Wilhelm Brenner

Photochemotherapy for cutaneous T cell lymphoma: A follow-up study

In 1975 we started a prospective study on oral methoxsalen photochemotherapy (PUVA) in cutaneous T cell lymphoma (CTCL). The first short-term follow-up of nineteen patients (1978) showed that PUVA may induce long-lasting remission in early stages, and that eventual relapses respond comparably well when PUVA is resumed. We now present the follow-up data of the original nineteen patients, covering a period of up to 7 years, and of an additional twenty-five patients who have entered the trial since April, 1977. Similar to earlier reports, all patients with eczematoid and plaque lesions (stages IA and IB) cleared. Likewise, eczematoid and plaque lesions in patients with early tumors (stage IIB) were cleared. During a mean follow-up of 44 months, 55% of stage IA patients and 39% of stage IB patients remained free of disease. In patients who experienced relapses, the mean disease-free interval was 20 months for stage IA and 17 months for stage IB. All patients with stage IIB experienced multiple relapses and only three of seven were alive after 6 years, despite additional x-ray or cytotoxic therapy. The observation in this study that five of nine stage IA patients and ten of twenty-six stage IB patients have remained in continuous remission after a single PUVA course for up to 79 months indicates that PUVA may induce long-lasting disease-free intervals if used in the early stage of disease. However, the observation period still does not prove whether permanent cure can be achieved in some cases or not.

5-Methoxypsoralen (Bergapten) in photochemotherapy of psoriasis

5‐Methoxypsoralen (5‐MOP, Bergapten) was evaluated as a potential photosensitizing drug in oral photochemotherapy of psoriasis. Treatment results indicate that (1) 5‐MOP is as effective as, and in high doses more effective than, 8‐methoxypsoralen in clearing psoriatic lesions; (2) therapeutic doses of 5‐MOP do not lead to erythema; the acute side‐effects of 8‐MOP PUVA therapy—erythema, blistering, pruritus—are thus avoided; (3) even high doses of 5‐MOP are not followed by nausea. 5‐MOP PUVA therapy thus represents a real alternative to 8‐MOP PUVA, its advantages over 8‐MOP PUVA being greater safety and patient acceptance.

Induction of UV light tolerance by PUVA in patients with polymorphous light eruption

A tan induced by 8‐methoxypsoralen‐long wave ultraviolet light has proved an effective photo‐ protective sunscreen in 5 patients with long wave ultraviolet light‐induced polymorphic light eruption.

Keratoses and nonmelanoma skin tumors in long-term photochemotherapy (PUVA)

Four hundred eighteen patients were treated with oral photochemotherapy up to 5 years and monitored regularly for the occurrence of precancerous conditions or tumors of the skin. Out of this group, six patients (1.4%) developed actinic keratoses and five (1.2%), epidermal tumors (three squamous cell carcinomas, one basal cell carcinoma, one keratoacanthoma) 12 to 53 months after initiation . of 8-methoxypsoralen-photochemotherapy (PUVA). Ten of these eleven patients belonged to a group of 172 individuals with a history of previous exposure to arsenic, ionizing radiation, and/or methotrexate who were considered a risk group. All of the four carcinoma patients had previously had one or more courses of arsenic therapy. No tumors were observed in the remaining 246 nonrisk patients. The mean age of the keratosis-tumor group (59 ± 9 years) and the total cumulative long-wave ultraviolet light (UVA) dose (1,045 ± 959 J/cm 2 ) were significantly higher (p 2 ) of the 407 patients without such skin changes. The skin type and the time period between initiation of PUVA therapy and the final evaluation of the patients did not exhibit substantial differences in both groups. The observed incidence of epidermal carcinomas in the risk group (2.3%) was considerably higher than the expected age-sex-specific incidence of a randomized population (0.1%), whereas the incidence in the nonrisk group (0%) corresponded to the expected rate. However, data on the tumor incidence in psoriatics not treated with PUVA and matched for previous treatments and risk factors were not available. This study shows that the incidence of nonmelanoma skin tumors in long-term PUVA patients without previous medication of arsenic or treatment with ionizing radiation does not differ from the expected incidence of the general population. However, there is an increased incidence of tumors in PUVA patients if certain risk factors are present. The risk factor in our series is previous medication with arsenic, which is carcinogenic per se.

Long‐term photochemotherapy: histopathological and immunofluorescence observations in 243 patients

Skin biopsies of 243 patients treated with photochemotherapy (PUVA) for 1–4 years were examined histologically. Two hundred and six patients were examined retrospectively after total cumulative UV‐A doses of 579·6 ± 598·0 J/cm2 (mean ± s.d.). An eosinophilic homogenization and a reduction of elastic fibres at the dermo‐epidermal junction, and an increase of dermal macrophages were found as possible abnormalities. However, except for the increase of melanophages there was no statistically significant correlation between the incidence of these changes, the total UV‐A dose applied and the skin type of the patients. Neither were such correlations found in thirty‐seven patients biopsied twice after 394·8 ± 267·6 J/cm2 and 808·5 ± 458·9 J/cm2 (mean±s.d.), respectively. Studies with direct immunofluorescence techniques revealed no immunoglobulin deposits in PUVA treated skin in fifty‐six patients after 469·2 ± 370·2 J/cm2; antinuclear antibodies were observed in 4·6% of 129 patients after 169 J/cm2 (mean); in 11%, of fifty‐three patients reexamined after 381 J/cm2 (mean) and in 13·6% of twenty‐two patients reexamined a second time after 643 J/cm2 (mean).

Non-inflammatory dermal elastolysis.

A 33‐year‐old woman is described who suffers from an idiopathic loss of mid‐dermal elastic tissue which leads to wrinkling of the skin and to discrete perifollicular protrusions. In accordance with Shelley & Wood (1977) we conclude that these findings represent a new entity for which we propose the term ‘non‐inflammatory dermal elastolysis’.

Photoprotective effect of a psoralen-UVA-induced tan

SummaryTo determine whether a tan produced by 8-MOP and UVA protects from subsequent solar light irradiation, volunteers were irradiated with unfiltered Xenon arc light before and 10 days after a 1 weeks course of four 8-MOP-UVA treatments. Evaluation of the minimal erythema doses and of histological changes before and after 8-MOP-UVA treatment revealed that the 8-MOP-UVA induced tan protected against the erythemogenic and cell damaging effects of Xenon arc light. Unscheduled repair DNA synthesis, used as a measure for UVB-induced DNA damage and repair, was also investigated in skin irradiated with the Xenon arc before and after 8-MOP-UVA induced tanning. Both the number of grains per sparse labeled cell and the number of sparse labeled cells per 1000 cells, were found to be significantly lower in tanned skin; taking decreased unscheduled repair DNA synthesis as a measure for decreased DNA-damage, these findings also demonstrate a photoprotective effect of the 8-MOP-UVA induced tan.ZusammenfassungZur Klärung der Frage, ob die durch 8-Methoxypsoralen (8-MOP) und langwelliges Ultraviolett-Licht (UV-A) induzierte Hautbräunung vor Sonnenbestrahlung schützt, wurden Testpersonen mit einer ungefilterten Xenon-Lampe vor und 10 Tage nach einer einwöchigen 8-MOP/UV-A-Behandlung (4 Expositionen) bestrahlt. Die Beurteilung erfolgte klinisch durch die Bestimmung minimaler Erythemdosen, cytomorphologisch durch Beurteilung UV-inducierter Gewebs- und Zellschäden in bioptischem Material und autoradiographisch durch die »unscheduled repair«-DNS-Synthese. Ein Vergleich der cutanen Reaktion auf eine definierte, von der Xenon-UV-Quelle (sonnenähnliches Spektrum) emittierten Energiedosis vor und nach Hautpigmentierung durch 8-MOP-UVA zeigte 1) klinisch eine signifikante Anhebung der minimalen Erythemschwelle, 2) histologisch eine signifikante Abnahme UV-inducierter Zellschäden und 3) autoradiographisch eine deutliche Abnahme von Repair-Aktivität als Maß eingetretener DNS-Schädigung. Sowohl die Zahl der Zellen mit Repair-Aktivität, als auch die Summe von Silberkörnern in markierten Zellen waren signifikant erniedrigt. Da die »unscheduled repair«-DNS-Synthese ein Maß für UVB induzierte DNS-Schäden und Reparaturvorgänge darstellt, wird auch anhand dieses Parameters ein Lichtschutzeffekt durch 8-MOP-UVA-Bräunung dokumentiert.

Coincidence of vitiligo, alopecia areata, onychodystrophy, localized scleroderma and lichen planus.

The unique coincidence of five dermatological disorders, which occurred in a 39-year-old patient, is discussed. The clinical and laboratory examination did not reveal a common underlying cause. It is hoped this report will stimulate the recognition of other cases and thus aid in determining whether the coincidence of these disorders is a true association of diseases with a common underlying factor or a rare abnormality.

UV-Induced unscheduled DNA synthesis in human skin: Dose response, correlation with erythema, time course and split dose exposure in vivo

Unscheduled DNA synthesis (UDS) has been shown to be saturated above a threshold dose of UV-C in human fibroblasts in vitro. We have investigated by autoradiography whether a similar saturation occurs in human skin in vivo with UV-B and whether this phenomenon correlates with the erythemal response. In addition, we determined the time course of UDS at 24 h after exposure and the effect of dual exposures separated by 24 h. The dose-response curve was established by exposure to 1/16, 1/8, 1/4, 1/2, 1, 2, 3, 4 and 6 MEDs UV-B. For the time-course study, areas exposed to 1/2 and 2 MEDs were biopsied after 1, 3, 6, 12 and 24 h. Autoradiography was performed in vitro. The dose-response curve showed a significant increase in UDS from 1/16 to 1 minimal erythema dose (MED), whereas no significant difference was observed between 1 MED and the higher UV-B doses tested. The 24 h time sequence revealed a gradual decrease in UDS activity. The 1/2 MED curve declined more rapidly and reached the zero-level between 12 h and 24 h, whereas about 50% of the initial UDS value was still retained 24 h after 2 MEDs. The dual-dose study revealed that a second hit of fractions of the MED resulted in lower levels of UDS than induced by these fractions alone in previously untreated areas. UDS increases with the erythemal dose between 1/16 and 1 MED. It reaches a plateau after 1 MED and cannot be increased by doses up to 6 MEDs, suggesting a saturation of excision repair in vivo. Time course studies support such a saturation phenomenon. The failure to increase significantly UDS by a second irradiation 24 h after the first exposure needs further clarification. Since persistence of DNA lesions may lead to an accumulation after repeated exposures, additional mechanisms other than excision repair may protect human skin by error-free removal of possibly mutagenic sites. Photoreactivation may be important in this respect.

Unscheduled DNA synthesis in normal human skin after single and combined doses of V‐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 htiman skin (1) 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.