INTRODUCTION — Psoralen plus ultraviolet A (PUVA) photochemotherapy combines the administration of psoralens, a class of phototoxic plant-derived compounds, with an exposure to ultraviolet A radiation (UVA). PUVA is used for the treatment of a variety of skin diseases, including psoriasis, mycosis fungoides, eczema, vitiligo, and graft-versus-host disease [1-3].
This topic will discuss the mechanism of action, treatment protocols, contraindications, adverse effects, and clinical indications of PUVA therapy. The use of PUVA for the treatment of specific skin conditions is discussed separately. UVB phototherapy and UVA1 phototherapy are discussed separately.
●(See "UVA1 phototherapy".)
PSORALENS — Psoralens are naturally occurring phototoxic compounds that are able to enter the cell, absorb light photons, and produce a photochemical reaction that alters the function of DNA and other cell constituents. As part of psoralen plus ultraviolet A (PUVA) therapy, psoralens may be applied topically or taken orally.
Psoralens are produced by a variety of plants of the Apiaceae and Rutaceae families, including fig, lime, celery, and parsnip. The medicinal properties of psoralens have been known for centuries and their use in treating vitiligo was recorded as long ago as 1550 BC .
Three psoralens are used for PUVA therapy (table 1). Methoxsalen or 8-methoxypsoralen (8-MOP) is the most widely used and the only psoralen available in the United States. Trioxsalen or 4,5',8-trimethylpsoralen and bergapten or 5-methoxypsoralen are available in Europe and elsewhere (figure 1).
Pharmacokinetics — The intestinal absorption rate of psoralens depends upon the physical characteristics of the preparation, concomitant food intake, and individual factors [5-8].
Variable absorption can impact the effect of psoralen on UVA exposure. Dissolved preparations (eg, soft gelatin capsules) are better absorbed than micronized, crystalline formulations (eg, hard gelatin capsules) and yield peak serum levels in a relatively reproducible time in all subjects (table 1). Food intake retards and decreases the absorption of psoralens. A first-pass effect (eg, the amount of drug that is metabolized by the liver after intestinal absorption, before entering the general circulation) may be the cause of the high interindividual variability in the plasma levels achieved after a fixed dose of methoxsalen.
In the blood, 75 to 80 percent of methoxsalen is reversibly bound to serum albumin and is distributed to all organs. In the absence of UVA exposure, the binding is short lived and the drug is rapidly metabolized in the liver and excreted with urine as inactive metabolites. Drugs that induce cytochrome P-450 enzymes accelerate the metabolism of methoxsalen and may decrease the biologic effect of PUVA [7,9-11].
The pharmacokinetics of methoxsalen after transepidermal absorption depends upon the method of application . Methoxsalen 0.15% emulsion or solution applied topically to large body areas leads to plasma levels comparable to those achieved with oral administration. In contrast, plasma levels after whole body bath PUVA treatment are very low. Bathwater-delivered psoralens are readily absorbed in the skin but are promptly eliminated without cutaneous accumulation.
Photochemistry — Psoralens penetrate into the cells and intercalate between DNA base pairs in the absence of UV exposure. Upon exposure to UVA radiation, the psoralen molecules absorb photons, become chemically activated and covalently bond with DNA base pairs, producing interstrand crosslinks of the double helix (figure 2).
DNA crosslinking suppresses DNA synthesis and mitosis and may cause cell apoptosis through the activation of the p53 pathway. Cells with sublethal damage repair the DNA through an error-prone repair process, resulting in mutagenesis and photocarcinogenesis.
Psoralens also interact with other cell components, including mitochondria, RNA, and proteins. In keratinocyte cultures, psoralens induce mitochondrial depolarization, cytochrome c release, production of reactive oxygen species, and activation of proteases such as caspase-3 and -9 that are implicated in cell apoptosis 
ULTRAVIOLET A SOURCES — The wavelengths of ultraviolet A (UVA) lie between 320 and 400 nm in the electromagnetic spectrum (figure 3). The most common sources of UVA radiation are fluorescent phototherapy light bulbs with maximum emission at 352 nm. UVA doses are measured in joules/cm2 (J/cm2), most often using a photometer with a maximum sensitivity at 350 to 360 nm. Although in vivo wavelengths most efficient at activating psoralens peak at 320 to 340 nm (UVA2 spectrum (figure 3)), the longer wavelength emitted by the available lamps is equally effective in clinical practice [14,15]. Psoralen activation also occurs in the UVB spectrum.
Although a convenient source of UVA, natural sunlight is not safe for use with psoralens because of inherent difficulties in defining the therapeutic dose and increased risk of severe phototoxic reactions . Similarly, the use of tanning beds, which have emission peaks in the range of 320 to 340 nm, may unpredictably activate psoralens with increased risk of severe erythema.
MECHANISMS OF ACTION OF PUVA — Psoralen plus ultraviolet A (PUVA) exerts its therapeutic effect through multiple mechanisms, some of which are not completely understood. Initially, the mechanism in psoriasis was believed to be the inhibition of keratinocyte proliferation. However, it is now well established that the efficacy of PUVA in the treatment of psoriasis is based upon its immunomodulatory properties. Proposed mechanisms include the following:
●Inhibition of cell proliferation – The mammalian target of rapamycin (mTOR) signaling, implicated in the regulation of cell growth and proliferation, appears to have a role in the pathogenesis of psoriasis . PUVA may reduce cell proliferation in psoriasis through downregulation of the mTOR signaling pathway .
●Immunosuppression – The effect of PUVA in inflammatory diseases (with or without a hyperproliferative component) is mediated by its immunomodulatory properties, including alteration of cytokine and cytokine receptor expression, lymphocyte apoptosis, functional perturbation in the types and function of antigen presenting cells, and reduced expression of adhesion molecules [19-23]. The effect of PUVA in the early stages of mycosis fungoides is likely related to the ability of PUVA to induce lymphocyte apoptosis in dermal infiltrates.
●Melanogenesis – PUVA stimulates melanocyte proliferation, melanogenesis, and transfer of melanosomes to keratinocytes . This mechanism of action, while therapeutic in vitiligo, leads to hyperpigmentation as an adverse effect of PUVA in the treatment of other conditions.
PHOTOSENSITIVITY EFFECTS — Delayed phototoxic erythema and pigmentation are the main photosensitivity effects of psoralen plus ultraviolet A (PUVA) treatment. The erythema intensity is proportional to the dose of psoralen and ultraviolet A (UVA) radiation, although there is variability in the photosensitivity response among individuals.
PUVA-induced erythema usually appears 36 to 48 hours after exposure to UVA radiation and peaks at 48 to 96 hours or even up to 120 hours . Erythema occurs in 10 percent of patients. PUVA treatments are usually given 48 hours apart because daily exposure may result in severe delayed cumulative phototoxicity. Excessive doses of PUVA may induce severe erythema with blistering, intense pruritus, or skin pain. (See 'Short-term adverse effects' below.)
PUVA-induced pigmentation may occur in the absence of erythema, particularly with trimethylpsoralen or 5-methoxypsoralen, and is more intense and longer lasting than that produced by sunlight. The efficacy of PUVA is reduced in the presence of intense pigmentation. Therefore, for skin diseases other than vitiligo, higher doses of UVA radiation may be required as treatment proceeds.
TREATMENT PROTOCOLS — Protocols for psoralen plus ultraviolet A (PUVA) treatment were initially developed for the treatment of psoriasis, but may be applied to its use in other conditions.
Oral PUVA — Methoxsalen capsules are taken orally at doses of 0.4 to 0.6 mg/kg actual body weight one to two hours before exposure to ultraviolet A (UVA) radiation (table 2). Soft gelatin formulations of methoxsalen are absorbed faster and provide higher and more reproducible plasma levels than microcrystalline preparations. (See 'Pharmacokinetics' above.)
Methoxsalen ideally should be taken with water on an empty stomach, or at least one hour after eating. However, nausea develops in about 30 percent of patients and is more common with soft gelatin preparations because of rapid absorption and increased blood levels. Nausea can be prevented by taking the drug with a small amount of food with high fat content (eg, cheese) or milk.
Initial treatment (clearance phase) — The initial dose of UVA radiation is based upon one of two factors: the patient's skin type (table 3A-B); or the minimal phototoxic dose (MPD) [12,26,27]. The latter is more commonly used in a few specialized centers in Europe.
The MPD is defined as the minimal dose of UVA that produces a barely perceptible but well-defined erythema when template areas of the skin are exposed to increasing doses of UVA after psoralen ingestion. Erythema readings are performed 48 or 72 hours after testing, at which time the psoralen phototoxicity reaction usually reaches its peak. The MPD test should be performed on previously nonexposed skin (eg, buttocks). Treatment is started using 50 to 70 percent of the MPD.
Treatments are delivered two or three times per week, at least 48 hours apart. If no erythema is noted, the UVA dose is increased by 0.5 to 1 J/cm2 in the subsequent treatments until satisfactory control of the disease has been obtained. The dose is then held at that level. If faint erythema is present, the dose of radiation is held constant.
If skin tenderness or definite erythema is present, treatment is stopped until erythema and pain have diminished. Treatment is then resumed at a lower dose. If localized erythema develops in previously unexposed parts of the body (eg, the breasts or buttocks), shielding may be employed using clothing or sunscreens that protect against UVA radiation and treatment may be continued.
Repeated exposures are usually required to clear PUVA-responsive diseases, with gradual increment in the UVA dose as pigmentation develops. As an example, improvement of moderate plaque psoriasis is generally noted after 8 to 10 treatments. On average, 25 to 30 treatments are needed for complete clearance [28-32].
Since arms and legs generally respond to treatment more slowly than the trunk, the extremities may require additional doses of UVA. After the whole body dose, the patient puts on a gown or shorts and t-shirt, and covers his or her head. In patients with skin type I or II, an additional dose of one J/cm2 is delivered to the limbs and increased by 0.5 J/cm2 at each subsequent treatment. In patients with skin type ≥III, additional doses of 2 to 4 J/cm2 are delivered to the limbs and increased by 0.5 to 1 J/cm2 at each treatment.
Adherence to the schedule is critical for treatment success. Decreased frequency of PUVA (eg, once weekly) can result in treatment failure.
Maintenance treatment — After satisfactory clearing of disease, the final dose of UVA is held constant and the frequency of treatments is gradually reduced to as low as once per month . Ultimately, PUVA therapy can be discontinued for patients in stable remission to avoid overtreatment and the long-term adverse effects of high cumulative doses of PUVA.
Schedules for maintenance treatment and when to discontinue therapy vary between institutions. The optimal interval between treatments and the duration of the maintenance treatment should be determined for the individual patient, based upon the type of disease and the time to relapse.
Treatment of relapses — If a significant relapse of the disease occurs after treatment discontinuation or during the maintenance phase, it is appropriate to resume a clearance schedule. For minor recurrences occurring during the maintenance phase, the frequency of treatments may be increased until disease control is achieved.
Alternative psoralen administration — To avoid the gastrointestinal side effects of oral psoralen, protocols have been developed for psoralen to be applied topically (for localized disease) or by bath immersion.
Topical PUVA — Topical PUVA may be used as an alternative to oral PUVA in patients with localized diseases, including limited plaque or palmoplantar psoriasis, hand eczema, or localized vitiligo.
Topical PUVA consists of direct application to the skin of psoralens in creams, ointments, or lotions followed by exposure to UVA radiation. As an example, Methoxsalen 1% lotion can be diluted 1:10 with ethanol to yield a 0.1% solution that is applied to affected skin 15 minutes before exposure to UVA radiation.
For vitiligo, the initial exposure is 0.5 J/cm2. Incremental increases of 0.25 J/cm2 are given at each treatment thereafter, until a light pink erythema is achieved in the depigmented skin. UVA dose is either held at this level or adjusted with the goal of maintaining a faint erythema in affected skin until repigmentation occurs. Treatment is given two or three times per week.
A frequent complication of topical PUVA is an unexpected, usually bullous phototoxic reaction, typically caused by inadvertent exposure to natural sunlight after treatment .
Bath PUVA — Bath PUVA consists of whole body immersion or localized skin soaking (eg, of hands or feet) in a 0.5 to 3 mg/L solution of methoxsalen for 15 to 30 minutes. UVA irradiation is performed immediately after, since the photosensitivity decreases rapidly over two hours following immersion.
The main advantage of bath PUVA is the absence of systemic adverse effects associated with oral psoralens . However, eye protection is still required after bath PUVA since methoxsalen is detectable in the blood after topical application .
Bath PUVA is not widely available and there is no consensus on the optimal treatment protocol . Bath PUVA is not FDA approved. In addition, the long-term adverse effects of bath PUVA, including skin carcinogenesis, are unknown.
SAFETY MEASURES — It is important to protect skin that is not involved in the disease process from both topical psoralen and ultraviolet A (UVA) exposure during topical psoralen plus ultraviolet A (PUVA). When systemic psoralen is taken, the patient must be protected from additional UV exposure after the treatment. The following measures are recommended:
●In PUVA units, small UV-blocking goggles are used to protect the eyes. If treatment is not required for facial involvement, the face is protected either by use of a broad spectrum sunscreen with an SPF of 50+ or a cloth barrier. Male genitalia are protected with the use of underwear or an athletic supporter.
●Patients must protect their eyes after ingesting psoralen (or after bath exposure). Wraparound UV-blocking glasses should be worn when the patient is exposed to sunlight, from the time methoxsalen is ingested until sunset that same day.
●Sun avoidance is advised to minimize pigmentation from natural sunlight. Excessive pigmentation may ultimately limit the effectiveness of PUVA therapy and require higher doses of UVA. The skin should be protected from natural sunlight through appropriate clothing and avoidance.
●The amount of UVA emitted by common fluorescent lights is insufficient to activate psoralens. Thus, photoprotection is not required in home or office settings.
DRUG INTERACTIONS — Phototoxic drugs (eg, thiazides, tetracyclines, fluoroquinolones, phenothiazines, or sulfonamides), and topical preparations (eg, anthralin or coal tar) may augment the action of psoralen plus ultraviolet A (PUVA) and increase the risk of acute phototoxic erythema. (See "Photosensitivity disorders (photodermatoses): Clinical manifestations, diagnosis, and treatment", section on 'Phototoxicity'.)
CONTRAINDICATIONS — Contraindications to psoralen plus ultraviolet A (PUVA) treatment are listed in the table (table 4). Absolute contraindications include:
●Pregnancy and lactation
●Lupus erythematosus with a history of photosensitivity or a positive Ro antibody
PUVA is not contraindicated in patients with cataract or aphakia because most lens implants are UV blocking. The cataracts are protective of the retina. However, patients with cataracts or aphakia should remain particularly vigilant with adequate eye protection measures. (See 'Safety measures' above.)
Short-term adverse effects — Short-term adverse effects of psoralen plus ultraviolet A (PUVA) therapy include:
●Nausea – Nausea is the most common adverse reaction induced by oral PUVA. Taking methoxsalen with a small amount of food with high fat content or milk may prevent or reduce nausea. If nausea persists, the dose of methoxsalen can be decreased by 10 mg. In some patients, antiemetics may be needed. Ginger (ginger ale, ginger snaps) has also been used to reduce the nausea.
●Erythema – Excessive phototoxicity ranging from intense delayed erythema to blistering occurs in about 10 percent of patients during the clearance phase . Treatment is symptomatic and includes cool baths and liberal use of emollients and antipruritics. (See "Sunburn", section on 'Management'.)
●Pruritus and skin pain – Mild pruritus is common and usually associated with skin dryness. Emollients are generally sufficient to relieve this symptom. Intense pruritus ("PUVA-itch") is often associated with erythema and is described as a deep, burning itch. PUVA-itch can also occur without erythema. It generally begins on the outer aspect of arms, thighs, buttocks, and, in women, on the breasts. Persistent skin pain is an uncommon complication of PUVA therapy [37-39]. Pruritus and pain are thought to be caused by phototoxic damage of the dermal nerve endings .
The treatment of pruritus is symptomatic. In severe cases, PUVA should be discontinued until the symptoms resolve (one to three weeks) and resumed using an ultraviolet A (UVA) dose reduced by 10 to 20 percent. There is no definite treatment for PUVA-induced skin pain. A single case report found benefit for gabapentin use .
●Subacute phototoxicity – Subacute phototoxicity manifests as a widespread scaly erythema accompanied by intense pruritus and may occur at any point during treatment, even if the UVA dose has been stable for some time . An important feature is sparing of areas not exposed to UVA light during treatment (eg, axilla and/or inner thigh). Management includes cessation of PUVA therapy, and use of emollients, cool baths, and antipruritic medications until the symptoms subside. PUVA can then be resumed with a UVA dose 30 to 40 percent lower than the last used dose, with gradual increases as tolerated.
●Excessive pigmentation – Excessive pigmentation is common, especially in patients with skin types ≥III and may decrease the efficacy of treatment .
●Other adverse effects – Other short-term adverse effects include reactivation of herpes simplex, bronchoconstriction, drug fever, heart rate increase, photo-onycholysis and melanonychia, friction blisters, and ankle edema [41-43]. Central nervous system disturbances reported with PUVA therapy include headache, dizziness, depression, insomnia, and hyperactivity .
Long-term adverse effects
Photoaging — Photoaging occurs in all patients with Fitzpatrick skin types I to IV after long-term PUVA therapy. These changes are partially reversible upon early discontinuation of therapy. Skin types I and II have more marked changes than types III and IV.
The photoaging changes are similar to those produced by natural sunlight and include hyper- or hypopigmentation, telangiectasia, wrinkles, lentigines, and actinic keratosis. Hypertrichosis has been reported to occur in both men and women treated with long-term PUVA . The lentigines seen with long-term PUVA therapy are composed of melanocytes of larger size and with some cellular atypia. Despite the histologic changes, there is no evidence that PUVA lentigines are precursors of melanoma [45-47].
Skin cancer — Long-term studies have demonstrated a dose-related increase in the incidence of nonmelanoma skin cancers among patients exposed to high cumulative doses of oral PUVA [48-50]. In a 30-year follow-up study of 1330 patients with psoriasis treated with PUVA, the risk of developing one or more squamous or basal cell carcinomas was greatly increased for those exposed to more than 350 treatments (incidence rate ratio 20.9, 95% CI 14.1-31.1) . In patients previously exposed to PUVA, treatment with cyclosporin further increases the risk of developing skin cancer .
Men exposed to PUVA have an increased risk of genital skin cancer. In a cohort of 892 men treated with PUVA, the incidence of invasive scrotal or penile squamous cell carcinoma was 53-fold higher than that expected in the general White population .
Controversy surrounds the issue of long-term PUVA and melanoma. In a 25-year follow-up study, melanoma incidence in patients treated with more than 200 PUVA treatments was eightfold higher than that expected in the general population . In contrast, other data (primarily from Europe) do not show an increased risk of melanoma .
Adding to the controversy, a retrospective study published in 2017 found that psoriasis patients had 1.53 times the risk of developing melanoma and hematologic cancers compared with patients without psoriasis. This risk was not impacted by psoriasis therapies including phototherapy . Prior studies have also identified increased risk of lymphoproliferative cancers and nonmelanoma skin cancers in patients with psoriasis .
Based on these findings, monitoring for skin cancers remains important in patients undergoing phototherapy, including PUVA.
Cataracts — Long-term PUVA carries a potential risk for cataract formation. However, a 25-year follow-up study did not show an increased risk of visual impairment or cataract formation in patients treated with PUVA .
MONITORING — Monitoring of patients undergoing psoralen plus ultraviolet A (PUVA) treatment includes [2,58]:
●Skin examination – Complete skin examination for skin cancer, premalignant lesions, and actinic damage is performed before starting treatment and annually thereafter . It is also important to educate patients to recognize the signs of skin cancer and perform skin self-examination.
●Eye examination – Eye examination, including slit-lamp exam of lens and cornea and funduscopic examination of the retina, is performed before starting treatment and annually thereafter. (See 'Safety measures' above.)
●Laboratory tests – Laboratory tests are not routinely performed before or during PUVA treatment, unless suggested by history (eg, lupus or photosensitivity).
●Outcome evaluation – The evaluation of disease activity and treatment efficacy is performed by the treating clinician at three to four month intervals.
Ongoing monitoring is indicated in patients who have received prolonged PUVA treatment, since an increased risk of skin cancer may persist after discontinuation of treatment .
CLINICAL INDICATIONS FOR PUVA — The potential benefits of psoralen plus ultraviolet A (PUVA) must be weighed against the dose-related risks of long-term therapy in the individual patient. Most common indications for PUVA include moderate to severe psoriasis that is unresponsive to topical therapy and mycosis fungoides. Recognition of the immunosuppressive and antiproliferative effects of PUVA has led to a role for PUVA in the treatment of many other skin diseases, including eczema, vitiligo, and chronic and acute graft-versus-host disease. Additional indications for PUVA therapy are summarized in the table (table 5) .
The use of PUVA for the treatment of specific skin conditions is discussed separately.
SUMMARY AND RECOMMENDATIONS
●Psoralen plus ultraviolet A (PUVA) photochemotherapy combines the administration of psoralens (table 1) with an exposure to ultraviolet A radiation. PUVA is used for the treatment of a variety of skin diseases, including psoriasis, mycosis fungoides, eczema, vitiligo, and graft-versus-host disease. (See 'Introduction' above and 'Psoralens' above and 'Ultraviolet A sources' above.)
●The mechanisms of action of PUVA include: suppression of DNA synthesis and cell proliferation; lymphocyte apoptosis and perturbation in the type and function of antigen presenting cells; changes in cytokine and cytokine receptor expression; melanocyte proliferation and increased melanogenesis. (See 'Mechanisms of action of PUVA' above.)
●The main photosensitivity effects of PUVA include a delayed phototoxic erythema that appears 36 to 48 hours after exposure, and peaks at 48 to 96 hours, and pigmentation. (See 'Photosensitivity effects' above.)
●Protocols for PUVA treatment initially developed for the treatment of psoriasis may be applied to the treatment of other conditions. For oral PUVA, which is the most common type of ultraviolet A (UVA) therapy, methoxsalen capsules are taken orally at doses of 0.4 to 0.6 mg/kg one to two hours before exposure to UVA radiation (table 2). (See 'Oral PUVA' above.)
●The eyes and the skin that is not involved must be protected during PUVA. Additionally, the eyes must be protected from natural sunlight by wearing UV-blocking sunglasses after ingesting psoralens until sunset that same day. (See 'Safety measures' above.)
●Short-term adverse effects of PUVA include nausea, erythema, pruritus, and excessive pigmentation. (See 'Short-term adverse effects' above.)
●Long-term adverse effects of PUVA include photoaging and increased risk of nonmelanoma skin cancer. Skin examination for skin cancer should be performed annually in patients on PUVA therapy. Ongoing monitoring is indicated in patients who have received prolonged PUVA treatment, since an increased risk of skin cancer may persist after discontinuation of treatment. (See 'Long-term adverse effects' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Warwick Morison, MD, who contributed to an earlier version of this topic review.