The beneficial effects of sunlight on a variety of dermatologic ailments has long been recognized. Ancient herbalists realized that certain plants contained substances that could potential the effects of the sun. Egyptian, Indian and Chinese manuscripts dating from 1550 B.C. to 700 A.D. refer to the use of seeds, now known to be those of Psoralea coryliforlia, in the treatment of vitiligo. Despite continued medicinal use of P. corylifolia seeds, it was not until the 1940s that Egyptian scientists isolated the active ingredients in these seeds and began using them in clinical trials. 
The active ingredients of P. corylifolia seeds are now known as psoralens, which are furocoumarin compounds capable of absorbing radiant energy. Psoralens are found in parsnip, celery, limes, lemons, figs and bergamot, as well as in other common plants. [1,2] Studies of the mechanism of action of the psoralens suggest that multiple phenomena occur when these substances are photoactivated. Interstrand crosslinking occurs in DNA, and lipid membranes and enzymes are oxidized by oxygen radicals.  An increase in the number and activity of melanocytes also occurs. 
In 1974, Parrish and colleagues  reported that ingestion of methoxsalen (8-methoxypsoralen [8-MOP]) followed by exposure to a high-intensity ultraviolet-a (UVA) light source was effective in treating psoriasis. This photochemical therapy is now known as PUVA, which is an acronym for psoralen and UVA. Inhibition of epidermal DNA synthesis is the likely mechanism of PUVA action. 
Many dermatologists view PUVA therapy as the treatment of choice for psoriasis when topical corticosteroid therapy or the Goeckerman regimen (use of crude coal tar ointment or cream in conjunction with exposure to ultraviolet-B radiation) proves ineffective.  PUVA therapy avoids the many side effects of the cytotoxic medications that would otherwise be needed for disease control.
Dosage and Administration
8-MOP is the psoralen most widely used in the treatment of psoriasis (Figures 1 and 2), and it is also used in the treatment of vitiligo (Figure 3 and 4). Initially, only crystalline 8-MOP (Oxsoralen) was available, and doses of approximately 0.6 mg per kg were necessary for maximal beneficial effect. A liquid formulation of 8-MOP, available is soft capsule form (Oxsoralen-Ultra), was developed to enhance bioavailability; in doses of 0.25 to 0.5 mg per kg, this preparation has been found to give results comparable to those achieved with crystalline 8-MOP. Unfortunately, we have found that liquid 8-MOP is associated with an increased incidence of nausea. Other psoralens include 5-methoxypsoralen
[TABULAR DATA OMITTED]
(5-MOP), which has a lower incidence of phototoxicity and gastrointestinal intolerence than 8-MOP but is not available in the United States, and 4,5',8-trimethylpsoralen (TMP; trioxsalen [Trisoralen]), which is less effective in the treatment of psoriasis  but useful in the treatment of vitiligo (Table 1).
Regardless of the psoralen chosen, the usual mode of treatment is to gradually increase the UVA dose (expressed in joules [J] per cm ) while keeping the psoralen dose constant. To determine a safe starting UVA dose, it may be helpful to expose a small area of skin to various increments of UVA radiation.  If no untoward reaction is noted, UVA exposure can be increased by approximately 0.5 to 1.5 J per cm  per treatment. To coincide with peak serum levels, UVA therapy is administered one and one-half to two hours after psoralen ingestion (Figure 5). Since phototoxicity may not manifest itself until 48 or more hours after UVA exposure, PUVA therapy should not be administered more frequently than every other day.
Side Effects and Contraindications
Because PUVA therapy is based on photosensitizing effects, it is contraindicated in patients with photosensitive diseases such as systemic lupus erythematosus and porphyria cutanea tarda. PUVA therapy is also contraindicated in pregnant women, because of concerns about possible teratogenicity. Patients with a history of photosensitizing, disorder should be screened for antinuclear and anti-Ro antibodies, and perhaps, for porphyrins.
PUVA therapy has both acute and chronic side effects  (Table 2). Acute effects include sunburn reactions, nausea, pruritus, headache and dizziness. A peculian but common process known as the isomorphic phenomenon may occur with treatment of certain disorders such as psoriasis. This phenomenon involves the spread of an underlying dermatosis to areas subject to sunburn reaction.
The most common chronic side effects of PUVA therapy include premature photoaging, pigmented macules, actinic keratoses, squamous cell carcinoma, basal cell carcinoma and, possibly, anterior cortical cataracts. Elevation of serum liver enzyme levels has also been reported. 
Because of the possibility of cataract formation, PUVA therapy is not used in children under 12 years of age. (since the eye is not full developed until age 12, the possibility of cataract formation is theoretically greater in young children). Geoggles are worn during UVA treatment, and special UVA-blocking glasses are worn for 24 hours after PUVA therapy.
A recent report  indicates that genital squamous cell carcinoma may occur 286 times more frequently in patients who have received PUVA therapy than in the population at large. Whether antecedent genital human papillomavirus infection is a major determinant in this high rate of cancerous change is unclear. Shielding of the genital area duing PUVA therapy is recommended.
Alternatives to Oral Psoralens
In an attempt to eliminate some side effects of PUVA therapy, alternatives to oral
Common Side Effects of PUVA Therapy
psoralen therapy have been developed. A 1 percent 8-MOP lotion (Oxsoralen) is available for the treatment of patches of vitiligo. In addition, bath-water delivery of psoralen for the treatment of psoriasis has been studied in Scandinavian countries.  Bath-water delivery has been shown to be particularly useful in the treatment of localized diseases such as palmoplantar pustulosis.
We have found bath-water delivery of psoralen to be especially helpful in patients who have experienced incapacitating nausea from oral psoralens. When using 8-MOP, we add 15 mL of a 1 percent solution to 80L of water; the patient bathes for 30 minutes and the receives UVA treatment. The results of bath-water delivery of psoralen may be comparable to the results achieved with oral therapy.  When using TMP, we add 25 mg of TMP in an alcohol solution to 80 L of water and bathe the patient for 15 minutes; immediately after bathing, the patient receives UVA treatment. Because of the relatively greater photosensitivity after bath-water psoralen treatment,
TABLES 3 Diseases Tretable by PUVA Therapy
UVA, exposure begins at a lower dose than with oral psoralen therapy. Although bath-water delivery of PUVA therapy is very effective in patients with widespread psoriasis, it may be cumbersome to accomplish in the private office.
Other Uses of PUVA Therapy
New indications for PUVA therapy have been discovered over the years (Table 3). Cutaneous T-cell lymphoma requires a PUVA dosage comparable to that used in the treatment of psoriasis. Diseases such as atopic dermatitis require comparatively lower doses of UVA to achieve optimal results.
TMP appears to be particularly useful in stimulating melanocyte activity and therefore is beneficial in the treatment of vitiligo. Because of a lower incidence of gastrointestinal side effects, 5-MOP is a useful alternative to 8-MOP. 
New photoactive compounds are being evaluated, and previously recognized agents are being reevaluated. The furocoumarin khellin may prove useful because it stimulates pigmentation with minimal phototoxicity. 
 Benedetto AV. The psoralens. An historical perspective. Cutis 1977;20:469-71.
 Anderson TF, Voorhees JJ. Psoralen photochemotherapy of cutaneous disorders. Annu Rev Pharmacol Toxicol 1980;20:235-57.
 Pathak MA. Mechanisms of psoralen photosensitization reactions. Natl Cancer Inst Monogr 1984;66:41-6.
 Parrish JA, Fitzpatrick TB, Tanenbaum L, Pathak MA. Photochemotherapy of psoriasis with oral methoxsalen and longware ultraviolet light. N Engl J Med 1974;291:1207-11.
 Lowe NJ. Practical psoriasis therapy. Chicago: Year Book Medical, 1986:83-98.
 GuPT k, Anderson TF. Psoralen photochemotherapy. J Am Acad Dermatol 1987;17 (5 Pt 1):703-34.
 Stern RS. Genital tumors among men with psoriasis exposed to psoralens and ultraviolet A radiation (PUVA) and ultraviolet B radiation. N Engl J Med 1990;322:1093-7.
 Hannuksela M, Karvonen J. Trioxsalen bath plus UVA effective and safe in the treatment of psoriasis. Br J Dermatol 1978;99:703-7.
 Lowe NJ, Weingarten D, Bourget T, Moy LS. PUVA therapy for psoriasis: comparison of oral and bath-water delivery of 8-methoxy-psoralen. J Am Acad Dermatol 1986;14(5 Pt 1):754-60.
 Tanew A, Ortel B Rappersberger K, Honigsmann H. 5-Methoxypsoralen (Bergapten) for photochemotherapy. Biovailability, phototoxicity, and clinical efficacy in psoriasis of a new drug preparation. J Am Acad Dermatol 1988;18)2 Pt 1):333-8.
 Ortel B, Tanew A, Honigsmann H. Treatment of vitiligo with khellin and ultraviolet A. J Am Acad Dermatol 1988; 18 (4 Pt 1):693-701.
THOMAS N. HELM, M.D. is chief resident in dermatology at the Cleveland Clinic Foundation and a graduate of the Albany (N.Y.) Medical College.
JACOBW.E. DIJKSTRA, M.D. is director of the Cutaneous Care Center at the Cleveland Clinic Foundation. Dr. Dijkstra received special training in dermatology at the University of Groningen, the Netherlands, and at the Cleveland Clinic.
RICHARD J. FERRARA, JR., M.D. is a resident in dermatology at the Cleveland Clinic Foundation and a graduate of the Wayne State Univerisity School of Medicine, Detroit.
STEVEN GLANZ, M.D. is a resident in dermatology at the Cleveland Clinic Foundation and a graduate of the Ohio State University College of Medicine, Columbus.
COPYRIGHT 1991 American Academy of Family Physicians
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