Dermatology Online Journal

A review of studies that have utilized different combinations of psoralen and ultraviolet B phototherapy and ultraviolet A phototherapy
Noah Scheinfeld MD, and Vincent Deleo MD
Dermatology Online Journal 9 (5): 7

Department of Dermatology St. Lukes Roosevelt Hospital Center, Scheinfeld@earthlink.net

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Introduction

Goeckerman introduced his combination of ultraviolet light and tar to treat psoriasis 80 years ago [1, 2]. Later it was noted that the ultraviolet light in the ultraviolet-B range (UVB) 290-320 nm provided the active source of this regimen's phototheraputic effect [3, 4]. Such UVB covers all parts of the UVB spectrum and thus was termed broadband therapy. This regimen was cumbersome. It was effective for psoriasis, but its utility in the treatment of other diseases had limitations. Technological advances such as fluorescent bulbs improved UVB's facility and efficacy, but limitations in its therapeutic effect remained.

In the 1970s the photobiologic effects of psoralens and ultraviolet-A light (320-400 nm) (PUVA) were elaborated. In the presence of UVA, the DNA of cells that contain psoralen produce bifunctional adducts and other products. These adducts and products are associated with the amelioration of skin diseases such as psoriasis, vitiligo, and mycosis fungoides. PUVA was found more effective than UVB in the treatment of most skin diseases [5]. PUVA, however, has side effects that include increased skin cancer and stomach upset (to oral psoralen). Different psoralen compounds are used. (Table 1)

In the 1970s and 1980s it was found that the therapeutic effect of UVB in ameliorating psoriasis centered at the 313-nm wavelength [6]. In the 1980s narrowband UVB (nbUVB) (311 nm) treatment was developed and found to be more effective than broadband UVB in the treatment of many dermatological diseases. This generalization is based on the assumption that treatment regimens for UVB and nbUVB have been fully optimized. That is, in similar treatment regimens nbUVB leads to more complete clearance of lesions than broadband UVB given with a similar discharge of light energy [7]. Although it is clear that a high dose of broadband UVB may be more effective than a low dose of nbUVB, joule for joule, nbUVB seems more potent in the treatment of skin disease. In the case of psoriasis, nbUVB has been found to be as effective as PUVA.

In a search to optimize therapy, studies have assessed whether psoralen can act synergistically with UVB and nbUVB as it does with UVA. The basis for such a combination is uncertain because psoralen is activated in the presence of UVA and its interaction with UVB remains undefined. Over a dozen studies have assessed this combination. This review explores the science behind such a combination, outlines the results of studies of their combined use in skin disease and assesses the utility of such a combination.

Psoralen effects independent of ultraviolet light

Psoralen intercalates between DNA base pairs without UV radiation; however, psoralen alone without the presence of light does not have any effect on the function of DNA synthesis of human cells grown in vitro [8]. This finding has been replicated in a study of S-180 cells, in which neither the psoralens nor UVA light alone inhibit cell growth but instead act synergistically [9]. However, psoralen has been shown to enhance the generation of reactive oxygen species and free radicals in the absence of light and to possess prooxidative effects [10].

The light absorption spectrum for oral psoralen peaks at 325 nm [11], but the absorption spectrum extends into the shorter wavelengths of ultraviolet light in the UVB range. PUVA treatment using 335-nm UVA is twice as effective as with 365-nm UVA with respect to both erythemogenicity and the cumulative dose required for clearing psoriasis; however, 335 nm and 365 nm are equally effective if delivered in equal erythema doses, suggesting that in human skin the antipsoriatic activity of 8-MOP parallels its erythemogenicity [12]. The action spectrum for phototoxic erythema after topical 8-MOP sensitization peaks around 330 nm [13].

Generally psoralen increases the sensitivity of skin to UVB and increases the minimal erythema dose [MED]. Topical 8-methoxypsoralen (8-MOP) and trimethyl psoralen (TMP) increase the photosensitivity in response to 311-nm ultraviolet light by 3.5 and 5.5 times respectively, but UVA makes skin even more photosensitive to these agents [14]. Oral ingestion of 8-MOP within hours of exposure to UVB increases MED; oral TMP decreases MED [15]. Vitiligo patients undergoing photochemotherapy with TMP are less susceptible to a sunburn, and the protective effect of TMP against UV-B erythema seems related to UV absorption by the drug while it is in the bloodstream [16].

Mechanism for UVB action

UVB has many effects on the skin. It induces the formation of cyclobutane pyrimidine dimers (CPD) in DNA. Through the induction of DNA photoproducts, UVB radiation transiently inhibits cell proliferation. UVB suppresses ICAM-1, depletes and modulates Langerhans cells, and induces apoptosis. UVB also modulates keratinocyte-derived interleukin, which decreases inflammation and has effects on soluble mediators. It downregulates TH-1 responses and upregulates TH-2 responses [17].

PUVA and PUVB work differently

PUVA and PUVB probably affect human cells through different mechanisms. Without psoralen, UVA and UVB have different effects on skin cells. UVA induces measurable changes neither in the skin surface structure nor in its viscoelastic properties; however, a single erythemogenic dose of UVB radiation is followed by a significant increase in the depths of furrows, an increase in skin viscosity, and a decrease in the skin's biological elasticity [18]. Erythemogenicity of 311 nm manifests with unsensitized erythema at around 24 hours with or without prior psoralen exposure. After 8-MOP plus UVA the erythema peaks 2 days later. The pattern of interleukin such as IL-6, ICAM-1 and TNF-α differ between UVA and UVB [19]. They affect Langerhans cell migration differently in mice [20].

Oral psoralen with UVB for the treatment of psoriasis

Some, but not all, studies indicate that PUVB is more effective in treating psoriasis than UVB alone. In a study of 44 patients in which half are treated with PUVB and other half with PUVA, PUVB therapy is as effective as conventional PUVA in the treatment of stable, plaque-type psoriasis in patients with Fitzpatrick type-IV skin [21]. A significantly lower dose of UVB is required for clearance as compared with PUVA. In another study involving 100 patients, nbPUVB treatment of psoriasis is as effective as conventional PUVA [22]. A 1995 study found PUVB and UVB phototherapy equally efficacious in the treatment of psoriasis; however, those areas of the body treated with PUVA responded more rapidly and to a greater extent than areas exposed to UVB [23].

Oral psoralen works with nbUVB for the treatment of psoriasis

Some studies indicate that psoralen seems to work in synergistically with 311-nm UVB (nbPUVB). The effect of psoralen in combination with nbPUVB has been studied in five subjects with normal skin and ten patients with psoriasis involving both forearms [24]. Treatment with oral 8-MOP augments the UVB erythema response at 6 hours after irradiation, but has no effect at 24-72 hours. In eight of the nine patients who complete the trial, lesions of psoriasis on the arms treated with PUVB clear before lesions on the arms treated with UVB alone. This study has shown that psoralen in combination with UVB has an erythema effect on normal skin and a therapeutic effect in psoriasis that is greater than the response to UVB alone.

Bath PUVB for psoriasis

In a preliminary trial, Ortel finds 311-nm radiation plus oral psoralen more effective than 311 nm radiation alone [25]. In 1993, with others, Ortel finds that oral psoralen increases the erythemogenic, pigmentogenic, and therapeutic effect of nbUVB. With systemic 8-methoxypsoralen, UVA is comparable to 311-nm UVB. After bathwater exposure, 311 nm was clearly superior to UVA [26]. These authors suggest that the differences between oral and topical psoralen administration are most likely a result of different skin levels of 8-MOP and thus a different relation between photoproducts. Furthermore, they state that 311-nm UVB shows a higher erythemogenicity, pigment induction, and treatment efficacy after psoralen sensitization. However, a more recent study published in 2001 finds no benefit in adding psoralens to the bath water prior to 311-nm UVB treatment [27].

Combinations of Psoralen, UVA, and UVB

Combinations of PUVA and UVB have shown increased efficacy in the treatment of psoriasis. For recalcitrant disease, a combination of PUVA and UVB clears psoriasis more rapidly than PUVA or UVB, buttressing the concept that UVB and PUVA have different and perhaps complementary mechanisms [28]. Similarly, a bilateral comparison study of ten patients treated with UVB and PUVA and in eleven patients, seven cases of psoriasis clear in the same number of treatments with PUVA-UV-B or PUVA, but in four cases the PUVA-UVB treated side clears significantly more rapidly [29]. Similarly, 311-nm exposure enhances the phototoxic activity of bath-PUVA. Bath-PUVA with nbUVB clears psoriasis with fewer exposures and lower cumulative UVA doses under the same minimally erythemogenic conditions [30].

Vitiligo

The standard of care for the treatment for generalized vitiligo is either broadband UVB or PUVA. In the treatment of vitiligo, psoralen with UVB or psoralen and nbUVB has not offered therapeutic advantages over standard care. Although the use of PUVB is as effective as PUVA in the treatment of vitiligo, there is a significant difference in the number of sessions needed to produce erythema and perifollicular pigmentation as well as a moderate response, with the response on the PUVA side always being earlier [31]. Psoralen has not been shown to add to the efficacy of narrow-band UVB in the treatment of vitiligo [32].

Mycosis fungoides and nbPUVB

The role of nbPUVB in the treatment of mycosis fungoides has been investigated. Psoralen-UVB 311-nm is found to be as effective as PUVA in the treatment of MF [33]. However, because studies have shown that nbUVB itself is an effective treatment for mycosis fungoides, the additive benefit of the psoralen when given with nbUVB in the aforementioned study is uncertain [34].

Conclusions

Although PUVB and nbPUVB are efficacious in the treatment of skin disease, neither have established a utility over nbUVB or PUVA alone. NbUVB is very effective for treating many skin diseases [35]. A key advantage to UVB or nbUVB is that avoiding the use of psoralen may minimize the side effects of therapy, an advantage that PUVB and PUVA lack. Combinations of UVA, UVB, and psoralen appear to be more effective than PUVA or UVB alone. One possible advantage of PUVB over PUVA may be long-term safety; there may be decreased skin cancer because UVB cutaneous penetration is more superficial; however, there are no studies to support this contention. Bath and oral PUVA both present a dose-related risk of increased skin cancer [36]. Thus the long-term safety of PUVB or nbPUVB remains to be defined. Further evaluations of psoralen and UVB need to be conducted.

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