Recent advances in phototherapy

ARTICLE

Introduction

Numerous studies have shown a beneficial effect of ultraviolet radiation for the treatment of chronic inflammatory or lymphoproliferative skin diseases. Advances in our understanding of the pathogenesis of these skin diseases have prompted the development of new phototherapeutic strategies such as long-wave UVA (UVA1), narrowband UVB (TL-01), bath water delivery of 8-MOP followed by UVA (bath-PUVA) or the combination of salt water brine baths and UVA/B, and extracorporeal photopheresis (ECP). Here we review these phototherapeutic approaches and discuss their indications and potential risks and benefits. In recent years great progress was also made in the development of photodynamic therapy (PDT) as an alternative therapeutic option for superficial skin tumours or psoriasis [1, 2]. However, PDT will not be the focus in this review.

UVA1 phototherapy

UVA1 phototherapy utilizes long wave UVA radiation (340-400 nm) while filtering out the erythematogenic UVA and UVB wavelengths (290-340 nm). It has been shown to be very effective in the treatment of several inflammatory skin diseases such as atopic dermatitis, localized scleroderma, urticaria pigmentosa, disseminated granuloma annulare and in some cases in systemic sclerosis, lichen sclerosus et atrophicans, graft-versus-host disease (GvHD), cutaneous T cell lymphoma and psoriasis in HIV-infected individuals. Different dosage regimen have been proposed for UVA1 phototherapy: low dose (10-20 J/cm² per single dose), medium dose (50-60 J/cm² per single dose) or high dose (130 J/cm² per single dose) UVA1 therapy. The therapeutic efficacy of high dose UVA1 irradiation in the treatment of patients with acutely exacerbated atopic dermatitis was first reported in 1991 and was confirmed in several subsequent studies [3-5]. It can be used as a monotherapy for a limited period of time (10-15 exposures, max. twice yearly) and as such seems to be an alternative to long-term glucocorticosteroid use [3, 4]. However, some patients with atopic dermatitis do not respond well to high dose UVA1. These Non-Responders are characterized by severe atopy and by concomitant bacterial or fungal superinfections and might benefit from a combination of high dose UVA1 with antibiotic or antimycotic treatment [5]. Of note, subsequent studies have demonstrated intermediate dose UVA1-phototherapy also to be effective in the treatment of moderate severity AD [6, 7]. In a recent pilot study, we demonstrated a statistically significant reduction of the SCORAD after 15 treatments with high or medium dose UVA1 therapy compared to low dose therapy [8]. Histopathological analysis of UVA1 irradiated skin revealed a reduction of mast cells and an induction of collagenase-I-activity. Based on these results, UVA1 was successfully used in the treatment of urticaria pigmentosa (130 J/cm² x 10) [9] and, in different dosage regimen, in localized scleroderma (130 J/cm² x 30 or 20 J/cm² x 24 respectively) [10, 11] and in scleroderma in systemic sclerosis [12]. Furthermore, improvement of skin lesions in patients with disseminated granuloma annulare by high dose UVA1 phototherapy (130 J/cm² x 15) has recently been reported [13]. Despite all the benefits of UVA1, little data exist on potential long-term safety risks such as photodamage and skin carcinogenesis in humans, particularly of the high dose regimen. Therefore, we recommend that patients should be treated with high dose UVA1 phototherapy no more than twice yearly for up to 15 irradiations per therapy cycle, they should be > 18 years, and they should be monitored at least once a year for the potential occurrence of photodamage or skin cancer.

Narrowband (TL-01) UVB

The narrowband UVB lamp with an emission spectrum peaking at 311-313 nm (Philips TL-01/100 W) was developed as an alternative to broadband UVB (290-320 nm) for the phototherapy of psoriasis to reduce erythemogenicity and the risk of skin carcinogenesis. Several studies comparing it with conventional broad-spectrum UVB phototherapy in patients with psoriasis reported greater therapeutic efficacy for narrowband UVB phototherapy [14, 15]. A combination of narrowband UVB with dithranol [14] or with oral retinoids [16] resulted in even faster clearance of the psoriatic lesions. In one study, narrowband UVB appeared to be almost as effective as systemic PUVA photochemotherapy [17]. Narrowband UVB used in combination with systemic 8-methoxypsoralen treatment (PUVB) proved as good as systemic PUVA [18]. When combined with topical (bath) 8-MOP delivery, narrowband UVB phototherapy was even superior to broadband UVA irradiation [18]. Narrowband UVB phototherapy was also used in the management of atopic eczema, resulting in the amelioration of pruritus, restoration of a normal sleep pattern and a reduction of topical steroid use [19]. In patients with photosensitivity diseases such as polymorphic light eruption, TL-01 produces a "hardening" photoprotective effect [20]. Long-term side effects of narrowband UVB phototherapy, such as potential skin carcinogenesis, seem to be at least equal to and possibly less frequent than would be expected from broadband UVB sources [21, 22].

Balneophototherapy

Balneophototherapy combines bath water delivery of water soluble photosensitizers or antiinflammatory agents for example 8-methoxypsoralen (8-MOP) or different salt solutions with a subsequent UVB- or UVA-irradiation [reviewed in 23]. In recent years, the combination of brine baths or 8-MOP-baths with UVB- or UVA-phototherapy using artificial light sources has been used increasingly in the treatment of psoriasis and atopic dermatitis [24, 25]. Administration of 8-MOP in a dilute bath water solution seems to be an effective alternative to its widely used systemic application, avoiding side effects such as nausea, vomiting, elevation of liver transaminases or even photodamage to the eyes and furthermore reduces cumulative UVA doses [26]. Furthermore, bath water delivery results in a uniform cutaneous absorption and a homogeneous skin distribution of 8-MOP. The optimal time for UVA irradiation is immediately after the 8-MOP bath. In contrast to systemic PUVA therapy, photosensitivity is lost within two hours after 8-MOP bath, which is a substantial advantage for patients, avoiding the need for prolonged UV protection of the skin and eyes [27, 28].

PUVA bath therapy proved to be effective in psoriasis, mycosis fungoides, lichen planus, localized scleroderma, urticaria pigmentosa and chronic palmoplantar eczema [23, 29]. PUVA bath therapy can also be combined with oral acitretin for the efficient treatment of severe psoriasis [30]. Several case reports documented a beneficial effect of bath PUVA in the treatment of prurigo, vitiligo or severe atopic dermatitis [reviewed in 23].

Investigation of the effectiveness of salt water baths containing either 15% synthetic Dead Sea salt called "Psorisal" or 3% NaCl solution in 40 patients with psoriasis and AD led to significantly better results in 80% of the patients of the "Psorisal" treatment group [31]. Balneophototherapy of atopic dermatitis with a combination of 3-5% salt water brine baths and subsequent UVA/B irradiation led to a SCORAD reduction from 70 to 37 after 20 treatments in 28 patients with atopic dermatitis [32]. The treatment of psoriasis with a combination of 15% salt water brine baths and subsequent UVB irradiation led to a PASI reduction about 83% from 16.2 to 2.75 after 21 treatments in 4,024 patients with psoriasis [33]. Possible modes of action of salt water baths are the elution of chemotactic and proinflammatory mediators, and immunomodulatory skin effects [34, 35]. Other mechanisms, such as increased photosensitivity may contribute to the efficacy of salt baths followed by UV radiation [36].

Extracorporeal photopheresis (ECP)

Extracorporeal photopheresis (ECP) was first introduced 1987 by Edelson et al. as a therapeutic regimen for Sezary's syndrome [37]. However, in recent years, it has been used successfully for other indications such as chronic graft-versus-host disease (GvHD), systemic scleroderma, pemphigus vulgaris, rheumatoid arthritis, lupus erythematodes and even severe atopic dermatitis [38-44]. ECP is a discontinuous leukapheresis procedure that combines administration of 8-methoxypsoralen (8-MOP) with extracorporeal UVA irradiation to a fraction of the peripheral blood leukocytes. Thus it targets the effects of photochemotherapy directly to circulating, pathogenic leukocytes [40]. 8-MOP photosensitization of leukocytes can be achieved either by systemic administration, where treatment efficacy depends essentially on sufficient 8-MOP plasma levels, or by direct administration of 8-MOP to the leucocyte fraction [39].

To date, ECP is considered as first-line treatment for CTCL-stages III and IV (TNM- classification) and can also be used in combination with interferon alfa or methotrexate in cases of treatment failure of an ECP monotherapy [44]. In patients with GvHD, ECP led to an omission of immunosuppressive drugs after 15 treatment cycles within 12 months because of noticeable improvement in cutaneous changes, liver function parameters and general condition [38]. Moreover, ECP was reported to be effective in the treatment of certain autoimmune diseases such as systemic scleroderma or pemphigus [42, 43]. ECP has also been used successfully in the treatment of severe atopic dermatitis. In the study of Prinz et al., ECP resulted in a marked clinical improvement of the skin lesions of 4 patients after 5 cycles (4-week-intervals) of ECP in average and was reflected by a marked reduction in IgE serum levels. Clinical remission was stable under maintenance therapy with prolonged intervals (6-week-intervals) between photopheresis sessions [41].

Outlook

In the past, research in photodermatology has led to refinements of phototherapy modalities such as UVA1, narrowband (TL-01) UVB, balneophototherapy and extracorporeal photopheresis. These new and promising approaches in the management of chronic inflammatory or lymphoproliferative skin diseases are effective, but a standardization of dosage regimen and quality control is necessary to avoid potential long-term safety risks such as photodamage and skin carcinogenesis.

Article accepted on 27/10/00

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