Topical calcipotriol as monotherapy and in combination with psoralen plus ultraviolet A in the treatment of vitiligo

BACKGROUND: Recent advances in the pathophysiology of vitiligo have demonstrated defective calcium homeostasis in depigmented skin. 1,25-Dihydroxyvitamin D3 may be involved in the regulation of melanin synthesis, and receptors for 1,25-dihydroxyvitamin D3 have been demonstrated on melanocytes. OBJECTIVES: We conducted an open study to determine the efficacy and tolerability of calcipotriol cream as monotherapy and in conjunction with psoralen plus ultraviolet A (PUVA) in the treatment of vitiligo. METHODS: Twenty-six patients with vitiligo affecting 5-40% of their skin were recruited. Twenty-two were treated with twice-daily topical calcipotriol monotherapy (50 microg g(-1)) and four were placed on combination treatment with twice-daily topical calcipotriol 50 microg g(-1) in conjunction with topical or oral 8-methoxypsoralen PUVA three times weekly. RESULTS: Treatment was well tolerated at all sites and no adverse effects were reported. After a therapy time of 3-9 months (mean 6 months), 77% (17 of 22) of those treated with monotherapy showed 30-100% improvement, and three of the four patients on combination treatment showed good response. CONCLUSIONS: Topical calcipotriol appears to be an effective and well-tolerated treatment for vitiligo and can be safely used in conjunction with PUVA, but controlled studies are necessary to exclude the possibility of spontaneous repigmentation.     

Cream psoralen plus ultraviolet A therapy for granuloma annulare

BACKGROUND: Treatment modalities for granuloma annulare (GA) often remain unsatisfactory or can be accompanied by potentially hazardous side-effects. Psoralen plus ultraviolet (UV) A (PUVA) bath photochemotherapy has been reported to be highly effective in the treatment of GA. Another form of topical PUVA therapy, using 8-methoxypsoralen-containing cream or gel preparations, has been proven to be as effective as bath PUVA therapy in the treatment of palmoplantar dermatoses. OBJECTIVES: To assess the efficacy of cream PUVA photochemotherapy in patients with GA. METHODS: Five patients with GA were treated. The diagnosis was confirmed by pretreatment skin biopsies. Cream PUVA therapy was performed four times a week: the mean number of treatments was 26 (range 17-40) and mean cumulative UVA dose was 55.9 J cm-2 (range 18.2-109.2). RESULTS: Cream PUVA photochemotherapy induced significant clinical improvement (one patient) or clearance (four patients) of GA in all patients. Clearance was documented clinically and histopathologically. CONCLUSIONS: Cream PUVA phototherapy can be highly effective in patients affected by localized forms of GA.     

Treatment of necrobiosis lipoidica with topical psoralen plus ultraviolet A

BACKGROUND: Necrobiosis lipoidica (NL) is a rare skin disease, mostly seen on the legs and often occurring in patients with diabetes mellitus. The disease belongs to the idiopathic cutaneous palisading granulomatous dermatitides associated with a degeneration of collagen, thus leading to skin atrophy. Application of topical corticosteroids is the most widely used treatment but the results are not always satisfactory and may worsen skin atrophy. Preliminary studies in patients with NL have shown a clinical response with psoralen plus ultraviolet (UV) A (PUVA). Objectives To study the effect of topical PUVA on NL in a multicentre prospective study. METHODS: Thirty patients (27 women and three men) including 13 with insulin-dependent diabetes mellitus, with a diagnosis of NL proven by histopathology, were included. All patients had been unsuccessfully treated with topical and/or intralesional corticosteroids. Patients were treated twice weekly with an aqueous gel containing 0.005% psoralen followed by irradiation with UVA. Clinical photographs were taken for evaluation. In addition, 20-MHz high-frequency ultrasound analysis was performed in 10 patients to evaluate the thickness and density of the dermis during topical PUVA therapy. RESULTS: Five patients (17%) showed complete clearing (healing of ulceration and disappearance of erythema) after a mean of 22 exposures (range 15-30). Eleven patients (37%) showed improvement, defined as healing of ulceration and/or reduction of erythema, after a mean of 23 exposures (range 11-42). Ten patients (33%) showed no effect and four patients (13%) worsened during topical PUVA therapy. The treatment results of the patients who suffered from diabetes mellitus were not different from those who did not have diabetes mellitus. No difference was seen in mean dermal thickness (1666 vs. 1706 micro m) and density (17 vs. 16 units) before and after topical PUVA therapy. Side-effects were seen in 10 patients: hyperpigmentation (n = 4), blistering (n = 4) and bacterial infection (n = 2). CONCLUSIONS: Topical PUVA may be a useful treatment modality for NL in patients not responding to topical or intralesional corticosteroids.     

A comparison of psoralen plus ultraviolet A (PUVA) monotherapy,tacalcitol plus PUVA and tazarotene plus PUVA in patients with chronic plaque-type psoriasis

BACKGROUND: Numerous studies have shown that the additional administration of topical or systemic antipsoriatic agents might serve as an effective means to increase the efficacy of photochemotherapy [psoralen plus ultraviolet (UV) A (PUVA)] for psoriasis. OBJECTIVES: To compare the therapeutic response to tacalcitol plus PUVA, tazarotene plus PUVA and PUVA monotherapy in patients with chronic plaque-type psoriasis. In addition, we also assessed the duration of remission induced by each regimen and the tolerability of the two combination treatments. METHODS: Thirty-one patients with chronic plaque-type psoriasis were included in this observer-blinded, intrapatient comparison trial. PUVA treatment was given four times weekly. Additionally, tacalcitol ointment and 0.1% tazarotene gel were applied separately on two target areas once daily in the evening. At the onset of therapy and every 2 weeks thereafter the response to treatment was determined by the Psoriasis Severity Index score, which assesses the degree of erythema, infiltration and scaling of the psoriatic lesions. After complete or near complete clearing patients were followed-up until relapse. RESULTS: Twenty-four patients completed the study. The treatment requirements to induce complete or near complete clearing were significantly lower for both combination treatments than for PUVA monotherapy (P < 0.01). The median cumulative UVA dose and number of exposures were 30.6 J cm-2 (95% confidence interval, CI 22.5-71.2) and 14 (95% CI 11-16) for tacalcitol plus PUVA, 32.3 J cm-2 (95% CI 22.5-73.8) and 14 (95% CI 11-19) for tazarotene plus PUVA, and 37.0 J cm-2 (95% CI 29.5-83.9) and 16 (95% CI 14-22) for PUVA monotherapy. No difference between the three regimens was observed with regard to duration of remission. Adverse reactions occurred more often with 0.1% tazarotene than with tacalcitol but were in general mild and completely reversible upon using a lower concentration of 0.05% tazarotene. CONCLUSIONS: Tacalcitol ointment and tazarotene gel are both comparably effective in improving the therapeutic result of PUVA therapy in patients with chronic plaque-type psoriasis. Besides accelerating the treatment response, both agents, by virtue of their UVA dose-sparing effect, might also help to reduce possible long-term hazards of PUVA treatment.     

The effect of psoralen plus ultraviolet A in vitro in HUT-78 enhances by 5-aminolevulinic acid

BACKGROUND: Sezary syndrome and mycosis fungoides are forms of cutaneous T-cell lymphoma, and in the early stage of these diseases psoralen plus ultraviolet A (PUVA) is one of the treatments of choice. Photodynamic therapy using 5-aminolevulinic acid (ALA-PDT) is an effective, non-invasive, and safe treatment for most superficial skin cancers. In order to obtain greater efficacy of PUVA, we investigated the synergistic anti-tumor effects of ALA-PDT and PUVA using 8-methoxypsoralen (8-MOP) and a UVA lamp. METHODS: The in vitro effects of PUVA and ALA-PDT and their combination in HUT-78 cell line from human SS were determined by MTT assay. RESULTS: In our results, cell proliferation compared with controls was inhibited to 53.2% with UVA alone, 52.3% with 1 microM 8-MOP, 43.8% with 100 microM ALA, and 19.2% with combined 8-MOP and ALA. CONCLUSION: Combined use of ALA and PUVA using 8-MOP and UVA lamps, which are widespread in Japan, had a strong anti-tumor effect in vitro. Combined treatment with ALA-PDT and PUVA using a UVA lamp appears to have a strong treatment effect.     

Kinetics and dose-response of photosensitivity in cream psoralen plus ultraviolet A photochemotherapy: comparative in vivo studies after topical application of three standard preparations

BACKGROUND: Topical photochemotherapy with bath psoralen plus ultraviolet (UV) A irradiation (PUVA) has been developed to reduce possible side-effects of oral PUVA therapy. Although the efficacy of bath PUVA therapy appears to be similar to oral PUVA therapy, provision of bathing facilities has obvious economic, logistic and sanitary implications. Cream PUVA therapy has recently been developed as a variation of topical PUVA. OBJECTIVES: To understand the photobiological effects and to increase the safety and effectiveness of this novel topical PUVA therapy, we assessed the kinetics and dose-response of phototoxicity of 8-methoxypsoralen (8-MOP) cream in order to develop a treatment schedule for this treatment option. METHODS: Ninety-eight patients (63 men and 35 women) undergoing cream PUVA therapy were studied. The phototoxic properties of topically applied 8-MOP in three different water-in-oil creams as vehicles were assessed. In a dose-response study, four concentrations of 8-MOP cream (0.0006-0.005%) were used for determination of the minimal phototoxic dose (MPD). The kinetics of photosensitization were tested by determination of MPDs after different application times of 8-MOP cream (10, 20, 30 and 60 min). The persistence of phototoxicity was assessed by UVA exposure at defined time intervals after application of 8-MOP cream (0, 30, 60 and 120 min). RESULTS: The concentration required to produce sufficient but not undue photosensitization of the skin was 0.001% 8-MOP. The duration of application leading to the lowest MPD was 30 min. Greatest photosensitization was achieved when UVA irradiation was performed between 0 and 30 min after 8-MOP removal. These findings showed no significant difference between the three vehicles used. CONCLUSIONS: Based on our data we recommend application of 0.001% 8-MOP in a water-in-oil cream for 30 min. Irradiation with UVA should be performed within 30 min after removal of 8-MOP cream, as there is a rapid decrease in photosensitivity thereafter.     

Variation in calibration of hand-held ultraviolet (UV) meters for psoralen plus UVA and narrow-band UVB phototherapy

BACKGROUND: Phototherapy units should regularly use hand-held ultraviolet (UV) meters to assess the output of treatment lamps, and these meters should be accurately calibrated. Several medical physics departments in the U.K. can calibrate UV meters traceable to national standards, but there is concern that there may be disagreement among departments. In particular, there may be difficulty in calibration for narrow-band UVB phototherapy lamps (TL-01). OBJECTIVES: To ascertain the level of agreement in UV meter calibration at expert centres in the U.K., and to survey methodology at these centres, consider sources of errors and to make recommendations on calibration methods. METHODS: The same UV meter with two detectors (for UVA and UVB) was calibrated by seven medical physics departments. A questionnaire on methods was also distributed and measured spectral outputs from each centre were examined. RESULTS: The calibration factors for the meter varied by +/- 18% for the UVA detector and by +/- 60% for the UVB detector (2 standard deviations). Six centres performed calibration using a spectroradiometer and one centre used a reference meter method. The spectra of lamps used for calibration were similar. For the spectroradiometric methods there were some differences in methodology and instrumentation that may account for the differences in calibration factors. CONCLUSIONS: UV meter calibration in the U.K. shows unacceptable variability, particularly for TL-01 lamps. An accuracy of around of +/- 10% would be clinically acceptable and should be technically achievable.     

Flegel's disease treated with psoralen ultraviolet A

Flegel's disease is an uncommon condition which causes asymptomatic keratotic papules on the limbs. It usually develops in the fourth or fifth decade. Therapeutic options are limited to emollients, topical 5-fluorouracil and retinoids, but none of these treatments is consistently helpful. We report a patient with Flegel's disease who responded to psoralen ultraviolet A treatment.     

Comparison of the efficacy of local narrowband ultraviolet B (NB-UVB) phototherapy versus psoralen plus ultraviolet A (PUVA) paint for palmoplantar psoriasis

Palmoplantar psoriasis is an idiopathic disabling condition, often resistant to conventional therapies. The purpose of this study was to evaluate the efficacy and safety of local narrowband ultraviolet B (NB-UVB) phototherapy and to compare it with local psoralen plus ultraviolet A (PUVA) paint in patients with palmoplantar psoriasis unresponsive to conventional therapies other than phototherapy. A cohort of 25 patients with palmoplantar psoriasis were included in this study, which was based on a left-to-right comparison pattern. The treatments were administered with local narrowband UVB irradiation on one side and local PUVA on the other side three times a week over 9 weeks. Clinical assessments were performed at baseline and every 3 weeks during the 9-week treatment. There was a statistically significant decrease in the mean clinical scores at the third, sixth and ninth week with both treatments. The difference in clinical response between the two treatment modalities was statistically significant at the end of the treatment period, with the percentage reduction in severity index scores with the PUVA-paint-treated side being 85.45% compared with 61.08% for the NB-UVB treated side (t = 5.379, P = 0.0001, Student's t-test for unpaired samples). Our results show that, although some clinical improvement was achieved with local NB-UVB phototherapy, the results were better with local PUVA, and such a treatment option may be reserved for patients with palmoplantar psoriasis who experience phototoxic reaction to psoralens.     

Ultrastructural changes induced in cutaneous collagen by ultraviolet-A1 and psoralen plus ultraviolet A therapy in systemic sclerosis

In the present study, we examined the ultrastructural alterations in collagen fibrils clinically softened by ultraviolet-A1 (UVA1, 340-400 nm) therapy and psoralen plus long-wave ultraviolet (PUVA) therapy and compared collagen fibril diameters in four patients with systemic sclerosis (SSc). In skin sclerosis, the dermis is compacted from the epidermal layer to the sweat glands, and the collagen bundles are thicker with decreased space between them. We obtained skin specimens before and after UVA1 or PUVA therapy, and compared cutaneous alterations in one diffuse-type patient and one limited-type patient following UVA1 therapy, and in two diffuse-type patients following PUVA treatment. Ultramicroscopic analysis revealed that UVA1 treatment decreased the diameter of the broad collagen fibrils, mainly in the upper reticular layer. PUVA induced similar alterations in the collagen fibrils, extending to the upper and middle reticular layers. PUVA therapy induced alterations in collagen fibril diameter in deeper layers than did UVA1 therapy, which might be related to the direct action of UV light and the depth of the light penetration. In three of four patients, collagen fibril diameter decreased, collagen fibril thickness equalized, and new, thin fibrils developed among the collagen fibrils, suggesting that collagen degradation and synthesis underlie the alterations induced by UVA1 and PUVA phototherapies.     

Psoralen cream plus ultraviolet A photochemotherapy (PUVA cream): our experience

BACKGROUND: Psoralen ultraviolet A (PUVA) bath photochemotherapy has been proved highly effective in the treatment of various dermatoses without potential side-effects of systemic therapy. Another form of topical PUVA therapy (PUVA cream) without the logistical requirements for bath tubs has recently been developed. OBJECTIVE: We sought to develop preparation and treatment standards to PUVA cream and to confirm its clinical efficacy in the treatment of various dermatoses. METHODS: In the first phase, the safety of a novel cream containing 0.002% 8-methoxypsoralen (8-MOP) was determined in six healthy volunteers. In a second phase, 40 patients with different dermatoses were treated with a minor concentration (0.001% 8-MOP), following the guidelines for topical PUVA of the British Photodermatology Group. RESULTS: Plasma levels of psoralen after the application of the novel cream containing 0.002% 8-MOP, were less than 34 ng/mL, the maximum 8-MOP concentration reported for topical PUVA. With a minor concentration (0.001% 8-MOP), important improvement or healing was found in 53.3% of the cycles, generally with a good response since the first month of treatment. Only mild side-effects were detected in 14 patients. CONCLUSIONS: Based on our data, PUVA cream photochemotherapy is well accepted by patients and may be a highly effective treatment even if previous therapy was unsuccessful. In addition, PUVA cream is easier to use than PUVA bath.     

Case of localized scleroderma successfully treated with bath psoralen and ultraviolet A therapy

The patient was a 12-year-old girl with linear scleroderma distributed on the right abdomen, dorsal aspect of the right thigh, lower leg and foot. The initial regimen of oral prednisolone and methotrexate, or i.v. methylprednisolone failed in the treatment of the scleroderma. Then bath psoralen and ultraviolet A therapy (bath-PUVA) therapy of 0.2 J–4.0 J/cm² daily to total doses 62.8 J/cm² combined with oral prednisolone was started. After bath-PUVA therapy, regression of the skin sclerosis was observed, the possible mobile range of the right ankle was increased and histological examination confirmed improvement of the sclerosis. The successful results of bath-PUVA therapy in this case suggest its utility for localized scleroderma.     

Differential effects of 5-aminolaevulinic acid photodynamic therapy and psoralen + ultraviolet A therapy on p53 phosphorylation in normal human skin in vivo

BACKGROUND: Phosphorylation of the tumour suppressor p53 by the CK2/FACT pathway plays a central role in suppressing ultraviolet (UV)-induced skin cancer in animal models. Although p53 protein stabilization is induced after solar-simulated irradiation of human skin in vivo, p53 phosphorylation has not been defined. OBJECTIVES: To investigate the effects of clinically effective treatments for skin diseases including psoralen + UVA (PUVA) and photodynamic therapy (PDT) on p53 phosphorylation to determine whether the tumour-suppressing p53 kinase pathways are activated upon use of these therapies. METHODS: We used antibodies to the ATM/ATR and CK2/FACT phosphorylation sites on p53. RESULTS: We found that p53 activation was induced selectively by PUVA treatment, while 8-oxo-7,8-dihydroguanine DNA damage was induced selectively by 5-aminolaevulinic acid (ALA)-PDT treatment. Importantly, PUVA treatment resulted in p53 kinase activation, as defined by p53 modification at AT (serine-15) and CK2/FACT (serine-392) sites within the proliferative compartment. CONCLUSIONS: These data demonstrate that PUVA provokes accumulation and phosphorylation of p53 by AT and CK2/FACT within critical proliferative focal points (as determined by p63 colocalization studies) where DNA damage may lead to tumorigenesis. PDT is mechanistically distinct in that there is a lower level of induction of p53 expression with no evidence of AT- or CK2/FACT-mediated phosphorylation. This suggests that the type of DNA damage created by the reactive oxygen species generated by ALA-PDT does not induce the p53 pathway classically required for the repair of DNA photoadducts induced by UV.     

角质形成细胞和成纤维细胞对白癜风发病和治疗的影响

黑素细胞在白癜风发病及治疗中是最关键的一环，但表皮、真皮间的沟通联系对皮损及非皮损皮肤的功能均具有重要影响，其中角质形成细胞、成纤维细胞及细胞外基质等非黑素细胞起了重要作用，并影响白癜风的发病。本文从细胞因子、氧化应激等角度总结了角质形成细胞、成纤维细胞对白癜风发病的影响及在临床治疗中的作用机制。     

CD30+ large cell transformation of mycosis fungoides after psoralen plus ultraviolet A photochemotherapy

Psoralen plus ultraviolet A (PUVA) photochemotherapy is widely used for the therapy of mycosis fungoides (MF). Clinical progression of MF is often associated with an increase in the size of tumour cells known as transformation. We report two patients with CD30+ large cell transformation that appeared after low-dose PUVA therapy for MF. Clinical data, histopathology, immunohistopathology and T-cell receptor gene rearrangement were studied. Nodules consisted of atypical large cells that expressed CD30. Monoclonal rearrangement of T-cell receptors was observed in one case. Low-dose PUVA therapy may be associated with CD30+ large cell transformation in patients with MF.