Effects of topical calcipotriol on the expression of adhesion molecules in psoriasis

Seven patients with chronic plaque psoriasis were treated with topical calcipotriol for 8 to 24 weeks; the lesions improved in 5 patients. Immunohistochemistry was performed on frozen sections, to evaluate the expression of adhesion molecules and extracellular matrix components before and after therapy. Changes in expression and topography of β and β4 integrins were found on psoriatic lesions before therapy and a reduction in the expression of tenascin was detected as well. Moreover, several activation markers such as ICAM-1, HLA-DR, CD26 were focally positive, with a diffuse cytoplasmic reactivity, in basal and suprabasal layers in untreated lesions.
In the 5 patients in whom lesions regressed after topical calcipotriol treatment, we observed a histological normalization of the epidermis and the inflammatory infiltrate was reduced. Moreover, not only was there a normalization in the expression and topography of adhesion molecules, but also the integrin pattern observed after therapy was superimposable to that of normal skin.     

Clobetasol propionate followed by calcipotriol is superior to calcipotriol alone in topical treatment of psoriasis

Background Although potent, topical corticosteroids offer effective and rapid healing of psoriatic lesions. Their long term use is limited because of the risk of side effects. Calcipotriol is safe for long-term treatment, but its initial efficacy is lower than with topical corticosteroids.
Objectives To investigate whether 2 weeks of treatment with clobetasol propionate 0.05% ointment bd followed by 4 weeks of treatment with calcipotriol 50 /μg/g bd would offer therapeutic advantages over 6 weeks of continuous treatment with calcipotriol.
Methods Forty-nine patients with moderate to severe plaque psoriasis were recruited from five centres in Norway. In a randomised, double-blind, right- versus left-side comparison, ointments were applied to two symmetrically-located areas.
Results Two weeks of treatment with clobetasol propionate produced a significantly greater decrease in total symptom score (combined scores of erythema, induration and scaling) than calcipotriol treatment ( P < 0.0001). This improvement on the clobetasol.propionate-treated side of the body was maintained throughout a subsequent 4-week treatment period when calcipotriol was applied to both sides of the body ( P < 0.0001). The superiority of the clobetasol propionate followed by calcipotriol treatment was maintained during a 4-week, treatment-free, observation period. Treatments were well tolerated with no rebound effect.
Conclusions Clobetasol propionate ointment bd for 2 weeks followed by treatment with calcipotriol ointment bd for 4 weeks was superior to calcipotriol ointment alone in the treatment of plaque psoriasis.     

The effects of calcipotriol and methylprednisolone aseponate on bcl-2, p53 and ki-67 expression in psoriasis

OBJECTIVE: The decrease of physiological apoptosis in the psoriatic lesions is thought to be involved in the pathogenesis of psoriasis, and induction of apoptosis was shown to contribute to the regression of psoriatic hyperplasia. In the present study, we compared the effects of calcipotriol and methylprednisolone aseponate (MPA) treatments on bcl-2, p53 and ki-67 expressions in psoriatic patients in order to define a relationship between regulation of apoptosis and healing process in psoriasis. METHODS: Thirty psoriatic patients with stable and moderate chronic plaque psoriasis applied either calcipotriol or MPA ointment for 6 weeks twice daily. Evaluation of bcl-2, p53 and ki-67 positivity was performed at baseline and was repeated at sixth week for each therapy. RESULTS: The mean percentage of positive keratinocytes was 8.63 +/- 7.15% for p53, 20.66 +/- 14.45% for ki-67, and 3.74 +/- 2.83% for bcl-2 in psoriatic skin at baseline. Normal skin values were 3.27 +/- 3.21% for p53, 4.93 +/- 4.77% for ki-67, and 1.80 +/- 0.41% for bcl-2. The psoriatic skin showed higher ki-67 (P < 0.05) and bcl-2 (P < 0.05) expression rates when compared to normal skin. The p53 positivity observed in psoriatic skin and normal skin was not significantly different (P > 0.05). Following calcipotriol and MPA treatments, there was a significant reduction in p53 and ki-67 positivity accompanied by an increase in bcl-2 positivity (P < 0.05 each). No significant differences were found at sixth week between calcipotriol and MPA groups with respect to p53, ki-67 and bcl-2 positivity (P > 0.05). The post-treatment psoriatic skin showed lower expression of p53, higher expressions of ki-67 and bcl-2 when compared to normal skin (P < 0.05 each). CONCLUSION: The results of this study provide evidence that both calcipotriol and MPA decrease the p53 and ki-67 expression and increase bcl-2 expression. However, it should further be elucidated if these changes were the common behaviour of psoriatic keratinocytes to any antipsoriatic medication.     

Comparison of calcipotriol monotherapy and a combination of calcipotriol and betamethasone valerate after 2 weeks' treatment with calcipotriol in the topical therapy of psoriasis vulgaris: a multicentre, double-blind, randomized study

A clinical study was conducted to determine whether, in the topical treatment of psoriasis, a combination of calcipotriol and betamethasone valerate after previous treatment with calcipotriol alone was more effective than the continuation of the monotherapy with calcipotriol, especially in 'low responders'. Patients ( n  = 169) with the clinical diagnosis 'chronic plaque-type psoriasis' were treated twice daily for 2 weeks with calcipotriol, followed by a 4-week treatment with calcipotriol monotherapy in 87 patients or combined calcipotriol/betamethasone valerate in 82 patients; all patients were followed for 8 weeks. The psoriasis area and severity index (PASI) was used to compare the two treatment groups. The overall therapeutic result was also assessed by the investigators and patients. The combination therapy was more effective, as assessed by all evaluated variables; moreover, patients showing insufficient response to calcipotriol alone after 2 weeks showed a regression of psoriatic lesions using the combination regimen. Thus, the combination of calcipotriol and topical steroids is recommended as the therapy of first choice for patients who do not respond well to treatment with 2 weeks of calcipotriol alone. Furthermore, this combination reduces the hazards associated with the long-term use of topical corticosteroids (atrophy and rebound) as well as the irritation associated with calcipotriol.     

High-dose topical calcipotriol in the treatment of extensive psoriasis vulgaris

Summary Ten patients with extensive plaque psoriasis were treated with calcipotriol ointment (50 μg/g) for 2 weeks (200 g for 1 week, followed by 300 g during the second week). Mean improvement in psoriasis area and severity index (PASI) was 71%. Mean 24 h urine calcium rose from 4.79 mmol/24 h to 7.27 mmol/24 h ( P <0.000l). Urine calcium returned towards baseline after stopping calcipotriol. Mean serum calcium also rose slightly, hut significantly, from 2.26 mmol/l to 2.32 mmol/l (P<0.005). and fell again in the washout phase. Individual serum calcium values remained within the normal range throughout the study. Topical calcipotriol is an effective, rapidly acting and safe in-patient treatment for extensive plaque psoriasis.     

Alteration of the expression of Bcl-2, Bcl-x,Bax, Fas,and Fas ligand in the involved skin of psoriasis vulgaris following topical anthralin therapy

Anthralin (dithranol) is frequently used for the treatment of psoriasis. However, the mode of action of anthralin has not been completely elucidated as yet. Recent findings suggest that psoriatic keratinocytes are resistant to the apoptotic process. In this study, we examined the immunohistochemical expression of apoptosis-regulated protein in the involved psoriatic skin following topical anthralin therapy. Biopsy specimens were obtained from back skins treated with topical anthralin or white petrolatum (control) in 4 patients with psoriasis vulgaris. Immunohistochemical examination revealed that psoriatic keratinocytes expressed high levels of Bcl-x, which was significantly reduced after anthralin treatment. Bax was not detected in the epidermal keratinocytes in the petrolatum-treated skin, while it was present in the upper keratinocytes after anthralin therapy. Bcl-2 was detected only in basal layers of psoriatic epidermis following both petrolatum and anthralin application. Psoriatic keratinocytes expressed higher levels of Fas in the lower epidermis, while only weak expression was detected in anthralin-treated plaques. On the other hand, hyperproliferative keratinocytes strongly expressed Fas ligand (FasL) on their plasma membranes as well as infiltrating lymphocytes in the upper dermis. Furthermore, anthralin-treated psoriatic epidermis did not express FasL. In normal skin, keratinocytes expressed low to absent levels of Bcl-x and Bax, while Bcl-2 was detected only in melanocytes in basal layers. Neither Fas nor FasL were detected in the epidermis of normal skin. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) staining revealed positive labeling on the majority of psoriatic keratinocytes through the epidermis in petrolatum-treated skin, whereas anthralin treatment markedly reduced TUNEL-positive keratinocytes. These in vivo results may reflect improvement of the psoriatic skin following effective anthralin therapy.     

Examination of Bcl-2, Bcl-X and bax protein expression in psoriasis

BACKGROUND: Psoriasis is an inflammatory skin disease characterized by epidermal hyperplasia and greatly accelerated epidermal turnover. The blockage of normal apoptotic process in the epidermis is one of the factors implicated in the pathogenesis of psoriasis. OBJECTIVE: The purpose of the present study was to elucidate whether bcl-family proteins are significantly involved in the hypothetical antiapoptotic cascade in lesional psoriatic epidermis. METHODS: Twenty-six lesional biopsy samples of 26 patients with psoriasis and five control specimens from normal skin were studied by immunohistochemical method for the differential expression of pro-apoptotic bax and antiapoptotic bcl-2 and bcl-x proteins. RESULTS: Compared with the normal epidermis, bcl-2 expression was significantly reduced, whereas bax and bcl-x were significantly overexpressed in the psoriatic epidermis. The localization of bcl-2/bax/bcl-x proteins in the psoriatic epidermis did not show a significant deviation from that in the normal epidermis. CONCLUSION: These findings indicate a discordant expression of bcl-2 and bax/bcl-x in psoriatic epidermis. Increased bcl-x expression might contribute to the antiapoptotic response in psoriatic keratinocytes. The presence of strong bax expression with a concomitant decrease in bcl-2 expression suggests either a functional defect in bax protein or an inherent/acquired resistance to bax-mediated apoptosis in psoriatic keratinocytes.     

Combination of topical calcipotriol (MC 903) and UVB radiation for psoriasis vulgaris

The synthetic compound MC 903 (calcipotriol) is a structural analogue of the naturally occurring, biologically active 1,25-dihydroxyvitamin D3 [1,25-(OH)2-D3]. MC 903 and 1,25-(OH)2-D3 show similar receptor binding and comparable effects on cell differentiation. However, MC 903 appears to be at least 100 times less potent in its effects on calcium metabolism. In previous double-blind placebo-controlled studies, topical MC 903 has been shown to have a therapeutic effect in psoriasis. The present open study involving 20 patients with psoriasis vulgaris was a right/left comparison of the efficacy and tolerability of MC 903 ointment (50 micrograms/g) alone or with UVB radiation. After treatment for 8 weeks, topical MC 903 alone resulted in marked improvement in 66% of the patients and in clearance in 17%. Combination of topical MC 903 with UVB resulted in marked improvement in 50% of the patients and in clearance in 39%. These differences were not statistically significant. No significant change in serum calcium levels was detected. Two patients developed a facial dermatitis which disappeared spontaneously during continued treatment. These results show that the combination of topical MC 903 and UVB radiation is well tolerated. Larger-scale studies are warranted to answer the question whether UVB radiation induces a significant improvement of the antipsoriatic effect of topical MC 903.     

Occlusion enhances the efficacy of topical calcipotriol in the treatment of psoriasis vulgaris

Forty-eight patients with symmetrical chronic plaque psoriasis affecting the limbs were recruited for a single-blind right/left within patient study to assess the effect of combining occlusion with topical calcipotriol. Subjects were randomized into two groups. Sites of similar severity on opposing limbs were selected as target areas. The first (group A) treated one side with calcipotriol alone and the opposite side with calcipotriol plus occlusion. The second (group 13) treated one side with placebo plus occlusion and the opposite side with calcipotriol plus occlusion. In group A the mean improvements were 40% (P< 0·001) for calcipotriol alone and 61% (P< 0·001) for calcipotriol plus occlusion. In group B, occlusion plus calcipotriol resulted in a mean 62% improvement (P< 0·001) while occlusion plus placebo produced no significant change. The combination of calcipotriol plus occlusion was significantly better than calcipotriol alone (P< 0·005). The results indicate that occlusion improves the response to calcipotriol by enhancing its penetration. Indices of calcium metabolsm remained unchanged throughout the study.     

New developments in topical sequential therapy for psoriasis

Topical agents for the treatment of psoriasis are indicated for patients whose affected area is less then 10% of their skin. However, for long-term use, their effectiveness can be limited. Topical sequential therapy involves the application of a class I corticosteroid and calcipotriene in three different phases: the clearance phase, the transition phase and the maintenance phase. It is an accepted and widely practiced technique that provides a balance between maximizing efficacy and minimizing side-effects thus offering patients rapid clearance of their psoriatic lesions and long-term maintenance of remission.     

卡泊三醇治疗前后银屑病皮损中Caspase-3和bcl-2的表达

目的：探讨卡泊三醇治疗前后银屑病皮损中Caspase-3和bcl-2中的表达及意义。方法采用免疫组化技术对12例银屑病患者经卡泊三醇治疗前后皮损及非皮损区皮肤中Caspase-3和bcl-2表达进行检测。结果经卡泊三醇治疗后银屑病患者皮损角质形成细胞中bcl-2的表达明显增加（P＜0.05）,Caspase-3的表达无明显差异（P＞0.05）。结论卡泊三醇治疗银屑病的可能作用机制之一是促进bcl-2诱导角质形成细胞的凋亡。     

Long-term efficacy and tolerability of topical calcipotriol in psoriasis. Results of an open study.

Calcipotriol is a non-calcaemic vitamin D3 analogue. In short-term studies, topically applied calcipotriol is both efficacious and safe for the treatment of psoriasis vulgaris. The purpose of the present study was to determine the efficacy and safety of calcipotriol ointment in patients treated for approximately 6 months. Fifteen patients with plaque-type psoriasis were treated daily with calcipotriol ointment 50 micrograms/g. After treatment for 6 weeks there was a significant alleviation of erythema, infiltration and scaling. This degree of improvement was maintained throughout the study, except in one patient, who was withdrawn at week 15 because of minimal improvement. At the end of treatment, 80% of the patients showed a moderate improvement at least. Local adverse events occurred in 3 patients. These were mild and transient. Hypercalcaemia or other laboratory abnormalities did not develop in any patient. Morphometric examination of biopsies taken from perilesional skin (i.e. skin exposed to calcipotriol) at the end of treatment did not show signs of epidermal or dermal atrophy compared with uninvolved psoriatic skin. Although only a limited number of patients participated in the study, these results indicate that calcipotriol ointment 50 mu/g is both efficacious and safe for the long-term treatment of psoriasis.     

The effects of topical calcipotriol on systemic calcium homeostasis in patients with chronic plaque psoriasis

Background: Calcipotriol is an effective treatment of chronic plaque psoriasis. We have previously demonstrated that it has a small effect on systemic calcium homeostasis even at recommended doses. Objective: We attempted to determine the mechanism of the effect of calcipotriol on sytemic calcium homeostasis so we could assess the possible consequences of long-term use. Methods: Sixteen patients with extensive chronic plaque psoriasis were hospitalized and treated with high-dose topical calcipotriol. Up to 360 gm of calcipotriol (50 μg/gm) ointment was applied per week for 2 weeks under controlled conditions. Results: There was a dose-dependent rise in intestinal absorption of calcium. No effect on bone turnover was demonstrated over this short period. Five patients became hypercalcemic, and there was a dose-dependent rise in serum total adjusted calcium, serum ionized calcium, serum phosphate, urine calcium, and urine phosphate. There was a dose-dependent fall in serum parathyroid hormone and serum 1,25 dihydroxyvitamin D₃. Conclusion: Calcipotriol exerts its effects on systemic calcium homeostasis by increasing intestinal absorption of calcium and probably phosphate. This results in suppression of parathyroid hormone and 1,25 dihydroxyvitamin D₃. (J Am Acad Dermatol 1997;37:929-34.)     

吡硫翁锌气雾剂联合钙泊三醇倍他米松软膏序贯治疗斑块型银屑病的观察

目的观察吡硫翁锌气雾剂联合钙泊三醇倍他米松软膏序贯治疗斑块型银屑病的疗效以及安全性。方法 182例斑块状银屑病患者随机分为观察组和对照组,观察组90例应用吡硫翁锌气雾剂联合钙泊三醇倍他米松软膏外用治疗,对照组92例单用钙泊三醇倍他米松软膏外用治疗;两组疗程均为4周。结果观察组有效率为83.3%;对照组有效率为52.2%;两组比较差异均有统计学意义(P0.05)。结论应用吡硫翁锌气雾剂联合钙泊三醇倍他米松软膏序贯治疗银屑病起效快、副作用小。     

Emollient for maintenance therapy after topical corticotherapy in mild psoriasis

Abstract: Emollients or moisturizers can act as an important adjunctive therapy of topical treatment in psoriatic patients. However, the interest of emollients has never been clearly demonstrated; i.e. are they able to improve topical treatment efficacy and/or maintain continuous remission of the disease? The aim of this study was to evaluate the effect of an emollient on patients with mild plaque psoriasis during and after standard local corticosteroid therapy. Results showed that the use of an emollient can limit relapses after the end of corticotherapy, and maintain the improvement obtained after 1 month corticotherapy at clinical level (physician global assessment) and skin dryness.