compounds had different effects on the composition and DNA synthesis of epidermal cell populations responsible for the psoriatic phenotype. For 8 weeks, 20 patients with psoriasis vulgaris were treated twice daily with calcipotriol and calcitriol ointment in a left/right comparative study. Before and after treatment, clinical assessment of target lesions was performed, together with flow cytometric analysis of epidermal subpopulations with respect to keratin (K) 10, K6, vimentin and DNA distribution. Treatment with each compound resulted in a substantial clinical improvement, a reduction of the K10-K6- population and an increase of the K10+K6- population. A correlation was found between the clinical response of calcipotriol and the K10+K6- population, and the clinical response of calcitriol and the K10+K6- population, as well as the percentage of cells in the S, G2 and M phase of the cell cycle within the K10-K6- population, suggesting that the analogues have a different preference for affecting the K10+K6- pool (committed differentiated cells) or affecting the K10-K6- pool (basal cells).

The hormonal form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is an immune system modulator and induces expression of the TLR coreceptor CD14. 1,25(OH)2D3 signals through the vitamin D receptor, a ligand-stimulated transcription factor that recognizes specific DNA sequences called vitamin D response elements. In this study, we show that 1,25(OH)2D3 is a direct regulator of antimicrobial innate immune responses. The promoters of the human cathelicidin antimicrobial peptide (camp) and defensin beta2 (defB2) genes contain consensus vitamin D response elements that mediate 1,25(OH)2D3-dependent gene expression. 1,25(OH)2D3 induces antimicrobial peptide gene expression in isolated human keratinocytes, monocytes and neutrophils, and human cell lines, and 1,25(OH)2D3 along with LPS synergistically induce camp expression in neutrophils. Moreover, 1,25(OH)2D3 induces corresponding increases in antimicrobial proteins and secretion of antimicrobial activity against pathogens including Pseudomonas aeruginosa. 1,25(OH)2D3 thus directly regulates antimicrobial peptide gene expression, revealing the potential of its analogues in treatment of opportunistic infections.

The potent calciotropic hormone calcitriol (1,25-dihydroxyvitamin D3, 1,25(OH)2D3) has been shown to be very effective and safe in the topical treatment of psoriasis. In vitro, 1,25(OH)2D3 inhibits proliferation and stimulates differentiation of human keratinocytes. Increasing evidence suggests an immunoregulatory function of this potent steroid hormone. To further characterize the biological effects of topical calcitriol treatment in psoriasis, we have analyzed immunohistochemically the expression of markers for epidermal proliferation (proliferating cell nuclear antigen=PCNA) and differentiation (transglutaminase K, involucrin, cytokeratin 16), as well as inflammation (CD1a, 55 kDa TNF-receptor, NAP-1/IL-8) in calcitriol-treated psoriatic skin in situ. Our findings strongly support the hypothesis that calcitriol modulates keratinocyte proliferation/differentiation as well as inflammation in human skin in vivo. The immunoreactivity of markers for epidermal proliferation and differentiation, as well as of CD1a and NAP-1/IL-8, changed after 8 weeks of calcitriol treatment almost completely to the pattern characteristic for non-lesional psoriatic skin, while a large number of 55 kDa TNF-receptor positive cells could be found in the dermal compartment.

Psoriasis is characterized by immune activation, increased proliferation and abnormal differentiation of keratinocytes. The reported anti-psoriatic mechanisms of action in vivo of vitamin D analogues include reduction of keratinocyte proliferation and induction of keratinocyte terminal differentiation. We investigated whether the anti-psoriatic effect of the natural active vitamin D analogue, calcitriol, applied topically, is due to direct effects on keratinocytes alone or also due to immunoregulatory effects of calcitriol. Psoriasis patients were treated with topical calcitriol (0.005%) and a vehicle control for 8 weeks. Disease activity was assessed by a severity index and quantitative histopathological markers. In vitro studies of lymphocyte proliferation and gamma interferon secretion and of keratinocyte proliferation complemented the clinicohistopathologic studies. A heterogeneous response to calcitriol treatment could be segregated based upon elimination of K-16 keratin expression. Calcitriol treatment decreased keratinocyte proliferation, normalized keratinocyte differentiation and decreased immune activation in plaques. The histologic response to vitamin D treatment of psoriasis includes suppression of both immune and keratinocyte activation in situ. These studies provide a basis for rational combination of anti-psoriatic treatments and for the design of new vitamin D analogues to treat psoriasis.

Calcitriol, 1 alpha,25 dihydroxycholecalciferol (1 alpha,25 (OH)2 D3) is a natural active vitamin D3 metabolite, which has been shown to have antipsoriatic efficacy. In vitro studies have demonstrated that calcitriol influences various aspects of inflammation, epidermal proliferation and keratinization. The aim of the present study was to determine to what extent calcitriol (3 micrograms/g in white petrolatum) affects these parameters in vivo. Using an immunohistochemical assessment of recruitment of cycling epidermal cells, filaggrin and involucrin expression, T-cell accumulation, polymorphonuclear neutrophil (PMN) accumulation, amount of endothelium and ICAM-1 expression, we demonstrated that: (i) modulation of all these parameters occurred during calcitriol treatment; (ii) there was early reduction of epidermal proliferation and PMN accumulation; (iii) the order of changes was comparable with the response to treatment with calcipotriol. In conclusion, at the cell biological level, calcitriol (3 micrograms/g in white petrolatum) has a substantial effect on various elements of the psoriatic lesion.

Vitamin D3 metabolites have been found to improve psoriasis but their mechanism of action is not clear. Keratinocyte proliferation and differentiation are known to be dependent on calcium concentrations in vitro. The aim of this study was to examine whether 1 alpha,25(OH)2 vitamin D3 had any direct effect on intracellular free calcium concentrations in cultured keratinocytes. A response to 1 alpha,25(OH)2 vitamin D3 was seen in 88% of monolayers of normal human keratinocytes attached to glass coverslips. An increase in intracellular free calcium was seen in 80% of the reactive cultures, with over half the responses occurring within 30 s of exposure to 1 alpha,25(OH)2 vitamin D3 and the remainder occurring within minutes. Responses could be seen at physiological concentrations of 1 alpha,25(OH)2 vitamin D3 and were not blocked by the protein synthesis inhibitor cycloheximide. The response to 1 alpha,25(OH)2 vitamin D3 took the form of rapid transient increases in intracellular free calcium in 29 out of 59 coverslips. The basal intracellular free calcium was calculated to be 245 +/- 47 nM rising to a maximum of 834 +/- 267 nM (mean +/- SEM; n = 20) following exposure to 1 alpha,25(OH)2 vitamin D3. We conclude that 1 alpha,25(OH)2 vitamin D3 acts directly on keratinocytes to increase intracellular free calcium and that this may be relevant to its mechanism of action in psoriasis.

In 2010, an expert committee of physicians and researchers in the field of dermatology working together as the Psoriasis Process of Care Consensus Panel developed consensus guidelines for the treatment of psoriasis. As much as possible, the guidelines were evidence based but also included the extensive clinical experience of the dermatologists. Psoriasis is a lifelong disease that requires long-term treatment and 80% of psoriasis patients have mild to moderate disease. Topical therapies play an important role in the treatment of psoriasis, especially in patients with mild to moderate disease. Patients usually start with monotherapy; however, in more severe cases (> 10% body surface area [BSA], severely impaired quality of life [QOL], or recalcitrant psoriatic lesions), multiple treatment modalities may be used as part of combination, sequential, or rotational therapeutic regimens. Main treatment options include topical steroids, systemic therapies, topical vitamin D treatments such as vitamin D3 ointment, retinoids, phototherapy, and biologic therapies. Other topical therapies include the following steroid-sparing agents: coal tar, anthralin, calcineurin inhibitors, keratolytics, and emollients. Therapeutic considerations also should focus on adherence, improving QOL, and promoting a good patient-physician relationship.

The keratinocytes of the skin are unique in being not only the primary source of vitamin D for the body, but also possessing the enzymatic machinery to metabolize vitamin D to active metabolites [in particular, 1,25 dihydroxyvitamin D (1,25(OH)(2)D)] and the vitamin D receptor (VDR) that enables the keratinocytes to respond to the 1,25(OH)(2)D they produce. Numerous functions of the skin are regulated by vitamin D and/or its receptor: these include inhibition of proliferation, stimulation of differentiation including formation of the permeability barrier, promotion of innate immunity, regulation of the hair follicle cycle, and suppression of tumor formation. Regulation of these actions is exerted by a number of different coregulators including the coactivators DRIP and SRC, a less well known inhibitor, hairless, and beta-catenin. Different coregulators appear to be involved in different VDR-regulated functions. This review examines the various functions of vitamin D and its receptor, and to the extent known explores the mechanisms by which these functions are regulated.

Vitamin D’s role in bone health has been well established. Recently, studies have identified additional roles of vitamin D in the immune system, cardiovascular system, and cancer prevention. The effect of vitamin D on the immune system is particularly relevant to the dermatologist in that it has implications for atopic dermatitis, psoriasis, and skin cancer. However, there is much disagreement on a dose of vitamin D that is both safe and effective as both ultraviolet exposure and certain vitamin D-rich foods come with unwanted consequences. This review aims to update the dermatologist on the roles of vitamin D in the immune system, the safety and dose of different sources, and risk factors for vitamin D deficiency that may necessitate supplementation. Immune consequences of vitamin D status represent one additional aspect that illustrates how guidelines for supplementation are needed and will only be useful clinically if they are presented in context with validated controlled clinical trials.

High-potency topical corticosteroids are very effective for the treatment of psoriasis, but are associated with a number of cutaneous adverse effects. Vitamin D modulators have emerged as an important alternative to corticosteroids for the long-term topical treatment of psoriasis. Calcitriol 3 µg/g ointment has long been used to treat psoriasis in Europe and is now the only vitamin D3 ointment available for use in the United States (U.S.). Several randomized clinical trials have compared the safety, efficacy, and cosmetic acceptability of calcitriol ointment with other topical psoriasis therapies. In a three-week investigator-blinded study of 25 healthy subjects, calcitriol 3 µg/g ointment was associated with markedly less cumulative skin irritation than was calcipotriene ointment. A multicenter, investigator-blinded study of patients with psoriasis found that investigator-rated global improvement of psoriasis symptoms with calcitriol ointment was statistically noninferior to calcipotriene ointment and that calcitriol use produced significantly fewer patients with cutaneous reactions or discomfort. A multicenter clinical trial of patients with psoriasis who had lesions affecting sensitive skin areas found that calcitriol use produced less skin irritation than did calcipotriene and was generally preferred to calcipotriene ointment by patients. Calcitriol was also significantly more effective for the treatment of psoriasis lesions affecting flexural areas. In another study, patients who received calcitriol ointment exhibited improvement in psoriasis symptoms that was similar to the corticosteroid betamethasone propionate, but were much less likely to have relapsed eight weeks after treatment discontinuation. Two clinical studies also suggested that calcitriol is similar in efficacy to short-contact dithranol, but with a lower incidence of skin irritation and staining. Together, the results of these studies demonstrate that calcitriol 3 µg/g ointment is a significant new option for topical therapy of psoriasis. Calcitriol ointment produces improvement in psoriasis symptoms that is generally similar to the improvement attained with other (except for high potency steroid) topical psoriasis therapies, with a low incidence of adverse events.

Psoriasis is a chronic inflammatory skin disease affecting approximately 2% of the US population. Plaque psoriasis, characterized by erythematous lesions covered with silvery scales, is the most common form. In the absence of a cure, long-term control is important for the management of this disease. Topical corticosteroids are the primary treatment strategy for most mild to moderate cases of psoriasis. For more severe cases, topical corticosteroids often are combined with other antipsoriatic agents to prolong the remission period between disease outbreaks, manage isolated flares during therapy, and ease the transition between therapies. With the availability of multiple formulations of topical antipsoriatic agents, including multiple formulations of topical corticosteroids with different potencies, physicians have a large number of treatment strategies for their patients with psoriasis.

Psoriasis affects more than 5 million adults in the United States (U.S.), causing significant impairments in quality of life and incurring substantial costs in treatment. The disease is characterized by hyperproliferation and abnormal differentiation of epidermal keratinocytes resulting from a disordered immune response. Topical therapies, such as corticosteroids, are the most common treatment for psoriasis. However, long-term use of more potent topical corticosteroids is associated with potential risk for side effects. Topical vitamin D agents have been developed as a newer therapeutic option for use in place of, or in addition to, topical corticosteroids. These agents act to inhibit keratinocyte proliferation, normalize differentiation and modulate the activity of immune cells with minimal effect on serum calcium hemostasis. Calcipotriene is the most widely used member of this class, and is one of the most frequently prescribed topical agents for psoriasis. Although evidence suggests that it is approximately as effective as low-to-medium potency corticosteroids, it is associated with cutaneous irritation, especially when used in sensitive areas. Calcitriol ointment is a new option for topical therapy and is the only vitamin D3 ointment available for use in the U.S. and contains the naturally occurring active form of vitamin D3 that is associated with a relatively low rate of side effects.

Topical vitamin D analogs are a safe and effective treatment for psoriasis vulgaris. This is a brief review of calcitriol 3 µg/g ointment in the treatment of psoriasis. Calcitriol has been safely used outside the USA in Europe under the trade name Silkis Ointment for almost a decade in the treatment of psoriasis, and it is currently FDA-approved as Vectical Ointment. Calcitriol 3 µg/g ointment is a synthetic topical vitamin D analog considered to be as effective as other vitamin D analogs but with a better tolerability in sensitive areas.

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.

Irradiation of human keratinocytes with UVB (280-320 nm) in vitro and in vivo activates the metabolism of 7-dehydrocholesterol to hormonally active calcitriol. The production of calcitriol in the skin strongly depends on the photosynthesis of vitamin D(3) which is biologically inactive in the first instance. Vitamin D(3) serves as the starting substrate for two subsequent enzymatic hydroxylation steps in epidermal keratinocytes. Both the amount of vitamin D(3) and the activity of anabolic and catabolic vitamin D hydroxylases determine the cutaneous level of calcitriol. The hormonally active metabolite of vitamin D(3) regulates a huge number of genes in keratinocytes, and thus acts in an autocrine and/or paracrine manner. This local pathway of vitamin D(3) is unique, but its relevance for healthy and diseased skin is widely unknown, yet. Experimental findings implicate several questions: (1) Is UVB-induced formation of calcitriol involved in regulation of growth and differentiation of epidermal cells as well as immunological and skin protective processes? (2) What endogenous and exogenous factors including drugs affect the cutaneous vitamin D(3) pathway? From a therapeutical point of view, it has been known for a long time that topical application of calcitriol and its analogs can improve hyperproliferative skin diseases like psoriasis. In spite of many encouraging studies in recent years, the fields of the routinely therapeutical application of calcitriol or vitamin D analogs in dermatology (e.g. treatment of immunological, inflammatory, malignancies and infectious skin diseases) have not been intensified. Why is that?

The surface of our skin is constantly challenged by a wide variety of microbial pathogens, still cutaneous infections are relatively rare. Within cutaneous innate immunity the production of antimicrobial peptides (AMPs) is a primary system for protection against infection. Many AMPs can be found on the skin, and these include molecules that were discovered for their antimicrobial properties, and other peptides and proteins first known for activity as chemokines, enzymes, enzyme inhibitors and neuropeptides. Cathelicidins were among the first families of AMPs discovered on the skin. They are now known to have two distinct functions; they have direct antimicrobial activity and will initiate a host cellular response resulting in cytokine release, inflammation and angiogenesis. Dysfunction of cathelicidin is relevant in the pathogenesis of several cutaneous diseases including atopic dermatitis where cathelicidin induction is suppressed, rosacea, where cathelicidin peptides are abnormally processed to forms that induce cutaneous inflammation and a vascular response, and psoriasis, where a cathelicidin peptide can convert self-DNA to a potent stimulus of an autoinflammatory cascade. Recent work has unexpectedly identified vitamin D3 as a major factor involved in the regulation of cathelicidin expression. Therapies targeting the vitamin D3 pathway and thereby cathelicidin may provide new treatment modalities in the management of infectious and inflammatory skin diseases.

Topical treatments remain the most widely prescribed medications for psoriasis, particularly for patients with mild to moderate or localized disease. In addition, topical therapies can substantially improve outcomes when used alone or in combination with systemic or biologic agents in patients with moderate to severe or more extensive disease. Combinations of different topical treatments frequently are prescribed to enhance clinical effectiveness and decrease potential side effects. However, certain topical agents become ineffective when used together or in combination with other therapies, such as phototherapy. These topical agents should be combined only with treatments that have been demonstrated to have no effect on the chemical stability or clinical effectiveness of topical agents. This article reviews the compatibility of different topical agents and identifies those agents that can be effectively and safely combined with each other and with phototherapy.

The epidermis is the largest organ in the body. It is comprised primarily of keratinocytes which are arranged in layers that recapitulates their programmed life cycle. Proliferating keratinocytes are on the bottom-the stratum basale. As keratinocytes leave the stratum basale they begin to differentiate, culminating in the enucleated stratum corneum which has the major role of permeability barrier. Calcium and the active metabolite of vitamin D, 1,25(OH)(2)D(3), play important roles in this differentiation process. The epidermis has a gradient of calcium with lowest concentrations in the stratum basale, and highest concentrations in the stratum granulosum where proteins critical for barrier function are produced. Vitamin D is made in different layers of the epidermis, but 1,25(OH)(2)D(3) is made primarily in the stratum basale. Together calcium and 1,25(OH)(2)D(3) regulate the ordered differentiation process by the sequential turning on and off the genes producing the elements required for differentiation as well as activating those enzymes involved in differentiation. Animal models in which the sensing mechanism for calcium, the receptor for 1,25(OH)(2)D(3), or the enzyme producing 1,25(OH)(2)D(3) have been rendered inoperative demonstrate the importance of these mechanisms for the differentiation process, although each animal model has its own phenotype. This review will examine the mechanisms by which calcium and 1,25(OH)(2)D(3) interact to control epidermal differentiation.

It has been shown that epidermal keratinocytes have the capacity for the UVB-induced photochemical conversion of 7-dehydrocholesterol to vitamin D3,and also for the enzymatically controlled hydroxylation of the photolysis product. This metabolic loop results in the formation of the biologically active final product 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3, calcitriol). The epidermal synthesis of calcitriol is of fundamental relevance because calcitriol regulates important cellular functions in keratinocytes and immunocompetent cells. Because of their anti-proliferative and prodifferentiating effects, calcitriol and other vitamin D analogs are highly efficient in the treatment of psoriasis vulgaris.In addition, the known therapeutic effect of UVB light therapy in the treatment of psoriasis may, at least in part, be mediated via UVB induced synthesis of calcitriol. Increasing evidence now indicates that cutaneous vitamin D synthesis is of great importance for the prevention of a broad variety of diseases, including various malignancies. It has been postulated that cancer mortality could be reduced via careful UV exposure or, more safely, via oral substitution with vitamin D. These new findings must be taken into account when establishing new sun protection guidelines for the prevention of skin cancer. In addition, better understanding of the metabolism of vitamin D in the skin has opened up new perspectives for the therapeutic application of vitamin D analogs, e.g. in inflammatory skin diseases.

Although topical vitamin D3 derivatives have been used in the treatment of patients with psoriasis for the past 15 years, questions remain about the indications and limitations of application. Extensive personal experience gained during the development of calcitriol (1alpha25-dihydroxyvitamin D3) is therefore reviewed. Three double-blind, vehicle-controlled trials have revealed that calcitriol 3 µg g^-1 ointment (Silkis ointment^®, Galderma Laboratories) has very good clinical efficacy. In a left-right comparison with vehicle ointment, complete clearance of psoriatic lesions was achieved in 48% of sites treated with calcitriol and a further 41% showed considerable or definite improvement. The clinical response to calcitriol in another study was as good as, or even better than, that achieved with betamethasone valerate 0.1% ointment. A preparation containing calcitriol 15 µg g^-1 did not show any clinical superiority to the lower dose but was associated with a higher risk of hypercalciuria, particularly when applied to extensive skin lesions. These results suggest that calcitriol 3 µg g^-1 ointment is an effective and safe treatment for chronic plaque psoriasis. NOTE: Silkis^® is the former brand name for Vectical^®.

The physiological VDR ligand, 1 alpha,25-dihydroxyvitamin D3, acts upon a wide variety of tissues and cells, both related to and unrelated to calcium and phosphate homeostasis. The noncalcemic actions of natural and synthetic VDR ligands are exemplified by their potent anti-proliferative, prodifferentiative and immunomodulatory activities. As a result, a VDR ligand is an approved drug for the topical treatment of psoriasis. A plethora of actions of 1 alpha,25-dihydroxyvitamin D3 in various systems have suggested wide clinical applications of VDR ligands in such diverse disease states as inflammation (rheumatoid arthritis, psoriatic arthritis), dermatological indications (psoriasis, photoaging and skin rejuvenation), osteoporosis, cancers (breast, prostate, colon, leukemia and myelodysplastic syndrome) and autoimmune diseases (multiple sclerosis, type I diabetes and systemic lupus erythematosus). VDR ligands have shown therapeutic potential in limited human clinical trials as well as in animal models of these diseases. Some of the VDR ligands have shown not only potent preventive but also therapeutic anabolic activities in animal models of osteoporosis. However, the use of VDR in above mentioned indications as well as in oral therapy for psoriasis and even topical therapy for severe psoriasis is hampered by its associated toxicity, namely hypercalcemia. New VDR ligands have been synthesized which exhibit greater specificity by retaining desirable properties, but with reduced calcemic potential. The discovery of novel vitamin D3 analogs along with an increased understanding of the biological functions and mechanisms of action of VDR are likely to result in improved treatments for responsive indications.

Calcitriol 3 µg g^-1 ointment (Silkis ointment, Galderma Laboratories) is a new treatment for psoriasis. Calcitriol is the biologically active metabolite of vitamin D3. It induces keratinocyte differentiation, inhibits keratinocyte, T-cell and fibroblast proliferation, and inhibits the production of some inflammatory mediators, all contributors to the pathogenesis of psoriasis. Preclinical studies have shown an effect of topical calcitriol on calcium homeostasis at doses higher than those in clinical use. No adverse local events were observed when calcitriol was applied to animal skin. Phase I clinical studies confirmed that calcitriol 3 µg g^-1 ointment is well tolerated in humans. These studies have demonstrated that at the minimal effective concentration of 3 µg g^-1, calcitriol ointment has no discernible photosensitizing or phototoxic potential and no skin irritant or allergic potential in healthy volunteers. Its low systemic absorption through human skin is unlikely to significantly affect calcium homeostasis. This paper summarizes the findings of the preclinical and early clinical studies that provided the foundation of the later Phase II and III clinical trials on efficacy and safety with topical calcitriol 3 µg g^-1 ointment for the treatment of plaque psoriasis.

Psoriasis is important to the clinician because it is common and has treatment implications beyond the care of skin lesions. It is important to the physician-scientist because it serves as a model for studies of mechanisms of chronic inflammation. It is important to the clinical-trial investigator because it is increasingly a first-choice disease indication for proof-of-principle studies of new pathogenesis-based therapeutic strategies. In recent years, substantial advances have been made in elucidating the molecular mechanisms of psoriasis. However, major issues remain unresolved, including the primary nature of the disease as an epithelial or immunologic disorder, the autoimmune cause of the inflammatory process, the relevance of cutaneous versus systemic factors, and the role of genetic versus environmental influences on disease initiation, progression, and response to therapy. This review summarizes recent progress in our understanding of the molecular and immunologic basis of psoriasis and shows how improved insight into disease mechanisms has already resulted in tangible benefits for patients, including the introduction of new targeted therapies.

Psoriasis is a complex disease presenting as a chronic inflammatory disorder of the skin, mediated by a network of soluble factors and a vast array of cell populations. Although we understand many of the molecular mechanisms and cellular alterations that underlie the disease, we do not yet have a clear view of what sparks off the pathophysiological process leading to plaque development. This review presents current concepts on the pathogenesis of psoriasis and new hypotheses that have emerged from recent research reports.

Psoriasis, a common inflammatory skin disorder, has received attention as a target for new pathogenesis-oriented biologic therapies. In this article, we review the genetic, clinical, and pathogenic aspects of psoriasis and discuss their implications for new therapies.