Psoralen-Ultraviolet Light A Therapy

Key points

Introduction

Photochemotherapy broadly refers to a treatment method that uses a photosensitizing compound and ultraviolet radiation. Psoralen-UV-A (PUVA) therapy more specifically involves use of either an oral or a topical psoralen followed by exposure to long-wave UV-A radiation (320–400 nm). This combination leads to a clinically beneficial phototoxic response, which has been used therapeutically for a wide array of dermatoses. The use of psoralen photochemotherapy dates back thousands of years to ancient Egypt and India, where the pigment-inducing qualities of naturally occurring plants were anecdotally described and applied to pigmentary disorders such as vitiligo. The period ranging from the 1930s to 1960s saw the chemical and structural identification of psoralens with extraction and synthesis. PUVA, in its modern form, was established by 1947 for the treatment of vitiligo and was subsequently adapted for use in psoriasis by Pinkus in 1951. The development of a high-intensity UV-A light source in 1974 firmly established the use of this modality as a highly effective treatment of psoriasis. Over time, treatment options for psoriasis have expanded and regular use of PUVA therapy has declined because of its photocarcinogenic potential. This chapter discusses the mechanism of PUVA as well as efficacy, dosing, safety, and precautions.

Mechanism of action

Psoralens are furocoumarins that are either naturally derived or synthetically produced. Currently, in North America, 8-methoxypsoralen (8-MOP) is the only available oral and topical formulation, whereas in Europe, 5-methoxypsoralen (5-MOP) is used due to its lower potential for phototoxicity and reduced gastrointestinal side effects. Trimethylpsoralen (TMP) has been traditionally used for bath PUVA, a practice that has been chiefly used in Scandinavian countries. The lower phototoxic potential of TMP has also led to its use, primarily in South Asia, in combination with sunlight exposure.

Following oral ingestion or topical application, the psoralen intercalates between DNA base pairs but remains quiescent in the absence of ultraviolet radiation. Upon initial exposure to UV-A, cyclobutane monoadducts are formed with pyrimidine bases. When a second photon of energy is absorbed, psoralen-DNA cross-linking occurs, which inhibits DNA replication and causes cell cycle arrest ( Fig. 3.1 ).

In addition to direct effects on cellular DNA, numerous changes in the cutaneous microenvironment have been observed following PUVA treatment. Psoralen photosensitization leads to altered cytokine secretion, including an increase in the expression of interleukins-1, -6, and -10 as well as immunosuppressive prostaglandins. Adhesion molecules and growth factor receptors are similarly modulated as is demonstrated by intercellular adhesion molecule-1, whose upregulation—a hallmark of inflammatory skin conditions—is effectively mitigated by photochemotherapy. Alteration in these mediators leads to transformation from a T helper 1 (Th1) and Th17 profile to a Th2 phenotype. Activated psoralens also interact with molecular oxygen, leading to the formation of reactive oxygen species. These reactive molecules and free radicals result in cell membrane damage by lipid peroxidation, disruption of mitochondria, and activation of eicosanoid pathways.

Following successful PUVA therapy, there is a decline in proliferating epidermal cells and a significant reduction in the epidermal thickness of psoriatic lesions. Current evidence suggests that this is mediated, in part, by induction of p53 and Fas pathways with subsequent keratinocyte apoptosis. There is evidence that differential expression of microRNAs plays a large role in p53-dependant apoptosis with significant upregulation of miR-4516 and increased Retinoic Acid Inducible Gene-1 signaling, leading to induction of autophagy and reduced cell migration.

Although effective at reducing epidermal keratinocyte proliferation, PUVA is far more potent at inducing apoptosis in lymphocytes, which may be related to suppression of Bcl-2 expression. In one in vitro study, there was virtual elimination of CD3 expression following bathwater treatment with either TMP or 8-MOP. The degree of lymphocyte depletion has been reported to correlate with clinical response.

A major advantage of PUVA over UV-B phototherapy is that UV-A penetrates deeper into the skin. As a result, cellular effects can be detected throughout the epidermis, papillary dermis, and superficial vascular plexus, leading to alterations in dermal dendritic cells, mast cells, endothelial cells, and infiltrating immune cell function.

Efficacy

Numerous studies have demonstrated the efficacy of PUVA in treating psoriasis. These studies include 2 early and integral investigations—one in the United States in 1977 and one in Europe in 1981—that firmly established PUVA as an effective therapeutic option. The American study used oral 8-MOP and high-intensity UV-A radiation. Of the 1139 patients included in the final analysis, clearance was noted in 88% and was reached at a mean of 23.6 treatments. Of note, clearance was defined as having macular erythema, hyperpigmentation, or normal-appearing skin. Initial dosing was based on skin phototype, and a fixed dose was used for escalation of therapy in the absence of erythema. In the European study, data from 18 separate institutions were pooled and evaluated. In agreement with the US cohort, 88.8% of the 3175 patients treated with PUVA achieved a response better than “marked improvement” over an average of 20 exposures. Dosing in this study was determined by the minimal phototoxicity dose, and subsequent adjustment was individualized to each patient. These findings were of paramount importance when considering that patients with severe, generalized involvement previously required inpatient hospitalization to achieve comparable results. Similarly, impressive response rates were noted in 2 comparative studies that evaluated the efficacy of PUVA in relation to narrowband (NB) UV-B. The PUVA-associated clearance rates reported in these studies were 70% and 84%, which, in both instances, were superior to NB-UV-B therapy. Clearance in these trials was defined as either 95% to 100% improvement or total clearance of psoriatic plaques above the knees, respectively. Of note, long-term remission (>6 months) was also achieved by a larger proportion of the subjects treated with PUVA (35% vs 12% in the NB-UV-B cohort).

A Cochrane Review formally comparing PUVA and NB-UV-B for the treatment of psoriasis was reported in 2013. As with most phototherapeutic interventions, the analyzed studies were confounded by disparate dosing strategies, frequency of use, and outcome measures. Of the 3 studies included, one revealed that NB-UV-B was as effective as oral PUVA, whereas the other 2 found PUVA to be superior to NB-UV-B. A European review similarly concluded that PUVA had superior efficacy, when compared with NB-UV-B, as well as a higher probability of remission at 6 months (odds ratio = 2.73; 95% confidence interval [CI] 1.19–6.27). The duration of remission has been correlated with Psoriasis Area and Severity Index scores at the end of treatment. In clinical practice, this difference in response and remission period must be weighed against the potential for carcinogenesis (to be discussed later in detail). Several studies have demonstrated that bath PUVA is not only as effective as orally administered PUVA but also requires a lower cumulative dose of UV-A and has fewer associated adverse effects. This treatment option, however, requires preparation of psoralen-containing bath water, immersion of the patient in the bathtub, and irradiation with UV-A immediately after completion of bathing. In light of the resources needed to properly administer bath PUVA, its use has been limited worldwide.