High-dose UVA1 Research Articles

PUVA-related punctate keratoses of the hands and feet

Background: We have observed, in patients undergoing high-dose PUVA treatment, a type of keratosis not previously described. The lesions usually occur on the sides of the palms or soles and are clinically distinct. They are generally painless and often go unnoticed by patients. Objective: We sought to further characterize these lesions both clinically and histologically. Methods: Patients attending a PUVA clinic were screened for these keratoses. Other PUVA-related complications were recorded. Representative lesions were photographed, and biopsy specimens were taken. Results: Biopsy specimens were taken from lesions in 10 patients. All had plaque psoriasis and had received high UVA doses (>1000 J/cm2) through PUVA therapy. All patients had PUVA-induced keratoses elsewhere, but the number varied greatly between patients. The hand and foot keratoses were well defined and circular and had a characteristic histologic appearance, with a sharp demarcation between normal and abnormal markedly pale–staining epidermis. Conclusion: These lesions are a further cutaneous manifestation of prolonged PUVA therapy. (J Am Acad Dermatol 2000;42:476-9.)

Atopic dermatitis: from the genes to skin lesions.

Atopic dermatitis: from the genes to skin lesions.

Medium-dose UVA1 cold-light phototherapy in the treatment of severe atopic dermatitis

Background: Recently, conventional high-dose UVA1 phototherapy (340-400 nm) has been shown to be more effective than combined UVA-UVB therapy in the treatment of severe atopic dermatitis (AD). However, there are limitations of this treatment, such as intense sweating caused by the immense heat load during therapy and the high cumulative UVA1 doses that are required. For this reason, lavish UVA1 equipment was developed containing an advanced filtering and cooling system resulting in almost complete absence of heat load and sweating during therapy. Objective: In this study we compared the monotherapeutic efficacy of conventional medium-dose UVA1, medium-dose UVA1 cold-light, and combined UVA-UVB phototherapy in the treatment of severe AD. Method: The study involved 120 patients with severe AD. Fifty patients each received conventional UVA1 or UVA1 cold-light phototherapy (15 days, 50 J/cm 2/day), and 20 patients were treated with combined UVA-UVB (15 days, minimal erythema dose dependent). Severity of AD was scored by means of the SCORAD score, and clinical improvement was additionally monitored by serologic cytokine markers. Results: Six (12%) of 50 patients treated with UVA1, 2 (4%) of 50 patients treated with UVA1 cold-light therapy, and 4 (20%) of 20 patients treated with combined UVA-UVB therapy discontinued treatment prematurely because of an unsatisfactory clinical outcome or adverse reactions. Skin status improved or even cleared completely in 77.3% of the patients treated for 3 weeks with conventional UVA1 therapy and in 85.4% of the patients treated for 3 weeks with UVA1 cold-light therapy, resulting in a significant decrease in the SCORAD score in both UVA1 groups ( P < .05 each). In the group treated with combined UVA-UVB, the SCORAD score also decreased but significantly less than in both groups treated with UVA1 photo-therapy ( P < .05 each). At follow-up after 4 weeks, the patients treated with UVA1 displayed a more prolonged therapeutic benefit than the patients treated with UVA-UVB therapy. Plasma levels of soluble interleukin 2 receptors and soluble interleukin 4 receptors significantly decreased under both UVA1 and UVA1 cold-light phototherapy but not under combined UVA-UVB phototherapy. Conclusion: Our study demonstrates that medium-dose UVA1 cold-light phototherapy displays advantages compared with conventional UVA1 phototherapy caused by the almost complete absence of heat load and intense sweating and is more effective than UVA-UVB phototherapy in the treatment of severe AD. (J Am Acad Dermatol 1999;41:931-7.)

Mechanisms of ultraviolet (UV) B and UVA phototherapy.

Ultraviolet (UV) radiation has been used for decades with great success and at a constantly increasing rate in the management of skin diseases, becoming an essential part of modern dermatologic therapy (Krutmann et al, 1999). For phototherapy, irradiation devices emitting either predominantly middlewave UV (UVB, 290-315 nm) or longwave UV (UVA, 315-400 nm) radiation are employed. In former years, patients were treated with broad-band UVB, broad-band UVA, or combination regimens. Broad-band UV phototherapy, however, is being replaced more frequently by the use of irradiation devices that allow treatment of patients' skin with selected emission spectra. Two such modalities which have their origin in European Photodermatology are 311 nm UVB phototherapy (which uses long-wave UVB radiation above 300 nm rather than broadband UVB) and high-dose UVA1 therapy (which selective employs long-wave UVA radiation above 340 nm). In Europe, 311 nm UVB phototherapy has almost replaced classical broad-band UVB phototherapy and has significantly improved therapeutic efficacy and safety of UVB phototherapy (van Welden et al, 1988; Krutmann et al, 1999). The constantly increasing use of UVA-1 phototherapy has not only improved UVA phototherapy for established indications such as atopic dermatitis (Krutmann et al, 1992a, 1998; Krutmann, 1996), but has also provided dermatologists with the opportunity to successfully treat previously untractable skin diseases, e.g., connective tissue diseases (Stege et al, 1997; Krutmann, 1997). These clinical developments have stimulated studies about the mechanisms by which UVB and UVA phototherapy work. The knowledge obtained from this work is an indispensable prerequisite to make treatment decisions on a rationale rather than an empirical basis. Modern dermatologic phototherapy has started to profit from this knowledge, and it is very likely that this development will continue and provide dermatologists with improved phototherapeutic modalities and regimens for established and new indications. This review aims to provide an overview about current concepts of the mode of action of dermatologic phototherapy. Special emphasis will be given on studies that have identified previously unrecognized immunosuppressive/anti-inflammatory principles of UV phototherapy.

Half-side comparison of erythemogenic versus suberythemogenic UVA doses in oral photochemotherapy of psoriasis

Background: Early American and European multicenter trials on the efficacy of photochemotherapy (PUVA) for psoriasis have clearly shown that the treatment protocol has a crucial impact on the cumulative UVA dose required for clearing patients. Most, if not all, treatment protocols rely on the PUVA-induced erythema as a guideline for UVA dosimetry. Objective: Our aim was to investigate whether phototoxic erythema is integral to an optimized PUVA protocol or reflects an unnecessary overexposure of patients. Methods: A standard high-dose UVA regimen using minimal phototoxic doses (MPD) was compared against two different low-dose regimens. To this purpose a bilateral comparison study was performed on 31 patients and divided in two parts. In the first trial on 14 patients, half of each patient’s body was irradiated at each visit with 1 MPD, whereas the other half received only two thirds of the MPD. In the second trial on 17 patients treatment with 1 MPD was compared against treatment with one half of the MPD. Results: A total of 27 patients (12 patients in the first trial, 15 patients in the second trial) completed the study. In both trials the suberythemogenic doses were therapeutically as effective as the minimal phototoxic doses. Conclusion: We conclude that PUVA-induced erythema is not a prerequisite for effective psoriasis treatment and that a low-dose UVA regimen is a promising approach to increase the short- and long-term safety of photochemotherapy. (J Am Acad Dermatol 1999;41:408-13.)

Turbo-PUVA: dihydroxyacetone-enhanced photochemotherapy for psoriasis: a pilot study.

Dihydroxyacetone (DHA), a colorless sugar in "sunless" tanning lotions, binds to stratum corneum to form a UV-A-protective brown pigment. Bound DHA polymer is shed faster from hyperproliferative skin sites such as psoriatic plaques. We tested the hypothesis that selective shedding of DHA pigment during psoralen-UV-A (PUVA) treatment of psoriasis may allow higher UV-A doses, thus accelerating clearing while protecting uninvolved skin. Concurrent use of lactic acid was investigated as an aid in removing scale and residual DHA from psoriatic plaques. Thirty psoriatic patients with more than 20% body surface area involvement were recruited. The 6 PUVA study groups were (1) standard American style, (2) American style plus lactic acid, (3) DHA-PUVA or "topical ultraviolet-resisting barrier to optiimize PUVA" (Turbo-PUVA), (4) Turbo-PUVA with lactic acid, (5) European style, and (6) European style plus DHA. Combinations of lactic acid and European-style treatment were not studied. Each subject received up to 30 oral PUVA treatments twice weekly 3 days apart. The DHA-PUVA groups used 15% DHA lotion twice weekly. Lactic acid groups used 7% lotion daily except on treatment days. Psoriasis area and severity index scores were recorded weekly. Turbo-PUVA allowed higher UV-A exposures with minimal burns, showed faster clearing, and required fewer treatments for 90% clearing (P<.001). Protection of uninvolved skin by DHA during PUVA treatment allows higher UV-A exposures to be tolerated, demonstrates faster clearing, and requires fewer treatments to clear psoriasis. By reducing the total body dose received, Turbo-PUVA may also reduce long-term risks.

Narrow band UVB (311 nm) phototherapy and PUVA photochemotherapy: A combination

Background: Psoralen-UVA (PUVA) photochemotherapy is widely used for the treatment of psoriasis despite concerns of skin carcinogenesis from high cumulative UVA doses and number of treatments. Objective: We attempted to determine whether combined bath-PUVA with narrow-band (311 nm) phototherapy improves efficacy and reduces long-term toxicity. Methods: Twelve psoriatic patients underwent phototesting with 311 nm lamps and, after topical bath-water psoralen sensitization, with 311 nm, UVA, or both radiations. Patients were treated with bath-PUVA on one side of the body and with bath-PUVA plus 311 nm exposures (bath-PUVA–311 nm) on the other side. On both sides, four weekly treatments were delivered and UVA doses were increased once weekly whereas 311 nm doses were adjusted at each exposure. Results: Psoralen sensitization did not modify the erythematous threshold to 311 nm radiation. However, 311 nm exposures enhanced the phototoxic activity of bath-PUVA. Bath-PUVA–311 nm cleared psoriasis with fewer exposures and lower cumulative UVA doses under the same minimally erythemogenic conditions. Conclusion: Combination with 311 nm exposures enhanced the phototoxic and therapeutic activities of bath-PUVA. (J Am Acad Dermatol 1998;38:687-90.)

High-dose UVA1 therapy for atopic dermatitis: Results of a multicenter trial

Background: The results of an open, single-center study suggested that phototherapy with high doses of UVA1 radiation (UVA1R; 340-400 nm) is effective for acute, severe exacerbations of atopic dermatitis (AD). Objective: The purpose of this study was to assess the effectiveness of high-dose UVA1 phototherapy for acute, severe AD in a randomized multicenter trial in direct comparison with topical glucocorticoid therapy. Methods: Patients were treated with high-dose UVA1R (10 days, 130 J/cm 2 /day; n = 20), topically with fluocortolone (10 days, 1 x daily; n = 17), or with UVA-UVB therapy (10 days, 1 x daily, minimal erythema dose–dependent; n = 16). Results: With a clinical scoring system, significant differences in favor of high-dose UVA1R and fluocortolone therapy were observed ( p < 0.0001), as compared with UVA-UVB therapy. At day 10, high-dose UVA1R was superior to fluocortolone ( p < 0.002) therapy. Serum levels of eosinophil cationic protein and the blood eosinophil count were significantly reduced after high-dose UVA1 or fluocortolone, but not UVA-UVB therapy. Conclusion: This study confirms the therapeutic effectiveness of high-dose UVA1 monotherapy for treatment of severe exacerbations of AD. (J Am Acad Dermatol 1998;38:589-93.)

High-dose UVA 1 radiation therapy for localized scleroderma

Fibrotic skin lesions in patients with localized scleroderma can cause muscle atrophy, disfigurement, and flexion contractures. There is no effective therapy for this disease. Skin fibrosis is thought to be caused by decreased collagenase activity. Collagenase activity can be induced in dermal fibroblasts by UVA1 irradiation. Our purpose was to assess whether UVA1 radiation therapy is effective for patients with localized scleroderma. Patients with localized scleroderma (n = 17) were exposed 30 times to 130 J/cm2 UVA1 (high-dose UVA1 therapy; n = 10) or 20 J/cm2 UVA1 (low-dose UVA1 therapy; n = 7). Therapeutic effectiveness was assessed by evaluation of (1) clinical features, (2) thickness of sclerotic plaques, and (3) cutaneous elastometry. Sequential biopsy specimens from treated lesions were analyzed for collagenase I messenger RNA (mRNA) expression by semiquantitative reverse transcriptase-polymerase chain reaction. In all patients, high-dose UVA1 therapy softened sclerotic plaques, and complete clearance was observed in four of 10 patients. High-dose UVA1 therapy significantly reduced thickness and increased elasticity of plaques. These changes could not be detected in unirradiated control plaques and were still present in 9 of 10 patients 3 months after cessation of therapy. For all factors assessed, high-dose UVA1 was superior to low-dose UVA1 therapy (p = 0.001). High-dose UVA1 therapy increased collagenase I mRNA expression about 20-fold in treated plaques. High-dose UVA1 therapy is effective in the treatment of localized scleroderma. Effectiveness is UVA1 dose dependent and is associated with induction of collagenase I expression.

Characterization of nonresponders in high dosage UVA1 therapy of acute exacerbated atopic dermatitis

High-dose UVA1 therapy is an effective treatment of patients with acute atopic dermatitis. However, some patients do not respond well to this new therapy. We attempted to further characterize the non-responder population in a retrospective study. Two closely matched groups of responders (n = 20) and non-responders (n = 20) were compared. No significant differences were observed between both groups with respect to the following parameters: skin type, minimal erythema dose, single and cumulative doses of UVA1, and peripheral blood eosinophils. However, non-responders were characterized by a highly elevated atopic score, and by high levels of total IgE and of specific IgE. Furthermore, colonization of the skin with Staphylococcus aureus occurred at higher densities, and intestinal growth of Candida albicans was more frequently observed. These data indicate that high-dose UVA1 irradiation is not effective in all patients suffering from atopic dermatitis. We conclude that non-responders with complicating infections might benefit from the combination of high-dose UVA1 therapy and antibiotic or antimycotic treatment.

High-dose UVA1 therapy in the treatment of patients with localized scleroderma

High-dose UVA1 therapy in the treatment of patients with localized scleroderma

Significant influence of UVA on the general metabolism in the growing Cichlid fish, Cichlasoma nigrofasciatum

A study on the influence of UVA on the metabolic rate (MR) in growing Cichlid fish is presented. The results show that, during a distinct period of development, the MR of fish maintained under additional UVA light is significantly lower (P < 0.01) than that of the control fish. The averages (±SD) of the specific oxygen consumption obtained from 129 “+UVA fish” and 122 control fish between 1 and 79 days after UVA onset are 0.44±0.11 mg O2g BW−1 h−1 and 0.48 ± 0.11 mg Om2g BW−1 h−1 respectively. The wide range of fish weight, due to the natural growth of the fish, and the variation in the experimental temperature during the measurements are responsible for the high values of the standard deviations. For different oxygen concentration ranges, a lower MR was observed in the UVA-exposed fish compared with the control fish for each range. The difference in MR between the control fish and the “UVA population” started to evolve about 3 weeks after the onset of the higher UVA dose. The difference in the MR was highly significant between 32 and 49 days after UVA was switched on. After this period, the difference in the MR between the two populations gradually disappeared.

Erythemal and therapeutic response of psoriasis to PUVA using high-dose UVA.

In PUVA treatment of psoriasis, clinical observation suggests that uninvolved skin is more susceptible to PUVA erythema than lesions of psoriasis. If this is the case, then the efficacy of PUVA treatment might be increased by using localized high-dose UVA restricted to lesional skin. We have therefore studied the erythemal and therapeutic response of psoriasis to PUVA using high-dose UVA and, for comparison, the erythemal response to UVB. In 14 patients, an area of psoriasis and adjacent uninvolved skin were exposed to a series of UVA doses (350 +/- 30 nm, 1-16J/cm2), using an irradiation monochromator. Six other patients were similarly phototested with a series of UVB doses (300 +/- 5 nm, 20-112 mJ/cm2) to both uninvolved and lesional skin. Erythema was judged visually at 72 h for psoralen-UVA, and at 24 h for UVB, and measured using a scanning laser-Doppler velocimeter. In 10 patients, PUVA therapy using high-dose UVA was subsequently given to lesional skin (8-16J/cm2 twice weekly) in addition to conventional whole-body PUVA. For psoralen-UVA, the minimal phototoxic dose within psoriasis was increased by a factor of 4 compared with non-lesional skin (P < 0.01, Wilcoxon signed-rank test). For UVB, the minimal erythema dose within psoriasis was higher than that for non-lesional skin (medians > 112 and 28 respectively, P < 0.05). Laser-Doppler measurements confirmed that the reduced erythemal sensitivity was not due to masking of response by pre-existing increased blood flux within psoriasis.(ABSTRACT TRUNCATED AT 250 WORDS)

Studies on the effects of a high dose UVA-1 radiation therapy on surface markers and function of epidermal Langerhans cells.

Recently, high-dose UVA-1 therapy (340-400 nm) was introduced as an effective treatment of severe exacerbated atopic dermatitis. Since the target of this type of radiation in the skin is not known we investigated using the mouse model whether surface markers of the antigen-presenting function of epidermal Langerhans cells are affected by UVA-1 radiation. Even repeated high doses of UVA-1 radiation (up to 50 J/cm2) had no detectable effect on surface ATPase activity and Ia antigen expression on Langerhans cells. Also, the contact allergen oxazolone was presented normally in skin treated with UVA-1 radiation. In contrast, if the mice were injected 1 h before irradiation with 8-methoxypsoralen a dramatic reduction in ATPase activity and Ia antigen expression on Langerhans cells was observed and the induction of contact sensitivity was suppressed (PUVA effect). These results show that epidermal Langerhans cells are not impaired either in structure or function and that these cells probably do not represent the primary target of UVA-1 radiation in the skin. No side effects resulting from a diminished Langerhans cell function should result from high-dose UVA-1 therapy.

High-dose UVA1 therapy in the treatment of patients with atopic dermatitis

Besides glucocorticosteroids, there is currently no known effective therapy for patients with acute atopic dermatitis. The therapeutic effectiveness of high-dose UVA1 irradiation in the management of patients with acute exacerbation of atopic dermatitis was examined. Patients in the high-dose UVA1 group (n = 15) were irradiated with 130 joules/cm2 UVA1; the control group (n = 10) was treated with UVA-UVB therapy in a minimal erythema dose-dependent manner (total number of treatments 15). High-dose UVA1 irradiation was found to induce a significant clinical improvement of atopic dermatitis (p less than 0.001). In comparison with UVA-UVB therapy, significant differences in favor of high-dose UVA1 were observed (p less than 0.01). High-dose UVA1, but not UVA-UVB treatment, significantly reduced the elevated serum level of eosinophil cationic protein in patients with atopic dermatitis (p less than 0.003). These studies indicate that high-dose UVA1 irradiation may represent a novel phototherapeutic modality for the treatment of patients with an acute exacerbation of atopic dermatitis.

Sensitivity to UV Light during Treatment with Chloroquine in Rheumatoid Arthritis

Chloroquine and hydroxychloroquine have long been suspected of causing light sensitivity in patients with rheumatoid arthritis (RA). To gain insight into the effect of chloroquines and ultraviolet (UV) light in RA we have phototested 25 RA patients with and without chloroquine. The thresholds for UVA and UVB did not change upon treatment with chloroquine or hydroxychloroquine. Provocation with high dose UVA and UVB was similar with and without treatment with chloroquine or hydroxychloroquine. Our results have shown that photosensitivity during medication with chloroquine and hydroxychloroquine is uncommon and that there is no need to stop this treatment due to sun exposure.

UVB serum factor: suppression of allergic contact dermatitis in guinea pigs.

Serum from guinea pigs exposed to a single high dose of UVB and from controls was injected into the spleen of normal animals 5 days prior to sensitization. When 1.0 ml was transferred 4.5 h after irradiation, immunosuppression was obtained. Transfer of 1.5 ml of serum 2.5 h after irradiation failed to induce immunosuppression. This experimental model in guinea pigs might be valuable in further studies investigating the effect of other modalities of ultraviolet exposure (e.g., PUVA or high-dose UVA) on the release of soluble serum factor(s) inducing immunosuppression in allergic contact dermatitis.

Cutaneous and ocular side-effects of oral photochemotherapy: results of an 8-year follow-up study.

To determine the long-term cutaneous side-effects of oral photochemotherapy (PUVA), we examined 95 patients, 59 with psoriasis and 36 with mycosis fungoides (MF). These comprised 80% and 69% respectively of the patients with these disorders treated with PUVA in our department from 1977 to 1985. Two psoriatic patients had squamous carcinomas, both of whom had received high cumulative UVA doses and also methotrexate concurrently with PUVA. Six patients with MF had actinic keratoses. The mean age of these patients (69 years) was significantly greater than the mean age of the patients without actinic keratoses (54 years), but there was no significant difference in their cumulative UVA doses. No patients developed basal cell carcinomas or malignant melanoma. 'PUVA lentigines' were found in 46% of the patients. They were most frequent in patients currently being treated and in those who had received high cumulative UVA doses, but persisted for up to 7 years after discontinuing therapy. Seventy-one patients had yearly ophthalmological examinations, or a single examination at least 3 months after commencing PUVA. This examination included retinal function tests to detect any subclinical visual impairment. Five of these patients had cataract prior to PUVA therapy, and were significantly older (mean age 71 years) than those without cataract (mean age 53 years). Three patients (mean age 61 years) developed new lens opacities whilst receiving PUVA. However, none of these patients was considered to have cataract as none had impairment of visual acuity due to lens opacity. No patients without lens opacity developed evidence of subclinical visual impairment.

Unscheduled DNA synthesis in normal human skin after single and combined doses of UV-A, UV-B and UV-A with methoxsalen (PUVA).

The aim of this study was to measure unscheduled DNA synthesis (UDS) by autoradiography in normal human skin (I) after high dose UV-A, (2) after low dose UV-A applied before or after erythemogenic doses of UV-B, (3) after high dose PUVA and (4) after therapeutic doses of PUVA applied before and after erythemogenic doses of UV-B. Single high dose UV-A exposure induced roughly 60% of the amount of UDS induced by equally erythemogenic doses of UV-B. Single low dose UV-A exposure did not induce UDS, nor did it significantly alter the amount of UV-B induced UDS when combined with UV-B exposure. Single high dose PUVA did not lead to UDS and had no influence on UV-B induced UDS when combined with UV-B exposure. Our findings indicate: (I) erythemogenic doses of UV-A induce a considerable DNA excision repair; (2) low dose UV-A neither augments UV-B induced DNA repair nor does it inhibit the repair process; (3) no UDS was shown to occur after eight high or therapeutic doses of PUVA. This was unexpected since psoralen-DNA monoadducts have been shown to be repairable by a mechanism similar to excision repair of pyrimidine dimers. It is therefore assumed that PUVA as performed for therapeutic purposes either preferentially induced interstrand crosslinks not repairable via the classical repair mechanism or the repair of monoadducts was below resolution in this study; (4) therapeutic PUVA doses apparently do not interfere with excision repair of UV-B induced DNA lesions.

Additive Erythemogenic Effects of Middle-(280–320 nm) and Long-(320–400 nm) Wave Ultraviolet Light

Recent observations and theories implicating long-wave ultraviolet radiation (320-400 nm) as the stimulus for various phenomena in human skin have prompted us to investigate the erythemogenic properties of middle (UV-B) and long (UV-A) wave ultraviolet light combinations. The backs of fair-skinned human volunteers were irradiated with varying doses of UV-A and UV-B to determine the minimal perceptible erythema (MPE) dose in each of these wavelength regions. The subjects then received overlapping suberythemal doses of UV-A and UV-B in each of several sites. When UV-A was held constant and UV-B was varied, the observed breakpoint dose (energy at which MPE was seen in doubly irradiated sites) quantitatively demonstrated an additive phenomenon. When combined energies approach threshold erythema values, the known erythemogenic properties of high-dose UV-A are additive to the subclinical or visible erythema induced by UV-B.