Psoralen Plus Ultraviolet A Photochemotherapy and Other Phototherapy Modalities

Questions

Q23.1 What is the pharmacologic importance of food intake and the hepatic ‘first-pass effect’ on methoxsalen bioavailability? (Pg. 264)
Q23.2 In which part of the ultraviolet A (UVA) spectrum does methoxsalen have its maximum absorption? (Pg. 264)
Q23.3 What is the risk of squamous cell carcinoma (SCC) from long-term psoralen plus UVA (PUVA) therapy and are these more biologically aggressive than actinically-induced SCC? (Pg. 266)
Q23.4 What is the true risk of melanoma from long-term PUVA photochemotherapy? (Pg. 266)
Q23.5 What is the peak of the action spectrum for PUVA treatment of psoriasis? (Pg. 267)
Q23.6 What is the optimal treatment frequency for narrow-band ultraviolet B (NB-UVB) phototherapy of psoriasis? (Pg. 267)
Q23.7 What is the depth of skin penetration of UVA and UVB, and how does this relate to clinical decisions concerning the choice of PUVA versus NB-UVB? (Pg. 267)
Q23.8 Does NB-UVB have a defined risk for nonmelanoma skin cancer? (Pg. 268)
Q23.9 Does NB-UVB have a defined risk in pregnancy and nursing? (Pg. 268)
Q23.10 What is the specific action spectrum of excimer laser? (Pg. 268)
Q23.11 What is the maximum body surface area involvement optimal for treatment with excimer laser? (Pg. 268)
Q23.12 What are the three main indications for UVA-1 phototherapy? (Pgs. 269x2, 270)
Q23.13 Concerning UVA-1 potential adverse effects, (1) is photosensitive lupus erythematosus a contraindication to UVA-1, and (2) what is the most common short-term adverse effect of UVA-1? (Pg. 270x2)

Abbreviations used in this chapter

AE

Adverse effects/events

CYP

Cytochrome P-450

MED

Minimal erythema dose

MOP

Methoxypsoralen

MPD

Minimal phototoxic dose

NB-UVB

Narrow-band ultraviolet B

NMSC

Nonmelanoma skin cancer

PASI

Psoriasis Area and Severity Index

PUVA

Psoralen plus ultraviolet A

SCC

Squamous cell carcinoma

SPF

Sun protection factor

UV

Ultraviolet

UVA

Ultraviolet A

UVB

Ultraviolet B

Acknowledgments

Special thank you to Warwick L. Morison (three prior editions) and Elisabeth G. Richard (third edition of Comprehensive Dermatologic Drug Therapy [CDDT]) for their contributions to the previous versions of this chapter.

Introduction

Psoralen plus ultraviolet A (PUVA) photochemotherapy is the photochemical interaction between a p soralen medication and u ltra v iolet A (UVA) (320–400 nm) radiation. This is most commonly known for its role in the treatment of psoriasis and has been used in over 30 other skin diseases.

Psoralens, together with sunlight as a source of UVA radiation, have been used in the Middle East and Asia for treatment of vitiligo for at least 3000 years, and are still used in this original way in some countries today. The use of 8-methoxypsoralen (8-MOP) gained momentum after the seminal studies by Parrish and associates in the United States and Henseler and colleagues in Europe demonstrating that in combination with UVA radiation, it was efficacious in treating psoriasis, a treatment now commonly known as PUVA.

Psoralen Plus Ultraviolet A Photochemotherapy

Pharmacology

PUVA therapy requires UVA radiation in order for the psoralens to have a therapeutic effect. Therefore, the aim of treatment is to consistently produce a high level of drug in the target organ (skin) only at the time of exposure to UV radiation.

Structure

The structure of 8-MOP is illustrated in Fig. 23.1 .

Absorption

Important features of psoralen absorption are listed in Box 23.1 . Solubility in water varies, with 8-MOP being three times more water-soluble than 5-MOP (also known as bergapten). This is the reason that for a given dose, 8-MOP is two to three times more phototoxic than 5-MOP, reflected in the recommended 8-MOP dose of 0.4 to 0.6 mg/kg, and 5-MOP, 1.2 mg/kg. Because of a first-pass effect, 8-MOP doses below 20 mg in a 70-kg adult are not clinically effective.

Box 23.1

Unique Features of Psoralen Pharmacology

Insolubility in water
Physical formulation influences absorption
Food reduces absorption
First-pass effect through liver
Large interindividual variation in absorption

Q23.1 Intake of food before taking psoralens slows absorption and reduces the peak serum levels. Therefore, in clinical practice, patients are usually instructed to take a light meal before ingesting psoralens. There are significant intra- and interindividual variations in peak photosensitivity and in minimal phototoxic dose (MPD).

Bioavailability

With oral therapy, 75% to 80% of 8-MOP, and 98% to 99% of 5-MOP, respectively, is reversibly bound to serum albumin. Epidermal tissue binding is about 90% for 8-MOP and 99% for 5-MOP.

Metabolism

In terms of metabolism, 8-MOP is rapidly and almost completely metabolized in the liver; only small amounts of the parent compound can be detected in urine and bile.

Excretion

In humans, after oral administration of 40 mg of 8-MOP, 74% of the drug is excreted in urine, and 14% in feces. The excretion is rapid, being virtually complete within 12 hours. This is the reason that clinically, rigorous photoprotection must be practiced only on the day of administration of oral PUVA.

Photochemistry

Q23.2 Ground state psoralen molecules are activated to the excited singlet state by absorption of photons in the UVA waveband, with peak absorption between 320 to 330 nm. The singlet state undergoes decay to the triplet state, and given that this is a relatively long-lived state, it is responsible for most photochemical effects. Two types of photochemical reaction occur. Type I (direct) photochemical reactions result in photoaddition of the compound to pyrimidines in deoxyribonucleic acid (DNA), forming monofunctional adducts and cross-linking of adjacent strands of DNA (bifunctional adducts) and conjugation of proteins. Type II (indirect) photochemical reactions result in the production of reactive oxygen species and free radicals that cause damage to cell membranes and cytoplasmic constituents.

Mechanism of Action

PUVA therapy suppresses DNA synthesis through the formation of monoadducts and cross-links in DNA. It also causes selective immunosuppression. In addition, cells responsible for mediating a disease are selectively sensitive to be killed by exposure to PUVA therapy. Stimulation of melanocytes has been thought to be the explanation of the therapeutic effect seen in vitiligo.

Clinical Use

US Food and Drug Administration-Approved Indications

Box 23.2 lists indications and contraindications for PUVA.

Box 23.2

Psoralen Plus Ultraviolet A Indications and Contraindications

US Food and Drug Administration-Approved Indications
Psoriasis ^a Mycosis fungoides/Sézary syndrome ^a Vitiligo ^a
Other Dermatologic Uses
Neoplastic Histiocytosis X (Langerhans’ cell histiocytosis) Papulosquamous/Dermatitis Atopic dermatitis Seborrheic dermatitis Chronic hand dermatitis Palmoplantar pustulosis Lichen planus Parapsoriasis Pityriasis lichenoides Lymphomatoid papulosis Photosensitivity Dermatoses Polymorphous light eruption Erythropoietic protoporphyria Solar urticaria Chronic actinic dermatitis	Other Pruritic Dermatoses Dermographism Aquagenic urticaria/pruritus Chronic urticaria Polycythemia vera Idiopathic pruritus Urticaria pigmentosa Prurigo nodularis Other Immunologic Dermatoses Alopecia areata Graft-versus-host disease Morphea Systemic sclerosis Miscellaneous Dermatoses Transient acantholytic dermatosis (Grover disease) Pigmented purpuric dermatoses Icthyosis linearis circumflexa Scleromyxedema Generalized granuloma annulare
Contraindications
Absolute Pemphigus and pemphigoid Lupus erythematosus with photosensitivity Xeroderma pigmentosum Pregnancy Lactation History of idiosyncratic reaction to psoralen compound	Relative Photosensitivity/photosensitizing medications Prior exposure to ionizing radiation or arsenic History or family history of melanoma History of skin cancer or chronic photodamage Severe cardiac, liver or renal disease Very young age
Pregnancy prescribing status—category C

a Methoxsalen capsules are approved for this indication.

Psoriasis

PUVA therapy is successful in clearing about 70% to 100% of patients with plaque-type psoriasis in a course of up to 30 treatments. Given that many PUVA clinical studies were done several decades ago, PASI scores, the current gold standard of clinical trials in psoriasis, were not used in these studies. However, extensive clinical experience would indicate that with the large majority of patients becoming clear or virtually clear, the vast majority of PUVA-treated patients would consistently exceed Psoriasis Area and Severity Index (PASI)-75 improvement.

The therapy is also effective as a maintenance treatment, although the potential benefits of long-term use must be balanced against the potential toxicity of the therapy. Psoriasis of the palms and soles responds well to ‘hand-foot’ PUVA therapy. Broad-band (BB) UVB therapy is much less effective than PUVA therapy in chronic psoriasis, whereas narrow-band (311 nm) UVB (NB-UVB) phototherapy is almost as effective as PUVA.

Off-Label Dermatologic Uses

Cutaneous T-cell Lymphoma

The patch and plaque stages of mycosis fungoides respond to PUVA therapy in almost all cases after 20 to 30 treatments. Up to 50% of patients will remain in remission after a single course of treatment, but because of this high relapse rate a better approach is to use long-term maintenance treatment at a frequency of once or twice a month.

Dermatitis and Papulosquamous Dermatoses

PUVA therapy has been commonly used for the treatment of atopic dermatitis. Lichen planus, both on the skin and in the mouth, responds to about 30 to 40 treatment sessions and maintenance treatment is usually not required. For oral lesions, a dental UVA light source is used.

Vitiligo

Oral PUVA therapy has now been replaced by NB-UVB phototherapy as the treatment of choice for vitiligo, as the latter is more effective than PUVA, is simpler to administer, and has a much lower risk of photocarcinogenesis.

Other Immunologic Dermatoses

PUVA therapy has been used in alopecia areata with moderate success. Graft-versus-host disease on the skin and in the mouth responds to PUVA therapy. Linear and generalized morphea respond reasonably well to PUVA therapy. Systemic sclerosis responds similarly. However, with the development of UVA-1 (340–400 nm) phototherapy, UVA-1 phototherapy has replaced PUVA as the UV-based treatment of choice for sclerodermoid skin conditions.

Contraindications

There are only a few absolute contraindications and more relative contraindications to PUVA therapy (see Box 23.2 ). Lactation is listed because psoralens are secreted in breast milk. When a patient is taking a potentially photosensitizing medication, this fact should be noted; however, adjustment of the dose of UVA radiation is only required when potent phototoxic agents are involved, such as doxycycline and the fluoroquinolones. A 25% reduction in the UVA dose is usually adequate in these circumstances. If need be, PUVA can be administered to patients with aphakia, provided proper eye protection is in place.

Treatment Procedure

Methoxsalen Administration

Patients take 8-MOP orally as capsules in a dose of 0.4 to 0.6 mg/kg body weight, 1 or 2 hours before exposure to UVA radiation. In general, 0.4 mg/kg is recommended for the Oxsoralen Ultra version of 8-MOP, because of its better and more predictable absorption. The lower dose reduces the problem of nausea and the 1-hour interval is more convenient for patients. The medication should be taken 30 minutes after a light meal, which would reduce nausea associated with 8-MOP. The pre-8-MOP meal should be kept consistent to minimize the fluctuation in serum levels.

Ultraviolet A Radiation

The doses of UVA radiation are usually determined by skin phototype. If disease is present only on the hands and feet, a hand and foot PUVA unit can be employed.

Clearance Schedule

Treatments are usually given two or three times weekly at least 48 hours apart to permit evaluation of any erythema resulting from the preceding treatment. If severe erythema is present and widespread, treatment should be held until it subsides.

Maintenance Schedule

The final clearance dose of radiation is held constant and the frequency of treatment is gradually reduced. If a significant (>5%) amount of psoriasis begins to return, the frequency of treatment can be increased or a clearance schedule can be restarted.

Combination Treatments

Although data are contradictory, it is common practice to use combination treatments with PUVA therapy, which could potentially reduce overall exposure to UVA radiation.

Protection

Eye protection with UVA-blocking glasses is required when the patient is exposed to sunlight on the day of treatment, from time of psoralen ingestion until sunset that day. Regular use of these glasses should be done even when patients are exposed to window-glass filtered sunlight, such as when driving. On the day of treatment, after ingestion of psoralens, photoprotection should be practiced, including application of broad-spectrum sunscreen with sun protection factor (SPF) of ≥30 on exposed areas, taking care that sunscreen is not on the skin when UVA exposure is administered. The amount of UVA emitted by fluorescent lights or a computer screen is not adequate to induce phototoxic reaction, therefore photoprotection, including the use of UV-blocking glasses, is not necessary in these settings. Men should wear a jockstrap or another means of genital protection.

Short-Term Adverse Effects

Short-term AE are listed in Box 23.3 . Nausea is a common AE and clearly correlates with the serum level of the drug. As a first step, nausea can usually be relieved by having the patient eat a light meal before ingestion of 8-MOP, given that food reduces and slows absorption. Dosage can also be divided over 15 minutes. The next step is to reduce the dose by one capsule (10 mg). Lastly, an antiemetic is sometimes (uncommonly) required.

Box 23.3

Short-Term Adverse Effects of Psoralen Plus Ultraviolet A Therapy

Data from Morison WL, Marwaha S, Beck L. PUVA-induced phototoxicity: Incidence and causes. J Am Acad Dermatol. 1997;36:183–185.

Phototoxic Reactions

Symptomatic erythema
Pruritus
Subacute phototoxicity
Photoonycholysis
Koebner phenomenon
Friction blisters on hands and feet
Ankle edema

Attributed to Methoxsalen Alone

Gastrointestinal disturbance
Central nervous system disturbance
Bronchoconstriction
Hepatic toxicity
Drug fever
Exanthems

Other Adverse Effects

Cardiovascular stress
Herpes simplex recurrences
Photosensitive eruptions

Long-Term Adverse Effects

Long-term AE are listed in Box 23.4 . Photoaging is the most consistent AE; this manifests as freckling, dyspigmentation, wrinkling, and the formation of actinic keratoses. The so-called PUVA lentigines, which are usually large, dark, and irregularly shaped, form part of this chronic photoaging spectrum.

Box 23.4

Long-Term Adverse Effects of Psoralen Plus Ultraviolet A Therapy

Photoaging
Nonmelanoma skin cancer
Melanoma
- ‘Negative’ studies
- ‘Positive’ study
- Single case reports

Nonmelanoma Skin Cancer Risk

Q23.3 Nonmelanoma skin cancer (NMSC) is markedly increased in patients who receive high cumulative UVA exposure. This risk is mainly confined to Caucasians. In a prospective US multicenter study that followed nearly 1400 patients treated with PUVA therapy for 30 years, about one-fourth developed squamous cell carcinoma (SCC) of the skin, with smaller increases in basal cell carcinomas. This increased risk of NMSC is dependent on number of treatments, and the risk is particularly evident in patients receiving more than 150 treatments, with a higher risk of multiple SCC in patients receiving over 350 treatments.

An increased risk of SCC on male genitalia was also found in the US multicenter study, prompting the recommendation to cover this region during treatment. This has not been reported in studies from Europe.

Melanoma Risk

Q23.4 In the US cohort, an increased incidence of melanoma was reported, which was detected in patients who had been followed for over 15 years. This was primarily found in patients who had received more than 250 treatments. In contrast, this risk of melanoma has not been confirmed in numerous other studies. Continued observation of patients and careful cohort studies are required to confirm this finding.

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