Dermatol Ther (Heidelb) (2016) 6:315–324 DOI 10.1007/s13555-016-0130-9

PATIENT GUIDE

The Patient’s Guide to Treatment. Part 2: PUVA Phototherapy

Benjamin Farahnik . Mio Nakamura . Rasnik K. Singh . Michael Abrouk . Tian Hao Zhu . Kristina M. Lee . Margareth V. Jose . Renee DaLovisio . John Koo . Tina Bhutani . Wilson Liao

Received: May 6, 2016 / Published online: July 29, 2016 Ó The Author(s) 2016. This article is published with open access at Springerlink.com

ABSTRACT have shown that patients who viewed videos explaining the treatment procedures for various Background: PUVA treatment is medical conditions had a greater understanding photochemotherapy for psoriasis that of their treatment and were more active combines with UVA radiation. participants in their health. Although PUVA is a very effective treatment Objective: To present a freely available online option for psoriasis, there is an absence of guide and video on PUVA treatment designed patient resources explaining and for patient education on PUVA. demonstrating the process of PUVA. Studies Methods: The PUVA treatment protocol used at Enhanced content To view enhanced content for this the University of California—San Francisco article go to http://www.medengine.com/Redeem/ Psoriasis and Skin Treatment Center as well as C9D4F0600C816B7E. available information from the literature was B. Farahnik (&) reviewed to design a comprehensive guide for College of Medicine, University of Vermont, patients receiving PUVA treatment. Burlington, VT, USA e-mail: [email protected] Results: We created a printable guide and video resource that reviews the benefits and risks of M. Nakamura Á K. M. Lee Á M. V. Jose Á R. DaLovisio Á J. Koo Á T. Bhutani Á W. Liao PUVA, discusses the three types of PUVA Department of Dermatology, Psoriasis and Skin (hand–foot soak, full body soak, and systemic), Treatment Center, University of California-San Francisco, San Francisco, CA, USA demonstrates the PUVA process, and provides practical tips for safe use. R. K. Singh David Geffen School of Medicine at UCLA, Conclusion: Online media and video delivers University of California-Los Angeles, Los Angeles, material in a way that is flexible and often CA, USA familiar to patients. This new format is M. Abrouk beneficial for prospective patients planning to School of Medicine, University of California-Irvine, Irvine, CA, USA undergo PUVA treatment, health-care providers, and trainees who want to learn T. H. Zhu Keck School of Medicine, University of Southern more about this treatment. California, Los Angeles, CA, USA 316 Dermatol Ther (Heidelb) (2016) 6:315–324

Keywords: Guide; OxsoralenÒ; Patient research was done as early as 1970 for the education; Phototherapy; Psoralen; Psoriasis; treatment of [5]. PUVA; A; UVA PUVA is used to treat a range of skin diseases in addition to psoriasis, including eczema, INTRODUCTION vitiligo, mycosis fungoides, prurigo nodularis, and graft-versus-host disease [6]. PUVA is Psoriasis is one of the most common chronic exceptionally effective. It has been shown to inflammatory skin conditions, affecting 3–4% reduce the Psoriasis Area and Severity Index by of the adult US population [1]. Untreated 75% or more (PASI-75) in 80% of patients, psoriasis can reduce social, occupational, and which is comparable to many of the biologic overall well-being [2]. Despite the availability of medications available today [7]. This makes topical, oral, and systemic treatments, many PUVA particularly useful as a second-line agent patients with psoriasis, especially those with when topical medications or UVB phototherapy moderate-to-severe generalized psoriasis, are have failed. As PUVA does not affect the not adequately treated with an effective, immune system, it may be a more appropriate long-term treatment regimen [3]. therapy for some patients compared to other PUVA, or psoralen plus ultraviolet A (UVA) oral and systemic treatments, which can have radiation, is one of the oldest, most effective the potential to cause immune suppression [7]. treatments for psoriasis. It is also known as As part of PUVA therapy, psoralen photochemotherapy, as it combines the use of may be applied topically or taken , a group of plant-derived compounds orally prior to exposure to UVA light. At the that make the skin more sensitive to light, and University of California–San Francisco (UCSF) exposure of skin to a source of high-intensity, Psoriasis and Skin Treatment Center, a specific Ò long-wavelength, ultraviolet (UV) light. UV formulation of methoxsalen called Oxsoralen light is a type of light given off by the sun’s Ultra (Valeant Pharmaceuticals North America rays and can be divided into UVC LLC, Bridgewater, NJ, USA) is used as it has (200–280 nm), UVB (280–320 nm), and UVA better bioavailability compared to other (320–400 nm). Both UVA and UVB are used for formulations of methoxsalen. There are three phototherapy today. Sunlight has been utilized types of PUVA therapy: systemic PUVA throughout centuries to treat various skin (methoxsalen taken orally), hand and foot conditions, with one Indian medical text from soak PUVA (methoxsalen dissolved in water 1500 BC describing a treatment combining for hand/foot soaking), and bath PUVA herbs (likely containing psoralens) and natural (methoxsalen dissolved in a bath tub for sunlight to treat a vitiligo-like skin condition whole body soaking). All three forms of PUVA [4]. Researchers first noticed that UV light has may be administered in an outpatient setting, an interesting effect of delaying the rapid such as a specialized dermatologic clinic, and growth of skin cells in people with psoriasis. patients may schedule their visits at their They then demonstrated the effectiveness of convenience. topical psoralens followed by UVA light in PUVA treatment is administered over the clearing psoriatic plaques in 1974, though long term in two separate phases: an initial Dermatol Ther (Heidelb) (2016) 6:315–324 317 clearing phase and a maintenance phase. For We will now describe important safety each method of PUVA, during the initial considerations, the flow of treatment, clearing phase, patients will be treated two to appropriate skin care, and possible side effects three times weekly, with a minimum of 48 h in of PUVA therapy. between each session. A general estimate for clearance is 25–30 treatment visits, or within METHODS 9–15 weeks [8–10]. However, this estimate will vary based on diagnosis, severity of disease, We reviewed the PUVA therapy treatment patient compliance with phototherapy protocol used at the UCSF Psoriasis and Skin treatments, and the overall treatment regimen. Treatment Center. We also performed an When it is determined that the psoriasis is 95% English language literature search using clear, the patient will be placed on a Pubmed including the key words ‘‘PUVA’’, or maintenance schedule for continuing ‘‘Oxsoralen’’ or ‘‘psoralens’’ and ‘‘phototherapy’’ treatment. During the maintenance schedule, or ‘‘UVA’’ or ‘‘ultraviolet A’’, to identify relevant the optimal dosing of light will be held constant articles to design a comprehensive guide for and the frequency of treatments will be steadily patients receiving PUVA treatment. decreased to as low as once per month [8, 11]. This article does not involve any new studies Ultimately, patients can discontinue PUVA of human or animal subjects performed by any treatments if in stable remission. Patients can of the authors. All photos are printed with the return to PUVA treatments at the clearing consent of the subject(s). schedule should they experience a flare of the psoriasis. RESULTS AND DISCUSSION The initial dosing of UV radiation at the UCSF Psoriasis and Skin Treatment Center is Overview based on the patient’s skin color and reaction to sun exposure, also known as a Fitzpatrick skin Every PUVA therapy treatment visit will type, and will be determined by the medical involve the patient, as well as a coordinated team. The initial dose exposure is generally care team consisting of nurses, support staff, 2 within 0.5–6 J/cm and may increase by and/or doctors. The first portion of PUVA 2 0.5–2.5 J/cm [11]. Throughout the treatment, treatment, involving methoxsalen (Oxsoralen the medical team may adjust the dosing based Ultra), will be undertaken by the patient and on the control of disease, skin redness, or burns the second portion, involving UVA radiation, to maximize the safety and effectiveness of light will be administered by the nurse. Methoxsalen treatment. Furthermore, the medical team may will be prescribed by the physician and suggest a combination treatment consisting of patients should have the prescription filled PUVA with topical vitamin D analogs, topical prior to starting PUVA treatment. Patients corticosteroids, topical retinoids, oral retinoids, receiving oral systemic PUVA should set aside or other systemic medications [11–13]. Of note, at least 15 min for each appointment, while however, cyclosporine and methotrexate are patients receiving hand and foot soak PUVA or typically not used in conjunction with PUVA bath PUVA should set aside at least 45 min therapy [11, 12]. (Table 1). 318 Dermatol Ther (Heidelb) (2016) 6:315–324

Table 1 Overview of PUVA phototherapy Table 2 Safety precautions for PUVA phototherapy

Three types of PUVA therapy: systemic PUVA (taken Disclosure of all current medications, herbs, and orally), hand and foot soak PUVA, and bath PUVA supplements Initial frequency of 2–3 sessions per week Disclosure of any history of skin cancer Appointments last between 15–45 min Eye examinations required prior to PUVA therapy and Minimum 48-h interval between each session annually thereafter Clearance rates around 80%, typically requiring 25–30 Eye protection with goggles sessions Face shielding with towel Oxsoralen Ultra prescription must be filled prior to the Male genital coverage with cone or towela first treatment visit Will not be used during pregnancy Administered in 2 separate phases: clearing phase and PUVA psoralen plus ultraviolet A maintenance phase a Unless an exception has been granted PUVA psoralen plus ultraviolet A

should not be used in pregnant women, and Safety Precautions women who become pregnant while on PUVA will need to stop their treatment. Contraception It is essential for the nursing staff and is recommended to women of childbearing age physicians to be aware of all current patient who wish to continue PUVA treatments medications, including herbs and supplements, (Table 2). and any new prescriptions prior to and during the course of PUVA treatment, as some Flow of Treatment medications or supplements may photosensitize the skin. In such cases, the Every patient receiving UVA will UVA dose will be reduced accordingly. The check in at the front desk and gather all medical team should also be made aware of any necessary supplies, including goggles, a gown, history of skin cancer prior to starting towels, and genital covering for men. Patients phototherapy treatments, as PUVA may receiving hand and foot soak PUVA or bath increase the risk of skin cancer. As UVA PUVA should also get a measuring cup and exposure to the eyes can cause cataracts [11], additional towels. Prior to stepping into the goggles are required while in the light box. UVA light box, patients receiving the three However, important to note is that cataracts different types of PUVA will follow three have only been observed in animal studies, different protocols, as described below. while studies following human PUVA patients For systemic PUVA treatment, patients must have found no increased risk of cataracts when take methoxsalen by mouth 75 min prior to proper eye protection is used [14]. Furthermore, each of their scheduled appointment times. if no disease is present on the face, a towel is Methoxsalen may be taken at home or used to cover the face. Men receiving UVA light anywhere the patient feels comfortable, so should use proper genital shielding to reduce long as it is taken 75 min prior to entering the the risk of genital skin cancer. Finally, PUVA light box. The dose of methoxsalen is modified Dermatol Ther (Heidelb) (2016) 6:315–324 319 for each patient based on individual body in the tubs should only be done from the weight, at a ratio of 0.4–0.6 mg/kg of weight. shoulders down to the feet. The face should Each patient should follow the specific never be soaked. After soaking for 30 min, instructions written on the prescription patients should carefully step out of the bath (Table 3a). and dry off without showering off the bath For hand and foot soak PUVA, patients will use solution. Patients may then drain the solution their measuring cup to mix 10 mg of methoxsalen and notify the nursing staff that they are ready with 2 quarts of warm water for just hands or feet, for the light box treatment (Table 3c; Fig. 2). or 20 mg of methoxsalen with 4 quarts of warm Once patients are ready for the light water for both hands and feet (the exact mixture treatment, they will be guided by the nurses to ratio may vary; each patient should follow the the UVA light box. Patients treated with hand specific instructions written on the prescription). and foot soak PUVA will be using a specialized Water can come from a warm water sink or can be light box that accommodates only the hands microwaved. Mixing the methoxsalen with warm and/or feet. Those being treated with systemic water will cause the pill to dissolve and the or bath PUVA will step into a whole body light solution will turn into a light aquamarine color. box. After making sure that all safety It is helpful if the nurse demonstrates this process precautions are followed, including goggles during the initial treatment visits. The nurse will and genital shielding, the nurse may wrap the want to examine the hands and feet prior to patient’s face in a towel. The nurse will position soaking in solution to determine a proper light the patient in a way that will maximize light dose. After making the solution, the affected areas penetration and this position will be on the hands and/or feet will be soaked within the maintained during the entire light treatment solution for 30 min prior to light exposure. After to clear the disease effectively and prevent soaking, the solution should be discarded into the burns. The nurse will then set the light sink and hands and feet dried prior to returning to settings according to the patient’s needs. Light the nurses’ station for the UVA treatment. will shine on the patient for several seconds to Patients should only dry, not rinse off, after minutes depending on the patient’s individual soaking (Table 3b; Fig. 1). dose. While in the light box, it is important for Bath PUVA involves soaking in a bathtub for patients to keep their eyes closed and goggles 30 min prior to light exposure. Patients will on, and bulbs should not be touched. Following dissolve 50 mg of methoxsalen in a measuring the UVA light treatment, the patient may return cup filled with hot water. The solution should to the dressing room to get dressed and the be mixed until an aquamarine-colored solution treatment session is complete. At each is formed. This solution will then be added to a subsequent treatment session, the dose of light bathtub that is prefilled with 100 L of warm (duration of light treatment) will be adjusted water. Nursing staff will demonstrate this depending on the patient’s reaction to the process during the initial treatment visits. The previous treatment session. nurse will want to examine the skin prior to soaking in solution to determine a proper light Post-phototherapy Skin Care dose. Timers will be available in each bathroom, so that patients may be able to time their soak It is important to take good care of the skin after for 30 min. It is important to note that soaking each treatment session. Methoxsalen can cause 320 Dermatol Ther (Heidelb) (2016) 6:315–324

Table 3 Flow of treatment for PUVA phototherapy (a) Oral systemic PUVA Patient ingests Oxsoralen Ultra 75 min prior to appointment ↓ Patient checks in at front desk ↓ Patient gathers supplies (gown, towels, goggles, genital coveragea) ↓ Patient changes into gown and nurse examines patients skin ↓ Patient enters UVA box ↓ Nurse adjusts light box settings ↓ Patient undergoes session (b) Hand and foot soak PUVA Patient checks in at front desk ↓ Patient gathers supplies (gown, towels, goggles, measuring cup, genital coveragea) ↓ Patient mixes 10 mg of Oxsoralen Ultra with 2 quarts of warm water ↓ Patient changes into gown and nurse examines patients skin prior to soaking ↓ Affected areas of hands/feet soaked in Oxsoralen Ultra solution for 30 min ↓ Patients should dry, not rinse, after soaking then retrieve nurse ↓ Patient enters hands and/or feet into UVA box ↓ Nurse adjusts light box settings ↓ Patient undergoes session (c) Bath PUVA Patient checks in at front desk ↓ Patient gathers supplies (gown, towels, goggles, measuring cup, genital coveragea) ↓ Patient mixes 50 mg of Oxsoralen Ultra in a cup with warm water ↓ Patient changes into gown and nurse examines patients skin prior to soaking ↓ Oxsoralen Ultra solution is added to a bathtub prefilled with 100 L warm water ↓ Patients should soak only from shoulders down to feet for 30 min ↓ Patients should dry, not rinse, after soaking then retrieve nurse ↓ Patient enters UVA box ↓ Nurse adjusts light box settings ↓ Patient undergoes session PUVA Psoralen plus ultraviolet A a Genital coverage may be required for male patients unless an exception has been granted Dermatol Ther (Heidelb) (2016) 6:315–324 321

Fig. 1 Hand and foot soak PUVA treatment procedure Fig. 2 Bath PUVA treatment procedure

the skin to become more sensitive to light and, Care should be taken to avoid scrubbing the therefore, patients are more susceptible to skin, as any trauma or breakdown of the skin sunburn. Patients should avoid exposure to can potentially cause worsening of psoriasis in a sunlight, even through window glass, for 24 h process called the Koebner phenomenon. after treatment with PUVA. Patients should Patients should limit makeup and nail polish apply sunscreen with Sun Protection Factor on areas receiving treatment to allow full light (SPF) of 15 or above to any sun-exposed skin penetration. While perfume and colognes are for at least 24 h after PUVA treatment. fine when applied to clothes, they should not be Sunscreen should be reapplied every 1.5 h if applied to skin, as some of the chemicals may be outdoors. Patients should also use moisturizers photosensitizing and may increase the risk of and lotions on the affected areas at least twice burning during PUVA treatment. Lastly, it is daily as part of their routine skin care regimen. important to limit sunbathing during the 322 Dermatol Ther (Heidelb) (2016) 6:315–324

Table 4 Post-phototherapy skin care for PUVA Table 5 Side effects of PUVA phototherapy phototherapy Side effect Signs/symptoms Avoid exposure to sunlight and use sunscreen of SPF 15 Short term or higher for at least 24 h after PUVA Burning Redness, tenderness, tightness, Moisturize skin twice daily and frequently in between blistering treatments Noticeable 24–72 h after Avoid scrubbing skin hard or tearing off skin treatment Limit nail polish and makeup on areas receiving Itching Usually mild and relieved with treatment emollients Avoid perfumes and colognes directly on skin Nausea Unique to oral systemic PUVA Avoid sunbathing during the clearing stage of PUVA Reduced by consuming treatment Oxsoralen Ultra with PUVA psoralen plus ultraviolet A, SPF sun protection protein, milk, or full meal factor Tanning Skin darkening clearing stage of PUVA treatment to reduce the Long term risk of sunburn, which can interfere with the Photoaging Coarseness, wrinkling, laxity, PUVA treatment regimen (Table 4). increased fragility, freckling Cataracts Blurry vision, as though looking Side Effects through frosted glass Theoretical risk that has not There are some risks and possible side effects of been confirmed in humans PUVA treatment. Some of the potential with proper eye protection short-term side effects include burning, Non-melanoma and Unusual shaped growths or itching, and pigmentation of the skin. Burns, melanoma skin lumps may appear to grow which often appear as redness, tenderness, and cancers quickly over time blistering, may start 24–72 h after treatment in Genital skin cancer possible, up to 10% of patients during the clearance but prevented with shielding phase [15]. For mild burns, a topical PUVA psoralen plus ultraviolet A corticosteroid cream or ointment may be applied as directed. Mild itching is common studies on humans with proper eye protection and can usually be relieved with topical have not confirmed an increase in the risk of emollients. A moderate-to-deep tan may cataracts with UVA exposure [14]. Skin aging develop while on treatment, but often fades changes may include dryness, wrinkling, and 6–8 weeks after stopping treatment. Nausea is freckling, which may disappear after treatment is the most common side effect unique to stopped, though freckling may persist systemic PUVA and may be reduced by taking indefinitely. PUVA can lead to an increased risk methoxsalen with protein, milk, or a full meal. of non-melanoma and melanoma skin cancers, Long-term risks of PUVA treatment include particularly among light-skinned individuals cataracts, skin aging changes, and skin cancer. and those who have previously received X-rays Cataracts are considered a theoretical risk, as or Grenz rays [16]. The risk of genital skin cancer Dermatol Ther (Heidelb) (2016) 6:315–324 323 may also be increased, but may be prevented with of the work as a whole, and have given final proper shielding (Table 5)[17]. approval for the version to be published.

CONCLUSIONS Disclosures. John Koo is a speaker for AbbVie, Leo, and Celgene, and conducts PUVA treatment is a very effective and safe research for Amgen, Janssen, Novartis, treatment option for patients whose psoriasis is Photomedex, Galderma, Pfizer, and Merck. not well controlled on topical therapies alone. Tina Bhutani is an advisor for Cutanea and PUVA may also be a viable option for patients conducts research for Abbvie, Janssen, and who have failed UVB therapy. PUVA requires Merck. Wilson Liao conducts research for patient compliance with consistent treatments Abbvie, Janssen, Novartis, and Pfizer, and for 9–15 weeks to achieve maximal results. receives funding from the NIH (R01AR065174, When administered and monitored properly, U01AI119125). John Koo, Tina Bhutani, and PUVA can help patients safely achieve clearance Wilson Liao have no stocks, employment, or and in many cases provide long-lasting board memberships with any pharmaceutical remission. The effectiveness of PUVA is company. Benjamin Farahnik, Mio Nakamura, comparable to some of the most effective Michael Abrouk, Tian Hao Zhu, Rasnik K. Singh, biologic agents available today for the Kristina M. Lee, Margareth V. Jose, and Renee treatment of moderate-to-severe psoriasis. It is DaLovisio have nothing to disclose. our hope that this guide can serve as a valuable Compliance with Ethics Guidelines. This resource for patients considering or preparing article does not involve any new studies of for PUVA treatment and the health-care human or animal subjects performed by any of providers who treat these patients. the authors. All photos are printed with the consent of the subject(s). ACKNOWLEDGMENTS Open Access. This article is distributed under the terms of the Creative Commons We would like to thank Tim Sarmiento for Attribution-NonCommercial 4.0 International producing, directing, and editing the License (http://creativecommons.org/licenses/ educational video that accompanies this by-nc/4.0/), which permits any noncommercial manuscript. We would also like to thank the use, distribution, and reproduction in any amazing staff and nurses from the UCSF medium, provided you give appropriate credit Psoriasis and Skin Treatment Center for to the original author(s) and the source, provide inspiring and helping to make the video a link to the Creative Commons license, and possible. We thank Olivia Chen for her help indicate if changes were made. reviewing the Spanish translation of the accompanying video. No funding or sponsorship was received for publication of this article. All named authors meet the REFERENCES International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this 1. Rachakonda TD, Schupp CW, Armstrong AW. Psoriasis prevalence among adults in the United manuscript, take responsibility for the integrity States. J Am Acad Dermatol. 2014;70(3):512–6. 324 Dermatol Ther (Heidelb) (2016) 6:315–324

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