PUVA erythemal sensitivity depends on plasma psoralen concentration and UVA sensitivity

The variation in erythemal sensitivity of the skin during PUVA therapy with oral 8-methoxypsoralen (8-MOP) was examined by measuring both UVA and PUVA erythemal responses, together with plasma 8-MOP concentration, in 27 patients about to start PUVA therapy for psoriasis. The erythema responses were judged visually, and also measured using a reflectance instrument in order to construct dose-response curves. No significant association was found between the UVA and PUVA minimal erythema responses. The plasma psoralen concentration showed significant association with the slope of the PUVA erythema dose-response curve. The slopes of the UVA and PUVA erythema dose-response curves were significantly associated, and this association became much stronger when allowance was made for plasma psoralen concentration. These results show that erythemal sensitivity during PUVA therapy is related to both plasma psoralen concentration and inherent UVA sensitivity, but that this relationship is not apparent when sensitivity is judged visually as the minimal erythema response. The association between PUVA and UVA erythemal sensitivity suggests a common pathway in the vascular response induced hy UVA radiation, with or without psoralen.     

Interleukin-6 in the epidermis of patients with psoriasis before and during PUVA treatment

Biopsies from lesional and unaffected skin of 6 patients with psoriasis, taken before and during treatment with psoralen plus UVA (PUVA) were examined immunohistologically, using partially purified polyclonal antibodies to crude supernatants of activated human blood monocytes. By absorption with recombinant derived human monokines, we were able to demonstrate that interleukin-6 (IL-6) (but not IL-1 alpha or IL-1 beta) was located in a laminar and granular pattern in stratum corneum, and on epidermal cell membranes in the viable cellular epidermis. Before PUVA treatment, the intensity and the extension of staining for IL-6 were both markedly increased in lesional skin compared with uninvolved skin. A weaker staining for IL-6 was observed in lesional skin, simultaneous with the clinical improvement of psoriasis. The staining patterns for IL-6 in biopsies from cleared lesional skin and uninvolved psoriatic skin were identical at the conclusion of therapy.     

Treatment of actinic prurigo with PUVA: mechanism of action

Five patients with actinic prurigo were treated twice weekly with PUVA. One area on the back was shielded from UVA throughout the 15-week treatment period. Before PUVA, all patients had increased erythemal sensitivity to UVA and showed abnormal augmentation of UVB erythema by topical indomethacin. After PUVA, all patients were free of photosensitive symptoms and skin that had been exposed to UVA showed normal erythemal responses. By contrast, the areas of skin that had been protected from UVA showed erythemal responses that were unchanged from pre-PUVA values. Augmentation of UVB erythema by topical indomethacin persisted, both on UVA exposed and UVA protected skin. These results show that, although PUVA is an effective treatment in actinic prurigo, it does not alter the underlying mechanism of photosensitivity. The protective effect is local and is due presumably to an increase in melanin pigmentation and epidermal thickness.     

DNA repair elicited by UVB during PUVA therapy for psoriasis

Summary The skin of patients receiving psoralen and UVA (PUVA) therapy for psoriasis is exposed to trace amounts of UVB radiation emitted by PUVA irradiators in addition to UVA. DNA repair activity was measured using autoradiography in the uninvolved skin of PUVA-treated patients in order to determine whether 8-methoxypsoralen (8-MOP) plus UVA elicits repair, inhibits the skin repair response to UVB, or protects epidermal-cell DNA from UVB damage by promoting a tan. Epidermal-DNA repair activity was observed in 27 out of 37 patients following the first PUVA treatment. Phototesting with multiples of the initial UV dose elicited a linear increase in repair activity. Glass-filtered radiation failed to stimulate repair, indicating that the reaction was due to UVB, not to 8-MOP plus UVA. The same amount of repair activity was observed in the skin of patients irradiated either before or after 8-MOP ingestion, demonstrating that the drug did not interfere with the response of the skin to UVB. At clearing, however, the repair activity was never greater than that elicited at the initial treatment and was often undetectable despite a tenfold increase in UV exposure. It is proposed that DNA damage should be measured to determine whether epidermal cells are entirely protected from UVB radiation at the completion of therapy.     

Can ultraviolet erythema be used to identify the basal cell carcinoma phenotype?

Since a prolonged duration of a strong UBV erythema has been suggested as a marker for propensity to develop skin cancer, we objectively followed the duration and intensity of erythemas induced by UVB and UVA radiation for 28 days in 18 patients with basal cell carcinoma (BCC), and in 15 healthy controls using reflectance spectrophotometry. The erythema index, defined as the difference in redness between UV-exposed skin and normal, adjacent skin on the lower abdomen, did not differ significantly between the two groups at 24 h, when the reaction was maximal, following a dose of 6 MED of UVB. Erythema values after 7 and 14 days were slightly higher in the BCC group, but this difference did not reach statistical significance. At day 7 some patients in the BCC group showed very strong erythemas. At days 21 and 28 the two groups had almost identical erythemal reactions. Following a standard dose of UVA of 100 J/cm², patients with BCC and healthy controls both showed weak erythemal reactions, which declined somewhat over the study period. No significant differences in pigmentary response were noted between the BCC and the control group, neither following UVB nor UVA. Although individual patients with BCC deviate from the normal erythemal curve for UVB, the UVB response is not a suitable predictive instrument in screening patients with the basal cell carcinoma phenotype.     

A comparison of the dose-response relationship for psoralen-UVA erythema and UVB erythema

Twenty patients with psoriasis were phototested to determine their erythemal responses to UVB and psoralen-UVA (PUVA) (oral 8-methoxypsoralen). The smallest ultraviolet radiation doses to produce erythema (minimal erythema dose and minimal phototoxic dose, respectively) were recorded and dose-response curves were constructed for UVB (24 hours after irradiation) and PUVA (48 hours) using objective measurement. The choice of a 48-hour measurement was validated by phototesting an additional 11 subjects to determine the time course of PUVA erythema. No correlation was demonstrated between minimal erythema dose for UVB, minimal phototoxic dose for PUVA, and sun-reactive skin type. The mean slope of the dose-response curve for UVB erythema was four times steeper than that for PUVA. Psoralen-UVA erythema reached a broad maximum between 48 and 96 hours after irradiation. Using objective methods we have demonstrated that the commonly accepted view of a steep dose-response relationship for PUVA erythema is not valid.     

Reduction in 8-methoxypsoralen immersion time alters the erythemal response to bath PUVA

Topical psoralen plus ultraviolet A (PUVA) using 8-methoxypsoralen (8-MOP) bath solution is a well established and effective treatment in dermatology. The standard immersion time in the UK is 15 min, but a shorter bathing period could potentially increase treatment convenience. In order to examine the effect of reduction in immersion time on skin phototoxicity, we compared the erythemal response to UVA following 5 min and 15 min psoralen baths. The study was performed on the forearm skin of 7 healthy volunteers using an 8-MOP psoralen concentration of 2.6 mg/l. One forearm of each volunteer was soaked for 15 min and the other for 5 min, followed by immediate irradiation with a series of 10 doses of broadband UVA ranging from 0.1 J/cm2 to 6.9 J/cm2. At 72 h, the minimal phototoxic doses (MPDs) were noted and erythema readings (erythema index) were taken in triplicate with a reflectance instrument. The median MPD following 5 min immersion was 1.7 (range 0.7-2.7) J/cm2 compared with 1.0 (range 0.4-1.7) J/cm2 after 15 min treatment, with no significant difference. However, the mean slope of erythema dose-response on the 15-min treated side was significantly steeper than on the 5-min treated side, 0.036 and 0.021 respectively, P < 0.05. Hence, this preliminary work shows that reducing 8-MOP immersion time to 5 min reduces the erythemal response to UVA. It will clearly be necessary to examine the effect of a shortened immersion period on disease clearance before considering such a change to the topical PUVA regime.     

Cutaneous carcinoma and PUVA lentigines in Thai patients treated with oral PUVA

A total of 113 Thai patients who were treated with oral PUVA from 1979 to 1992 were examined for long-term cutaneous side effects of PUVA. Two psoriatic patients developed PUVA keratosis on non-sun-exposed areas. Both were skin type IV and had had phototherapy with UVB and sunlight previously. The total doses of UVA were 909 J/cm² and 242 J/cm² respectively. One psoriatic patient developed Bowen's disease. He had had a cumulative dose of UVA 2207 J/cm². He also had a past history of arsenic intake and phototherapy with UVB and sunlight. PUVA lentigines were seen in 58 patients (51.4%). It was associated with older age at starting PUVA, higher cumulative UVA dose and greater number of PUVA treatment. This study suggests that previous exposure to other risk factors is important for inducing skin cancer in populations with skin phototype III, IV and V treated with oral PUVA.     

Comparison of the relative therapeutic efficacy of 7-methyl pyridopsoralen and 8-methoxypsoralen in photochemotherapy in psoriasis treatment

A newly-synthesized, monofunctional psoralen derivative, 7-methyl pyrido (3,4-C) psoralen (MPP) was compared with 8-methoxypsoralen (8MOP) with respect to their therapeutic efficacy in photochemotherapy of psoriasis. Psoriatic lesions of six patients were treated with topical application of MPP plus UVA (MPP PUVA) or with 8MOP plus UVA (8MOP PUVA). The UVA doses used in each treatment were 7.5 or 10 J/cm² with MPP and from 1.2 to 3.6 J/cm² with 8MOP. In every patient, marked improvement was observed after 2 to 6 treatments with MPP PUVA or 8MOP PUVA. Three patients showed clearance of each psoriatic lesion treated 9 to 17 times with MPP or 8MOP PUVA. Althought MPP required much higher UVA doses than 8MOP, MPP PUVA was as effective as 8MOP PUVA in treating psoriasis. When irradiating with identical doses of UVA, MPP PUVA appeared to be less active than 8MOP PUVA. None of the patients developed any severe dermatitis reactions during 20 exposures to MPP PUVA, indicating that the probability of inducing allergic contact and photocontact dermatitis may be extremely low. Erythemogenic and pigmentogenic activities of MPP and 8MOP were also compared. The data demonstrated that 8MOP is more than 8 times as effective as MPP for both activities. With the UV doses used in this study, however, every patient produced marked pigmentation after MPP PUVA therapy. Finally, the UVA dose-dependency of MPP PUVA was studied with an additional patient. Both therapeutic and pigmentogenic effects increased as a function of the UVA dose; it appeared impossible to clear psoriasis without producing pigmentation.     

Immunologic implications of PUVA therapy in psoriasis vulgaris

Summary During the combined effects of psoralen and UVA irradiation (PUVA therapy) a significant decrease (P<0.005 in T cells has been noted in 10 psoriasis patients and 10 healthy controls especially after four exposures. Based on the fact that the total number of circulating lymphocytes of the patients and the PUVA-treated healthy controls remained within the normal range, this decrease may be due to temporary physicochemical changes of the membranes of these cells but not to T cell lysis. After eight exposures these decreased T cell values returned to starting range. The starting T cell range in psoriasis patients is significantly lower (P<0.005) compared to that of healthy controls.It is of importance that before PUVA therapy in all the patients antibodies reactive with a basal cell nuclear antigen belonging to the four main Ig classes (IgM, IgD, IgE, and IgA) could be removed from the membrane of circulating lymphocytes by means of acid elution. In contrast, mainly the IgA antinuclear basal cell antibody could be eluted from circulating PMN leukocytes in the patients under investigation. After eight PUVA exposures, however, corresponding antibodies, belonging to the three main Ig classes (IgM, IgD and IgE) could also be eluted from the membranes of circulating PMN-leukocytes of the same patients. This implies an exchange of molecules during photochemotherapy. Finally, it could be shown that after effective PUVA therapy antinuclear basal cell antibodies of the psoriasis patients under study were reactive not only with the nuclei of the basal cell layer but also with almost all the nucleic of the epidermis of the uninvolved and lesional skin. The latter finding points to the fact that PUVA treatment causes at least antigenic changes of nuclear proteins in all the nuclei of the epidermis of the PUVA treated skin. Moreover, inflammatory cells with Fab fragments within the cells present in the lesional skin before PUVA disappear during this treatment.Based on a poster session presented at the occasion of the seventh joint meeting of the ESDR, Amsterdam, The Netherlands, May 1977     

Suppressive effect of ultraviolet (UVB and PUVA) radiation on superantigen production by Staphylococcus aureus

It is well known that Staphylococcus aureus (S. aureus) proliferates on the moist skin lesion of atopic dermatitis. Reduction of bacteria colonization from skin lesions by antibiotics has been reported to be effective for the treatment of atopic dermatitis. S. aureus produces superantigens which can activate T cells and possibly enhance the inflammatory reaction. Photo(chemo)therapy has been successfully used for the treatment of severe cases of atopic dermatitis. We have previously reported that photo(chemo)therapy had bacteriostatic effect on S. aureus. Now we examined the effect of UVB and psoralen plus UVA (PUVA) on superantigen production from S. aureus. We isolated S. aureus from six atopic dermatitis patients. S. aureus was irradiated in vitro with UVB (0, 5, 10 mJ/cm²) or PUVA (0.001% psoralen plus 0, 5, 10 mJ/cm² UVA) and incubated 4 h with 100 strokes per min. After incubation, the amounts of superantigens in the supernatant were measured using ELISA kit. The production of superantigens decreased in an ultraviolet dose-dependent manner. The suppressive effects of UV radiation on superantigen production may be involved in the therapeutic efficacy of photo(chemo)therapy for atopic dermatitis.     

A large scale analytical study on efficacy of different photo(chemo)therapeutic modalities in the treatment of psoriasis,vitiligo and mycosis fungoides

Psoriasis, vitiligo, and mycosis fungoides (MF) are among the most frequently treated dermatological diseases by photo(chemo)therapy. The objectives are to determine which photo (chemo) therapeutic modality could achieve the best response in the treatment of psoriasis, vitiligo, and MF. The design used in this study is retrospective analytical study. The study included 745 patients' records; 293 with psoriasis, 309 with vitiligo, and 143 with early MF, treated in the Phototherapy Unit, Dermatology Department, Kasr El‐Aini Hospital, Cairo University by either psoralen and ultraviolet A (PUVA), narrow band ultraviolet B (NB‐UVB), psoralen and narrow band UVB (P‐NBUVB), broad band UVB (BB‐UVB), or broad band UVA (ΒΒ‐UVA). Data were retrieved from the computer database of the unit and statistically analyzed. In psoriasis, oral and topical PUVA and NB‐UVB were found to be equally effective, whereas oral PUVA had significantly better results than both UVA and BB‐UVB at the end of therapy. In generalized vitiligo, PUVA and P‐NBUVB had significantly better results than NB‐UVB alone. In early MF, there was no statistically significant difference between the response to oral PUVA and NB‐UVB. PUVA and NB‐UVB are good choices in patients with psoriasis and early stage MF, whereas PUVA appears the best choice in the treatment of vitiligo.     

Response of psoriasis to psoralen-UVB photochemotherapy

The effect of psoralen in combination with 31 1 nm (UVB) radiation was studied in five subjects with normal skin and 10 patients with psoriasis involving both forearms. Treatment with oral 8-methoxypsoralen augmented the UVB erythemal response at 6 h after irradiation, but had no effect at 24–72 h. In eight of the nine patients who completed the trial, lesions of psoriasis on the arms treated with psoralen-LlVB cleared hefore lesions on the arms treated with UVB alone. This study has shown that psoralen in comhination with UVB has an erythemal effect on normal skin, and a therapeutic effect in psoriasis which is greater than the response to UVB alone.     

Expression of nerve growth factor receptors in cutaneous inflammation

Evidence indicates that the neurotrophin nerve growth factor (NGF) is a mediator of cutaneous inflammatory responses. Cellular responses to NGF are facilitated by two receptors called trk A and p75 neurotrophin receptor (p75^NTR). In the current study we have investigated the expression of these receptors in lesional and non-lesional skin from patients with plaque psoriasis and in normal skin exposed to three times the minimal erythema dose of ultraviolet (UV) B radiation. Trk A immunostaining was confined to the basal keratinocytes in normal skin. There was a significant reduction in trk A immunostaining in both non-lesional and lesional psoriatic skin compared with control skin. In UVB-irradiated normal skin, there was a significant reduction in trk A immunostaining at 4 h after irradiation, which was still evident at 48 h. In normal skin, p75^NTR immunopositive fine nerve fibres were present throughout the dermis and occasionally seen in the epidermis. Thick nerve fibres were evident in the deep dermis and in the middle region of the dermis. p75^NTR immunopositive basal keratinocytes were occasionally seen. There was a statistically significant loss of p75^NTR immunopositive fine nerve fibres in the epidermis of lesional psoriatic skin and a statistically significant loss of p75^NTR immunopositive fine nerve fibres in the dermis in both non-lesional and lesional psoriatic skin. p75^NTR immunopositive thick nerve fibres were reduced in lesional psoriatic skin compared with normal skin. UVB irradiation of normal skin led to a statistically significant decrease in the p75^NTR immunopositive fine nerve fibres in the epidermis at 48 h after irradiation. There was no significant reduction in the dermal p75^NTR immunoreactivity. These results demonstrated that expression of both NGF receptors is decreased following an acute inflammatory stimulus and also in association with a chronic inflammatory dermatosis.     

Psoralen-ultraviolet A therapy vs. psoralen-ultraviolet B therapy in the treatment of plaque-type psoriasis: our experience with fitzpatrick skin type IV

BACKGROUND: Oral psoralen, when combined with UVB, shows an increased response in psoriasis. In this study, conventional psoralen-UVA (PUVA) therapy was compared with psoralen-UVB (PUVB) therapy in plaque-type psoriasis in patients with Fitzpatrick skin type IV. PATIENTS AND METHODS: Equal numbers of patients with stable, plaque-type psoriasis were treated with either PUVA (n = 22) or PUVB (n = 22), three times weekly until 90% clearance was achieved. A final evaluation was made 3 months later. RESULTS: The two groups showed no significant differences in terms of clearance of disease, mean number of exposures, or the average duration of therapy; however, the cumulative dose of UVB required for clearance was significantly lower than that of UVA. Both groups had a similar acute side-effects' profile. CONCLUSIONS: PUVB therapy is as effective as conventional PUVA in the treatment of stable, plaque-type psoriasis in patients with Fitzpatrick skin type IV. A significantly lower dose of UVB is required for clearance as compared with UVA.     

Comparison of turbo‐PUVA and conventional American‐style PUVA in the treatment of psoriatic patients

Background: Ultraviolet (UV)A protective properties of dihydroxyacetone (DHA) have been used as a topical UV‐resisting barrier to optimize psoralens and UVA (turbo‐PUVA). Starting doses and increments were based on the DHA diffuse reflectance spectroscopy‐derived protection factor. Objective: To evaluate the efficacy of turbo‐PUVA in psoriatic patients using a simpler method for determining starting doses and increments, in comparison to the conventional American‐style PUVA photochemotherapy. Methods: Thirty psoriasis patients (15 on American‐style PUVA and 15 on turbo‐PUVA) were evaluated, each receiving PUVA twice weekly. Starting UVA dose was determined according to skin phototype for the American‐style PUVA group and according to the patient's skin phototype × DHA SPF 3 in turbo‐PUVA group. UVA increments used were 0.5–1.5 J/cm² per treatment in American‐style PUVA and 25% of the previous dose in turbo‐PUVA. Results: Turbo‐PUVA group showed a significantly lower mean cumulative dose, a significantly higher psoriasis area and severity index score reduction, lesser mean number of treatment sessions, and less duration of treatment till remission (188.44±106.2 J/cm², 92.164±1.975%, 11.2±3.52 session, and 1.4±0.44 months, respectively) than conventional American‐style PUVA group (255.13±18.304 J/cm², 74.725±10.976%, 30±0.00 sessions, and 3.75±0.00 months, respectively). Conclusion: Turbo‐PUVA is more effective and time convenient for the treatment of psoriasis with less cumulative dose than the conventional American‐style PUVA.     

The Relationship among Minimal Erythema Dose,Minimal Delayed Tanning Dose,and Skin Color

The relationship among minimal erythema dose (MED), minimal delayed tanning dose (MDTD), and skin color was examined in 16 healthy volunteers using three different spectra. The subjects were exposed to UVB, UVA+B, and UV+Visible light (UV+Visible) with a xenon arc solar simulator as a light source. The MEDs for UVB and UVA+B were less than the MDTDs, whereas the MED for UV+Visible was higher than the MDTD. There was no significant correlation between the MED and the MDTD for UVB or UVA+B. The MED for UV+Visible was significantly correlated to the MDTD (p<0.01). Skin color significantly correlated with MEDs for UVB and UVA+B (p<0.01), but not for UV+Visible. There was no significant correlation between skin color and the MDTD for any spectra. From these results, it is suggested that the relationship between erythemal and melanogenic responses is dependent on spectral bands of the light source and that skin color is a predictor of UV-induced erythema.     

The effectiveness of PUVA treatment in severe psoriasis is significantly increased by additional UV 308-nm excimer laser sessions

In most cases, patients with moderate to severe psoriasis are treated with narrow-band UVB phototherapy or with psoralen UVA (PUVA-) photochemotherapy. This UV-radiation is given to the whole skin, including unaffected skin. Normally, these two PUVA- and UVB-radiation procedures cannot be combined on account of the phototherapeutic side-effects on unaffected skin. The 308-nm excimer laser has been shown to be safe and effective in the treatment of localized mild-to-moderate plaque-type psoriasis whilst sparing healthy skin. Our aim was to compare the therapeutic response to PUVA plus up to 4 UVB308-nm radiations and PUVA monotherapy in patients with moderate-severe plaque-type psoriasis. 272 hospitalized adult patients were enrolled on this prospective random study. 256 patients completed the full course of treatment. PUVA treatment was given 4 times weekly to all patients. 123 patients received PUVA as a monotherapy. During the first two weeks, 149 patients were additionally treated up to four times with 308-nm excimer-derived UVB on the affected skin and treatment was evaluated for its efficacy, duration, number of times necessary for complete (CR) or partial remission (PASI reduction > 90 or > 50%, respectively), cumulative light dose, side effects of therapy and duration of remission after therapy. Statistically, there is no significant difference when comparing the efficacy of PUVA (CR 67.3%) and PUVA plus excimer (CR 63.6%). On average, patients treated by the combination method went into remission in half the treatment time (15 +/- 6 versus 27 +/- 7 days) and with half the cumulative UVA dose (22.9 +/- 5.8 versus 53.2 +/- 26.3), p < 0.05. In conclusion, skin heals considerably quicker when treated with a combination of photochemotherapy and a short course of UVB 308 nm laser treatment applied directly to the affected skin, resulting in a shorter hospital stay and quicker rehabilitation of patients with moderate-severe psoriasis.     

A new psoralen-containing gel for topical PUVA therapy: development,and treatment results in patients with palmoplantar and plaque-type psoriasis,and hyperkeratotic eczema

Summary Topical photochemotherapy with psoralen and its derivatives 4.5′,8-trimethylpsoralen (TMP) and 8-methoxypsoralen (8-MOP), with UVA irradiation, was evaluated with regard to minimum phototoxic dose, concentration, timing of UVA irradiation and systemic and local side-effects, in healthy volunteers. Psoralen (0.005%) in aqueous gel was found to be superior to TMP and 8-MOP in aqueous gel. No hyperpigmentation was seen after topical PUVA treatment with psoralen in aqueous gel. Patients with plaque-type psoriasis (n = 7), palmoplantar psoriasis (n = 7) and hyperkeratotic eczema (n = 2) were treated. Topical PUVA therapy was effective in most psoriasis patients, without the occurrence of local or systemic side-effects. Moreover, hyperkeratotic eczema patients who did not respond to conventional therapy showed partial remission. These results indicate that topical PUVA therapy with psoralen in aqueous gel is a useful therapeutic modality for treatment of psoriasis patients, and patients with recalcitrant dermatoses such as palmoplantar psoriasis and hyperkeratotic eczema.