http://informahealthcare.com/jdt ISSN: 0954-6634 (print), 1471-1753 (electronic) J Dermatolog Treat, Early Online: 1–6 ! 2014 Informa UK Ltd. DOI: 10.3109/09546634.2014.927816
REVIEW ARTICLE
Photodynamic therapy for psoriasis Young M. Choi1, Lily Adelzadeh1, and Jashin J. Wu2 David Geffen School of Medicine, UCLA, Los Angeles, CA, USA and 2Department of Dermatology, Kaiser Permanente Medical Center, Los Angeles, CA, USA
J Dermatolog Treat Downloaded from informahealthcare.com by University of Melbourne on 10/27/14 For personal use only.
1
Abstract
Keywords
Introduction: Photodynamic therapy for psoriasis showed promise in the early 1990s with reports of plaque clearance following topical aminolevulinic acid – photodynamic therapy (ALA-PDT). Methods: In December 2013, we conducted a systematic search of the PubMed Medline database using the keywords ‘‘psoriasis’’ and ‘‘photodynamic therapy’’. Results: Numerous clinical studies have failed to demonstrate a consistent, efficacious response to topical ALA-PDT. Furthermore, severe pain and burning sensations were repeatedly reported, many cases being intolerable for patients. Discussion: The variability in clinical response and the painful side effects have made topical ALA-PDT an unsuitable treatment option for chronic plaque psoriasis. Nonetheless, early clinical studies of other modalities such as topical hypericin and methylene blue, as well as systemic ALA and verteporfin, have shown that these photosensitizers are efficacious and much better tolerated than topical ALA. Conclusion: With the current landscape of phototherapy dominated by psoralen combined with ultraviolet A (PUVA) and narrow-band ultraviolet B (NB-UVB), an alternative light therapy utilizing the visible spectrum is certainly promising and a worthwhile endeavor to pursue.
ALA, aminolevulinic acid, hypericin, methylene blue, PpIX, verteporfin
Introduction Psoriasis is a chronic, inflammatory skin disorder affecting 2–3% of the population (1,2). As a multisystem disease, psoriasis is also known to affect the joints in 6–42% of patients (3), and more recent studies have uncovered an increased risk of myocardial infarction and stroke, possibly due to chronic elevation of inflammatory cytokines (4). Current therapies for psoriasis include topical agents (corticosteroids, calcipotriene, coal tar, anthralin, tazarotene), oral systemics (acitretin, cyclosporine, methotrexate), and biologic agents (adalimumab, etanercept, infliximab, ustekinumab) (5). For moderate to severe cases, phototherapy has also been proven to be effective. In clinical studies, narrow-band ultraviolet B (NB-UVB) therapy was shown to reduce the psoriasis area and severity index (PASI) by a mean of 84.1% after 12 weeks of treatment (6). Psoralen combined with ultraviolet A (PUVA) therapy demonstrated a PASI 90 and PASI 75 of 69% and 86%, respectively, after 12 weeks of treatment (7). Photodynamic therapy (PDT) is a technique that involves the delivery of a photosensitive agent to targeted areas of the skin, leading to selective cell death upon irradiation with visible light. Since the early 1900s, clinical applications have included the treatment of skin malignancies, lupus vulgaris, syphilis, molluscum
Correspondence: Jashin J. Wu, MD, Department of Dermatology, Kaiser Permanente Los Angeles Medical Center, 1515 North Vermont Ave, 5th floor, Los Angeles, CA 90027, USA. Tel: (323) 783-4171. Fax: (323) 783-1629. E-mail: [email protected]
History Received 25 February 2014 Accepted 03 May 2014 Published online 17 June 2014
contagiosum, pityriasis versicolor, and psoriasis (8). In 1994, Boehncke et al. (9) reported complete clearance of psoriatic plaques treated with topical ALA and PDT in three patients. In this review, we will examine the use of photodynamic therapy in psoriasis, highlighting its efficacy, side effects, and current role in the treatment of this chronic disease.
Methods In December 2013, we conducted a thorough systematic search of the PubMed Medline database using the keywords ‘‘psoriasis’’ and ‘‘photodynamic therapy’’. The search was not restricted to any timeframe. All clinical studies of psoriasis treated with photodynamic therapy were reviewed. Only publications in English were considered. Photodynamic therapy Photodynamic therapy began in the early 20th century with the discovery that the photosensitive agent hematoporphyrin (Hp) selectively accumulated in neoplastic tissues. Yet, its clinical application was barred by the side effect of prolonged photosensitivity, which could last for several weeks (8). In 1990, a major advancement occurred with the advent of 5-aminolevulinic acid (ALA), a precursor of endogenous protoporphyrin IX (PpIX). It was described that the topical application of ALA led to its intracellular accumulation, where it could then be converted to PpIX via the heme biosynthetic pathway (10). Like hematoporphyrin, PpIX is a photosensitizing agent that preferentially localizes in abnormal epithelium, but unlike HpD, the phototoxic effects only last for about 24 h (8).
2
Y. M. Choi et al.
When a photosensitizer absorbs a photon, it is excited to a transitory singlet state, which can further convert to a more stable, long-lasting triplet excited form. This reactive state is able to undergo chemical reactions with molecular oxygen (3O2), producing reactive oxygen species (ROS) such as singlet oxygen (1O2), hydroxyl radical (OH), and superoxide (O 2 ). Ultimately, ROS lead to cell death from apoptosis and necrosis (11,12). The first report of selective accumulation of PpIX in psoriatic plaques after topical ALA application was described in 1990 (8). The specific mechanism behind PDT for psoriasis is not completely known, but evidence suggests that key components involve the apoptosis of lesional T-lymphocytes and inhibition of inflammatory cytokines (TNF-a, IL-1, and IL-6) (13).
J Dermatolog Treat Downloaded from informahealthcare.com by University of Melbourne on 10/27/14 For personal use only.
Efficacy of ALA-PDT for psoriasis In 1997, Collins et al. (14) enrolled 22 patients with chronic plaque psoriasis to receive a single treatment with topical ALA-PDT. Two groups of 11 patients were allocated, and every patient had four treatment sites delineated within areas of plaque psoriasis. Group 1 patients received topical 20% ALA, 400– 650 nm light, and doses of 2, 4, 8, and 16 J/cm2 at 25 m/W/cm2. Group 2 patients received the same ALA preparation and light wavelength, but treatment sites received light doses of 8 and 16 J/cm2 at power densities of 10 and 40 m/W/cm2. Two patients from group 1 withdrew from the study (non-compliance, improvement seen in control site). Of the remaining 80 treatment sites, 14 (18%) cleared, 6 (8%) showed a 30–50% reduction in the scale, erythema, and induration (SEI) index, and 60 (75%) had minimal or no improvement. Robinson et al. (15) performed a study on 10 patients with chronic plaque psoriasis using multiple treatment exposures as compared to the single treatment in the study by Collins et al. (14). All patients received topical 20% ALA with broad-band visible radiation and a dose of 8 J/cm2 at 15 m/W/cm2. Treatment sessions were performed up to 3 times per week with a maximum number of 12 sessions. Nine of the patients had two treatment sites delineated on an area of plaque psoriasis, and one patient had one dedicated treatment site. Of the 19 treated sites, four (22%) cleared, five (26%) showed a reduction in SEI index of greater than 50%, five (26%) showed a 30–50% reduction in SEI index, and five (26%) had minimal or no improvement. The use of systemic ALA-PDT for psoriasis was addressed by Bissonnette et al. (16) in 2000. Twelve patients were enrolled into three groups of four, receiving a single oral dose of ALA at 5, 10, or 15 mg/kg. Blue light was used for irradiation, and the power density was 9–11 mW/cm2. Each patient had 15 areas of psoriatic skin delineated within three different plaques. For patients receiving 5 or 10 mg/kg ALA, the five squares within each plaque were exposed to 1, 3, 6, 12, or 20 J/cm2 of blue light. For those receiving 15 mg per kg ALA, the dosages used were 1, 2, 4, 8, or 10 J/cm2. The 5 or 10 mg/kg groups did not show any statistically significant change in plaque severity score. Improvement in plaque severity was seen in those receiving 15 mg/kg ALA, with one patient, at 10 J/cm2, demonstrating a 42% improvement compared to baseline. In order to compare the efficacy of topical PDT versus narrow-band UVB phototherapy, Beattie et al. (17) enrolled four patients with chronic plaque psoriasis to receive weekly treatment of a single entire plaque with topical 20% ALA, 630 nm light, and a dose of 10 J/cm2 at 120 m/W/cm2. Three times weekly, every patient also underwent whole body narrow-band therapy with the PDT treatment plaque covered by a UV light opaque card. By 12 weeks of treatment, the SEI index of the PDT treated plaques reduced by 50% in two patients, 17% in one, and was unchanged in the fourth patient. These results were significantly inferior to the NB-UVB-treated
J Dermatolog Treat, Early Online: 1–6
plaques, which achieved clearance or minimal residual activity in the same amount of time. The PDT-treated plaques were also noted to have increased in area, possibly due to Koebnerization. Another study by Fransson et al. (18) enrolled 12 patients with chronic plaque psoriasis to receive topical ALA-PDT on a single entire plaque. Patients were scheduled to receive 3 weekly treatments with topical 20% ALA, red light, a variable dose between 10 and 30 J/cm2, and a power density between 20 and 315 m/W/cm2. One patient received two treatment sessions before clearance was achieved, and two patients received five sessions due to unsatisfactory response. Four patients withdrew from the study due to pain. In all of the remaining patients, improvement of the psoriatic plaques was observed. The median SEI index decreased from 7 (range 5–9) to 1.5 (range 0–3) (p50.0001). In the first randomized, observer-blinded study, RadakovicFijan et al. (19) assessed the efficacy of topical ALA-PDT on 29 patients with chronic plaque psoriasis. For each patient, three comparable plaques were selected, followed by a computergenerated randomization to determine the irradiation dose for each plaque. Before initiation of PDT, all plaques were pretreated with a keratolytic preparation containing 10% salicylic acid. Treatment sessions occurred twice weekly until complete clearance or up to 12 irradiations using topical 1% ALA, 600–740 nm light, power density of 60 m/W/cm2, and the randomly allocated dose of 5, 10, or 20 J/cm2. Eight patients withdrew from the study (four due to time constraints, two due to poor compliance, one due to slow response, and one due to pain). Of the remaining 63 treatment plaques, 8 (13%) completely cleared, 4 (6%) substantially improved, 21 (33%) moderately improved, 28 (45%) showed slight or minimal response, and 2 (3%) increased in severity. There was a 59% final reduction in the mean psoriasis severity index (PSI) for the 20 J/cm2 treated plaques, a statistically significant difference compared to those treated with 10 J/cm2 (46% reduction, p ¼ 0.003) and 5 J/cm2 (49% reduction, p ¼ 0.02). A follow-up prospective, randomized, double-blind, phase I/II study was performed by Schleyer et al. (20) in 2006. Twelve patients with chronic plaque psoriasis were enrolled, and every patient had three plaques randomly assigned to 0.1%, 1%, or 5% topical ALA. Prior to beginning therapy, every patient underwent keratolytic pretreatment with 10% salicylic acid. Treatment sessions occurred twice weekly until complete clearance or up to 12 irradiations using 600–740 nm light and a dose of 20 J/cm2 at 60 m/W/cm2. One patient withdrew from the study, and two patients discontinued therapy at the higher ALA concentrations due to pain. Therefore, the last three patients enrolled only received treatment with 0.1% and 1% ALA. The mean PSI improvement from baseline was 37.5% in the 0.1% ALA-treated plaques, 45.6% in the 1% ALA-treated plaques, and 51.2% in the 5% ALA-treated plaques, clearly demonstrating a dose-dependent relationship. No plaques achieved complete clearance in the study. Smits et al. (21) performed a placebo-controlled, randomized study of topical ALA-PDT for psoriasis. Eight patients with chronic plaque psoriasis were enrolled, and in every patient two comparable contralateral plaques were randomized to receive topical 10% ALA or the placebo vehicle. Prior to therapy, lesions were pretreated with 10% salicylic acid for 1 week. Treatment sessions occurred weekly for 4 weeks using 600–750 nm light and power density of 40 m/W/cm2. The plaques were first treated with a dose of 2 J/cm2 followed by another dose of 8 J/cm2. There was a statistically significant decrease in the mean plaque severity score of the ALA-treated plaques versus placebo (p ¼ 0.009), but minimal or completely clear results were not achieved. Two ALAtreated plaques increased in total psoriatic surface area. Kleinpenning et al. (22) performed a study to assess the effect of keratolytic pretreatment on PDT for psoriasis. Seven patients
PDT for psoriasis
J Dermatolog Treat Downloaded from informahealthcare.com by University of Melbourne on 10/27/14 For personal use only.
DOI: 10.3109/09546634.2014.927816
with chronic plaque psoriasis were enrolled. Two comparable contralateral plaques were selected from each patient; one plaque was assigned to receive 10% salicylic acid pretreatment for 1 week prior to PDT, while the other plaque was covered with hydrocolloid occlusive dressing. After pretreatment, PDT was performed on both plaques with topical 10% ALA, 600–750 nm light, and a dose of 10 J/cm2 at 40 m/W/cm2. Treatment sessions occurred weekly for 6 weeks, with the aforementioned pretreatment regimen applied in between sessions. Following PDT, the final reduction in the total psoriasis severity score was 37% in the hydrocolloid dressing group (p50.001) and 43% in the 10% salicylic acid group (p50.001). However, the difference between the groups was not statistically significant. In 2012, Maytin et al. (23) performed a pilot study assessing the use of Vitamin D combined with ALA-PDT. Seven patients with chronic plaque psoriasis were enrolled, and two symmetric, comparable plaques were chosen from each patient. In a doubleblind manner, each plaque was treated with topical 0.005% calcipotriol (cream or ointment) or a matched vehicle control twice daily for 6 d. On day 7, patients underwent one PDT session with topical 20% ALA, red or blue light, and a power density of 100 m/W/cm2. Each study plaque was divided into three areas, which separately received light doses of 10, 20, or 40 J/cm2. For plaques treated with calcipotriol cream, no clinical improvement in psoriasis was observed, either with or without calcipotriol. In the calcipotriol ointment-treated plaques, there was a greater decline in PSI and reported itching with calcipotriol versus vehicle control. Efficacy of non-ALA-PDT for psoriasis In 1997, Schick et al. (24) reported treating three patients with chronic plaque psoriasis with PDT using ALA and methylene blue (MB) as photosensitizers. To comparable regions of psoriatic involvement, either 10% ALA or 10% MB was applied topically. Treatment sessions occurred twice weekly with 600–700 nm light and a dose of 5 J/cm2 at 70 m/W/cm2. On the contralateral side, lesions were treated with 0.1–2% topical dithranol based on clinical response. Similar to the findings of Boehncke et al. (13), both ALA-PDT and MB-PDT-treated plaques paralleled the clinical response of dithranol treatment. All plaques achieved clearance within 5–6 weeks of therapy. Boehncke et al. (25) tested a systemic photosensitizer called verteporfin. Twenty patients with chronic plaque psoriasis were treated with intravenous verteporfin, 600–700 nm light, and a dose of 60 J/cm2 at 5.5 m/W/cm2. Treatment sessions occurred weekly for a total of 5 weeks. Five patients were terminated prematurely from the study (thrombophlebitis, non-compliance, infection, two cases of acute dermatitis from verteporfin extravasation). In the remaining 15 patients, by 2 weeks into therapy, lesions improved in erythema and elevation in all cases compared to control lesions. The use of MB-PDT for psoriasis was addressed again by Salah et al. (26) in 2009. Sixteen patients with chronic plaque psoriasis were treated with topical 0.1% MB, 570 nm light, and a dose of 5 J/cm2 at 565 m/W/cm2. Results showed that 68% of patients achieved at least a 75% reduction in their psoriasis severity score after a mean of nine treatments. All sixteen patients eventually achieved complete clearance. Rook et al. (27) tested topical hypericin, another known photodynamic compound. Eleven patients with chronic plaque psoriasis were enrolled into a multi-center, phase II, open-label, placebo-controlled study. One site administered topical hypericin at concentrations of 0.05% and 0.1%, while the other sites utilized concentrations of 0.1% and 0.25%. In each patient, comparable plaques were selected and treated with one of the hypericin
3
preparations or a placebo preparation. Treatment sessions occurred twice weekly for 6 weeks using 590–650 nm light, a light dose ranging from 8 to 20 J/cm2, and irradiation periods not exceeding 15 min. Patients were considered responsive to therapy if there was a 50% or greater improvement in the lesional area. Plaques that received topical 0.1% hypericin demonstrated a 36.4% response rate and those that received topical 0.25% hypericin had a 45.4% response rate (p50.02). Lesions treated with 0.05% hypericin did not show a statistically significant difference compared to placebo. It was also shown that liquid-based hypericin was far superior with an 80% response rate (p50.02), while the ointment-based hypericin did not produce statistically significant results compared to placebo (Table 1). Side effects By far the most common side effect experienced with topical ALA-PDT was pain at the irradiation site, lasting up to 2 d in some patients (14). The pain was described as a stinging or burning sensation in nearly all of the studies we reviewed. In five studies, the pain was severe enough to cause patients to discontinue further treatment (15,18–20,22). Robinson et al. (15) reported that the severity of discomfort increased with the calculated photodynamic dose (the product of the tissue concentration of photosensitizer and light dose). However, studies that utilized lower photodynamic doses still reported stinging and burning sensations as well as pain severe enough to cause discontinuation (19). On the contrary, the use of systemic ALA-PDT was welltolerated with only mild burning in one patient (16). Other photosensitizers were also better tolerated than ALA. Systemic verteporfin (25) and topical hypericin (27) caused only mild burning in some patients. Two studies addressing topical MB-PDT did not report any discomfort with this modality (24,26). Skin erosions were seen in early studies due to very high photodynamic doses (14,15). In some cases, patients experienced worsening of plaque psoriasis in PDT-treated areas, possibly due to Koebnerization (17,19,21) (Table 2).
Conclusion Early reports on the complete clearance of plaques after topical ALA-PDT were promising for the birth of a new phototherapeutic modality for psoriasis. However, as more research was performed, including randomized, blinded, and placebo-controlled studies, the clinical efficacy of topical ALA-PDT was underwhelming and inconsistent. There was no clear correlation between the photodynamic dose and clinical response (15), nor was there a predictable relationship between the mean fluorescence and treatment outcome (17). Biopsy studies showed an inhomogeneous distribution of PpIX in the epidermis of sections from the same biopsy sample, as well as from different patients (15). As this variability may be attributed to differential hyperkeratosis within psoriatic plaques, more recent studies included keratolytic pretreatment to improve topical ALA absorption into the skin. The results of these studies were also variable and largely unremarkable (20–22). Compounding the relatively unimpressive clinical results, the painful side effect of topical ALA-PDT is another major drawback to its use. Even with lower photodynamic doses, burning and stinging sensations were still prevalent enough to cause significant discomfort to patients (19). Pain associated with ALA-PDT has been well documented in the treatment of other cutaneous diseases as well, such as acne vulgaris, benign growths, and skin cancers (28). In their review, Warren et al. (28) concluded that the use of topical anesthetics such as EMLA,
Comparison of topical ALA-PDT versus narrowband UVB photo- therapy for chronic plaque psoriasis
Clinical evaluation of the response of plaque psoriasis to multiple treatments of topical ALA-PDT at varying light parameters Randomized, observer-blinded study of topical ALA-PDT on keratolyticpretreated psoriatic plaques randomly allocated to different light doses
Prospective, randomized, double- blind phase I/II study of different topical ALA concentrations in PDT of keratolytic-pretreated psoriatic plaques
Randomized, placebo-controlled study of topical ALA-PDT on keratolyticpretreated psoriatic plaques
Clinical evaluation of the effect of keratolytic pretreatment of psoriatic plaques on the efficacy of topical ALA-PDT
Pilot study on the use of vitamin D combined with topical ALA-PDT for chronic plaque psoriasis
Beattie et al. (17)
Fransson et al. (18)
Schleyer et al. (20)
Smits et al. (21)
Kleinpenning et al. (22)
Maytin et al. (23)
Radakovic-Fijan et al. (19)
Clinical evaluation of the response of plaque psoriasis to a single treatment of systemic ALA-PDT at varying light parameters
Clinical evaluation of the response of plaque psoriasis to a single treatment of topical ALA-PDT at varying light dosages Clinical evaluation of the response of plaque psoriasis to multiple treatments of topical ALA-PDT at fixed light parameters
Study design
Bissonnette et al. (16)
Robinson et al. (15)
Collins et al. (14)
References 20% ALA
20% ALA
5, 10, or 15 mg/kg ALA
20% ALA
20% ALA
1% ALA
0.1%, 1%, or 5% ALA
10% ALA
10% ALA
20% ALA
10
12
4
12
29
12
8
7
7
Photosensitizer
22
n
Table 1. Clinical studies assessing the efficacy of photodynamic therapy for psoriasis.
Topical
Red or Blue light
600–750
600–750
600–740
600–740
Red light
630
Blue light
Broadband light
400–650
Wavelength (nm)
1
Max. 12
Max. 5
Max. 12
Max. 12
4
6
1
10 J/cm2 at 120 m/W/cm2
10–30 J/cm2 at 20–315 m/W/cm2 5, 10, or 20 J/cm2 at 60 m/W/cm2
20 J/cm2 at 60 m/W/cm2
2 J/cm2 followed by 8 J/cm2 at 40 m/W/cm2 10 J/cm2 at 40 m/W/cm2
10, 20, or 40 J/cm2 at 100 m/W/cm2
12
1
No. of sessions
1,3,6,12,20 J/cm2 or 1,2,4,8,10 J/cm2 at 9-11 m/W/cm2
2,4,8,16 J/cm2 at 25 m/W/cm2 or 8,16 J/cm2 at 10,40 m/W/cm2 8 J/cm2 at 15 m/W/cm2
Treatment parameters Results
Eighty treatment sites: 14 (18%) cleared, six (8%) had a 30–50% reduction in SEI index, and 60 (75%) had minimal or no improvement Nineteen treatment sites: four (22%) cleared, five (26%) had a greater than 50% reduction in SEI index, five (26%) had 30–50% reduction, and five (26%) had minimal or no improvement The 5 or 10 mg/kg ALA recipients did not show a statistically significant improvement. The 15 mg/kg ALA recipients did improve, with a best response of 42% in one patient. SEI index of PDT-treated plaques reduced by 50% in two patients, 17% in one patient, and was unchanged in the fourth patient. These results were significantly inferior to NB-UVB Improvement in psoriatic plaques was observed in all eight remaining patients. The median SEI index decreased from 7 (range 5–9) to 1.5 (range 0–3) (p50.0001) Sixty-three treatment plaques: eight (13%) cleared, four (6%) substantially improved, 21 (33%) moderately improved, 28 (45%) showed slight or minimal response, and two (3%) increased in severity The mean PSI improvement was 37.5% in the 0.1% ALA-treated plaques, 45.6% in the 1% ALA-treated plaques, and 51.2% in the 5% ALA-treated plaques. No plaques achieved complete clearance There was a statistically significant decrease in the mean plaque severity score of ALAtreated plaques versus placebo (p ¼ 0.009), but minimal or completely clear results were not achieved Total psoriasis severity score decreased by 43% in the 10% salicylic acid group (p50.001) versus 37% in the control group (p50.001), but the difference between the groups was not statistically significant No clinical improvement in psoriasis was observed with calcipotriol cream treatment. Calcipotriol ointment-treated
Y. M. Choi et al.
Topical
Topical
Topical
Topical
Topical
Topical
PO
Topical
Topical
Mode of delivery
J Dermatolog Treat Downloaded from informahealthcare.com by University of Melbourne on 10/27/14 For personal use only.
4 J Dermatolog Treat, Early Online: 1–6
PDT for psoriasis
12
After a mean of nine treatments, 68% of patients achieved at least a 75% reduction in psoriasis severity score. All 16 patients eventually achieved complete clearance Topical 0.1% hypericin demonstrated a 45.4% response rate and 0.25% hypericin had a 36.4% response rate (p50.02). Liquid-based hypericin was far superior to ointment-based hypericin –
5
Max. 12
References Collins et al. (14) Robinson et al. (15)
Bissonnette et al. (16) Beattie et al. (17) Fransson et al. (18)
8–20 J/cm2 not exceeding 15 min
5 J/cm2 at 565 m/W/cm2
60 J/cm2 at 5.5 m/W/cm2
5 J/cm2 at 70 m/W/cm2
Schleyer et al. (20)
590–650
570
600–700
600–700
Smits et al. (21)
Salah et al. (26)
Topical 0.05%, 0.1%, or 0.25% hypericin 11 Multicenter, phase II, open-label, placebo-controlled study on the efficacy of topical hypericin-PDT for chronic plaque psoriasis Rook et al. (27)
Topical 0.1% MB 16
IV 8 mg/m2 verteporfin 20
Open, non-randomized, phase I/II study on the use of systemic verteporfin for PDT in the treatment of plaque psoriasis Clinical evaluation of the response of chronic plaque psoriasis to MB-PDT Boehncke et al. (25)
3
10% ALA or 10% MB
Topical
Kleinpenning et al. (22)
Comparison of dithranol and topical ALA-PDT and MB-PDT for chronic plaque psoriasis
5
Table 2. Side effects noted in clinical trials of PDT for psoriasis.
Radakovic-Fijan et al. (19)
Schick et al. (24)
J Dermatolog Treat Downloaded from informahealthcare.com by University of Melbourne on 10/27/14 For personal use only.
plaques demonstrated a decline in PSI and itching versus control Both ALA-PDT and MB-PDT-treated plaques paralleled the clinical response of dithranol-treated lesions. All plaques achieved clearance within five to 6 weeks of therapy By 2 weeks into therapy, all treated lesions demonstrated improvement in erythema and elevation compared to control lesions
DOI: 10.3109/09546634.2014.927816
Maytin et al. (23) Schick et al. (24) Boehncke et al. (25) Rook et al. (27)
Side effects Four patients developed erosions Stinging or burning sensation lasting from a few hours to 2 d Two patients developed erosions Eight patients experienced a sensation during irradiation, ranging from tingling to stinging to burning Three patients had very severe pain, causing one patient to discontinue the study One patient had mild burning sensation One patient experienced nausea Plaque area increased in three patients Pain scores ranged from mild to moderate in all four patients Median VAS score was 7 Four patients discontinued the study due to severe pain All patients experienced stinging or burning One patient discontinued the study due to severe pain Two plaques increased in severity score Three patients experienced severe pain and burning One patient discontinued the study after the first treatment due to unbearable pain Generally well-tolerated with some patients experiencing mild burning and stinging Two plaques increased in surface area Mean pain score of 6.5 (range 0–10) One patient discontinued the study due to severe pain Tolerable pain and stinging Slight burning sensation experienced by all patients in areas treated with ALA-PDT Mild burning sensation Mild to moderate burning and itching
lidocaine hydrochloride cream, and capsaicin cream have not shown any benefit for pain from ALA-PDT. However, cooling measures with ice water or a high-airflow cooling device did show promise as an effective means of analgesia (28). One study of topical ALA-PDT for psoriasis applied intense cooling measures with liquid nitrogen and laser cooler without much avail, as severe pain still occurred in several cases (20). Based on the variable clinical response and poor tolerability, the British Association of Dermatologists guidelines (29) in 2008 did not support the use of topical ALA-PDT ‘‘as a practical therapy for psoriasis’’. Nevertheless, the long-term carcinogenic effects of PUVA therapy, as well as the favorability of visible light over UV radiation, make further exploration of PDT a worthwhile endeavor (30). In our review, the use of systemic ALA (16) and verteporfin (25) for PDT was well-tolerated and efficacious for psoriasis, warranting further studies. Other topical photosensitizers such as hypericin (27) and MB (24,26) were also very promising. The two studies assessing MB-PDT demonstrated excellent tolerability as well as eventual complete clearance of all treated lesions (24,26). As future studies explore these potential opportunities as well as emerging novel photosensitizers (31,32), more comparative studies between PDT, PUVA, and NB-UVB will need to be executed to assess the role of PDT in the light-based treatment of psoriasis.
6
Y. M. Choi et al.
J Dermatolog Treat, Early Online: 1–6
J Dermatolog Treat Downloaded from informahealthcare.com by University of Melbourne on 10/27/14 For personal use only.
Declaration of interest J. J. W. received research funding from AbbVie, Amgen, Coherus Biosciences, Eli Lilly, Merck, Pfizer, and Sandoz; he is a consultant for Eli Lilly. Y. M. C. and L. A. do not have any potential conflicts of interest.
18.
References
19.
1. Flatz L, Conrad C. Role of T-cell-mediated inflammation in psoriasis: pathogenesis and targeted therapy. Psoriasis: Targets Therap. 2013;3:1–10. 2. Villasen˜or-Park J, Wheeler D, Grandinetti L. Psoriasis: evolving treatment for a complex disease. Cleve Clin J Med. 2012;79:413–23. 3. Gladman DD, Antoni C, Mease P, et al. Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann Rheum Dis. 2005;64:il 14–17. 4. Miller IM, Ellervik C, Yazdanyar S, Jemec GB. Meta-analysis of psoriasis, cardiovascular disease, and associated risk factors. J Am Acad Dermatol. 2013;69:1014–24. 5. Pardasani AG, Feldman SR, Clark AR. Treatment of psoriasis: an algorithm-based approach for primary care physicians. Am Fam Physician. 2000;61:725–33. 6. Ra´cz E, Prens EP, Kurek D, et al. Effective treatment of psoriasis with narrow-band UVB phototherapy is linked to suppression of the IFN and Th17 pathways. J Invest Dermatol. 2011;131:1547–58. 7. Inzinger M, Heschl B, Weger W, et al. Efficacy of psoralen plus ultraviolet A therapy vs. biologics in moderated to severe chronic plaque psoriasis: retrospective data analysis of a patient registry. Br J Dermatol. 2011;165:640–5. 8. Lee Y, Baron ED. Photodynamic therapy: current evidence and applications in dermatology. Semin Cutan Med Surg. 2011;30: 199–209. 9. Boehncke WH, Sterry W, Kaufmann R. Treatment of psoriasis by topical photodynamic therapy with polychromatic light. Lancet. 1994;343:801. 10. Calzavara-Pinton PG, Venturini M, Sala R. Photodynamic therapy: update 2006. Part 1: photochemistry and photobiology. J Eur Acad Dermatol Venereol. 2007;21:293–302. 11. Kurwa HA, Barlow RJ. The role of photodynamic therapy in dermatology. Clin Exp Dermatol. 1999;24:143–8. 12. Josefsen LB, Boyle RW. Photodynamic therapy and the development of metal-based photosensitisers. Met Based Drugs. 2008;2008:1–24. 13. Tandon YK, Yang MF, Baron ED. Role of photodynamic therapy in psoriasis: a brief review. Photodermatol Photoimmunol Photomed. 2008;24:222–30. 14. Collins P, Robinson DJ, Stringer MR, et al. The variable response of plaque psoriasis after a single treatment with topical 5-aminolaevulinic acid photodynamic therapy. Br J Dermatol. 1997;137:743–9. 15. Robinson DJ, Collins P, Stringer MR, et al. Improved response of plaque psoriasis after multiple treatments with topical 5-aminolaevulinic acid photodynamic therapy. Acta Derm Venereol. 1999;79: 451–5. 16. Bissonnette R, Tremblay JF, Juzenas P, et al. Systemic photodynamic therapy with aminolevulinic acid induced apoptosis in lesional T lymphocytes of psoriatic plaques. J Invest Dermatol. 2002;119:77–83. 17. Beattie PE, Dawe RS, Ferguson J, Ibbotson SH. Lack of efficacy and tolerability of topical PDT for psoriasis in comparison
20.
21.
22.
23.
24. 25. 26. 27.
28. 29. 30.
31.
32.
with narrowband UVB phototherapy. Clin Exp Dermatol. 2004;29: 560–2. Fransson J, Ros AM. Clinical and immunohistochemical evaluation of psoriatic plaques treated with topical 5-aminolaevulinic acid photodynamic therapy. Photodermatol Photoimmunol Photomed. 2005;21:326–32. Radakovic-Fijan S, Blecha-Thalhammer U, Schleyer V, et al. Topical aminolaevulinic acid-based photodynamic therapy as a treatment option for psoriasis? Results of a randomized, observer-blinded study. Br J Dermatol. 2005;152:279–83. Schleyer V, Radakovic-Fijan S, Karrer S, et al. Disappointing results and low tolerability of photodynamic therapy with topical 5-aminolaevulinic acid in psoriasis. A randomized, double-blind phase I/II study. J Eur Acad Dermatol Venereol. 2006:20:823–8. Smits T, Kleinpenning MM, van Erp PEJ, et al. A placebocontrolled randomized study on the clinical effectiveness, immunohistochemical changes and protoporphyrin IX accumulation in fractionated 5-aminolaevulinic acid-photodynamic therapy in patients with psoriasis. Br J Dermatol. 2006;155:429–36. Kleinpenning MM, Kanis JH, Smits T, et al. The effects of keratolytic pretreatment prior to fluorescence diagnosis and photodynamic therapy with aminolevulinic acid-induced porphyrins in psoriasis. J Dermatolog Treat. 2010;21:245–51. Maytin EV, Honari G, Khachemoune A, et al. Vitamin D combined with aminolevulinate (ALA)-mediated photodynamic therapy (PDT) for human psoriasis: a proof-of-principle study. Isr J Chem. 2012;52: 767–75. Schick E, Ru¨ck A, Boehncke WH, Kaufmann R. Topical photodynamic therapy using methylene blue and 5-aminolaevulinic acid in psoriasis. J Dermatol Treat. 1997;8:17–19. Boehncke WH, Elshorst-Schmidt T, Kaufmann R. Systemic photodynamic therapy is a safe and effective treatment for psoriasis. Arch Dermatol. 2000;136:271–2. Salah M, Samy N, Fadel M. Methylene blue mediated photodynamic therapy for resistant plaque psoriasis. J Drugs Dermatol. 2009;8: 42–9. Rook AH, Wood GS, Duvic M, et al. A phase II placebo-controlled study of photodynamic therapy with topical hypericin and visible light irradiation in the treatment of cutaneous T-cell lymphoma and psoriasis. J Am Acad Dermatol. 2010;63:984–90. Warren CB, Karai LJ, Vidimos A, Maytin EV. Pain associated with aminolevulinic acid-photodynamic therapy of skin disease. J Am Acad Dermatol. 2009;61:1033–43. Morton CA, McKenna KE, Rhodes LE. Guidelines for topical photodynamic therapy: update. Br J Dermatol. 2008;159:1245–66. Archier E, Devaux S, Castela E, et al. Carcinogenic risks of psoralen UV-A therapy and narrowband UV-B therapy in chronic plaque psoriasis: a systematic literature review. J Eur Acad Dermatol Venereol. 2012;26:22–31. Takahashi H, Nakajima S, Sakata I, et al. Photodynamic therapy using a novel photosensitizer, ATX-S10(Na): comparative effect with 5-aminolevulinic acid on squamous cell carcinoma line, SCC15, ultraviolet B-induced skin tumor, and phorbol ester-induced hyperproliferative skin. Arch Dermatol Res. 2005;296:496–502. Baron ED, Malbasa CL, Santo-Domingo D, et al. Silicon phthalocyanine (Pc4) photodynamic therapy is a safe modality for cutaneous neoplasms: results of a phase 1 clinical trial. Laser Surg Med. 2010;42:728–35.
REVIEW ARTICLE
Photodynamic therapy for psoriasis Young M. Choi1, Lily Adelzadeh1, and Jashin J. Wu2 David Geffen School of Medicine, UCLA, Los Angeles, CA, USA and 2Department of Dermatology, Kaiser Permanente Medical Center, Los Angeles, CA, USA
J Dermatolog Treat Downloaded from informahealthcare.com by University of Melbourne on 10/27/14 For personal use only.
1
Abstract
Keywords
Introduction: Photodynamic therapy for psoriasis showed promise in the early 1990s with reports of plaque clearance following topical aminolevulinic acid – photodynamic therapy (ALA-PDT). Methods: In December 2013, we conducted a systematic search of the PubMed Medline database using the keywords ‘‘psoriasis’’ and ‘‘photodynamic therapy’’. Results: Numerous clinical studies have failed to demonstrate a consistent, efficacious response to topical ALA-PDT. Furthermore, severe pain and burning sensations were repeatedly reported, many cases being intolerable for patients. Discussion: The variability in clinical response and the painful side effects have made topical ALA-PDT an unsuitable treatment option for chronic plaque psoriasis. Nonetheless, early clinical studies of other modalities such as topical hypericin and methylene blue, as well as systemic ALA and verteporfin, have shown that these photosensitizers are efficacious and much better tolerated than topical ALA. Conclusion: With the current landscape of phototherapy dominated by psoralen combined with ultraviolet A (PUVA) and narrow-band ultraviolet B (NB-UVB), an alternative light therapy utilizing the visible spectrum is certainly promising and a worthwhile endeavor to pursue.
ALA, aminolevulinic acid, hypericin, methylene blue, PpIX, verteporfin
Introduction Psoriasis is a chronic, inflammatory skin disorder affecting 2–3% of the population (1,2). As a multisystem disease, psoriasis is also known to affect the joints in 6–42% of patients (3), and more recent studies have uncovered an increased risk of myocardial infarction and stroke, possibly due to chronic elevation of inflammatory cytokines (4). Current therapies for psoriasis include topical agents (corticosteroids, calcipotriene, coal tar, anthralin, tazarotene), oral systemics (acitretin, cyclosporine, methotrexate), and biologic agents (adalimumab, etanercept, infliximab, ustekinumab) (5). For moderate to severe cases, phototherapy has also been proven to be effective. In clinical studies, narrow-band ultraviolet B (NB-UVB) therapy was shown to reduce the psoriasis area and severity index (PASI) by a mean of 84.1% after 12 weeks of treatment (6). Psoralen combined with ultraviolet A (PUVA) therapy demonstrated a PASI 90 and PASI 75 of 69% and 86%, respectively, after 12 weeks of treatment (7). Photodynamic therapy (PDT) is a technique that involves the delivery of a photosensitive agent to targeted areas of the skin, leading to selective cell death upon irradiation with visible light. Since the early 1900s, clinical applications have included the treatment of skin malignancies, lupus vulgaris, syphilis, molluscum
Correspondence: Jashin J. Wu, MD, Department of Dermatology, Kaiser Permanente Los Angeles Medical Center, 1515 North Vermont Ave, 5th floor, Los Angeles, CA 90027, USA. Tel: (323) 783-4171. Fax: (323) 783-1629. E-mail: [email protected]
History Received 25 February 2014 Accepted 03 May 2014 Published online 17 June 2014
contagiosum, pityriasis versicolor, and psoriasis (8). In 1994, Boehncke et al. (9) reported complete clearance of psoriatic plaques treated with topical ALA and PDT in three patients. In this review, we will examine the use of photodynamic therapy in psoriasis, highlighting its efficacy, side effects, and current role in the treatment of this chronic disease.
Methods In December 2013, we conducted a thorough systematic search of the PubMed Medline database using the keywords ‘‘psoriasis’’ and ‘‘photodynamic therapy’’. The search was not restricted to any timeframe. All clinical studies of psoriasis treated with photodynamic therapy were reviewed. Only publications in English were considered. Photodynamic therapy Photodynamic therapy began in the early 20th century with the discovery that the photosensitive agent hematoporphyrin (Hp) selectively accumulated in neoplastic tissues. Yet, its clinical application was barred by the side effect of prolonged photosensitivity, which could last for several weeks (8). In 1990, a major advancement occurred with the advent of 5-aminolevulinic acid (ALA), a precursor of endogenous protoporphyrin IX (PpIX). It was described that the topical application of ALA led to its intracellular accumulation, where it could then be converted to PpIX via the heme biosynthetic pathway (10). Like hematoporphyrin, PpIX is a photosensitizing agent that preferentially localizes in abnormal epithelium, but unlike HpD, the phototoxic effects only last for about 24 h (8).
2
Y. M. Choi et al.
When a photosensitizer absorbs a photon, it is excited to a transitory singlet state, which can further convert to a more stable, long-lasting triplet excited form. This reactive state is able to undergo chemical reactions with molecular oxygen (3O2), producing reactive oxygen species (ROS) such as singlet oxygen (1O2), hydroxyl radical (OH), and superoxide (O 2 ). Ultimately, ROS lead to cell death from apoptosis and necrosis (11,12). The first report of selective accumulation of PpIX in psoriatic plaques after topical ALA application was described in 1990 (8). The specific mechanism behind PDT for psoriasis is not completely known, but evidence suggests that key components involve the apoptosis of lesional T-lymphocytes and inhibition of inflammatory cytokines (TNF-a, IL-1, and IL-6) (13).
J Dermatolog Treat Downloaded from informahealthcare.com by University of Melbourne on 10/27/14 For personal use only.
Efficacy of ALA-PDT for psoriasis In 1997, Collins et al. (14) enrolled 22 patients with chronic plaque psoriasis to receive a single treatment with topical ALA-PDT. Two groups of 11 patients were allocated, and every patient had four treatment sites delineated within areas of plaque psoriasis. Group 1 patients received topical 20% ALA, 400– 650 nm light, and doses of 2, 4, 8, and 16 J/cm2 at 25 m/W/cm2. Group 2 patients received the same ALA preparation and light wavelength, but treatment sites received light doses of 8 and 16 J/cm2 at power densities of 10 and 40 m/W/cm2. Two patients from group 1 withdrew from the study (non-compliance, improvement seen in control site). Of the remaining 80 treatment sites, 14 (18%) cleared, 6 (8%) showed a 30–50% reduction in the scale, erythema, and induration (SEI) index, and 60 (75%) had minimal or no improvement. Robinson et al. (15) performed a study on 10 patients with chronic plaque psoriasis using multiple treatment exposures as compared to the single treatment in the study by Collins et al. (14). All patients received topical 20% ALA with broad-band visible radiation and a dose of 8 J/cm2 at 15 m/W/cm2. Treatment sessions were performed up to 3 times per week with a maximum number of 12 sessions. Nine of the patients had two treatment sites delineated on an area of plaque psoriasis, and one patient had one dedicated treatment site. Of the 19 treated sites, four (22%) cleared, five (26%) showed a reduction in SEI index of greater than 50%, five (26%) showed a 30–50% reduction in SEI index, and five (26%) had minimal or no improvement. The use of systemic ALA-PDT for psoriasis was addressed by Bissonnette et al. (16) in 2000. Twelve patients were enrolled into three groups of four, receiving a single oral dose of ALA at 5, 10, or 15 mg/kg. Blue light was used for irradiation, and the power density was 9–11 mW/cm2. Each patient had 15 areas of psoriatic skin delineated within three different plaques. For patients receiving 5 or 10 mg/kg ALA, the five squares within each plaque were exposed to 1, 3, 6, 12, or 20 J/cm2 of blue light. For those receiving 15 mg per kg ALA, the dosages used were 1, 2, 4, 8, or 10 J/cm2. The 5 or 10 mg/kg groups did not show any statistically significant change in plaque severity score. Improvement in plaque severity was seen in those receiving 15 mg/kg ALA, with one patient, at 10 J/cm2, demonstrating a 42% improvement compared to baseline. In order to compare the efficacy of topical PDT versus narrow-band UVB phototherapy, Beattie et al. (17) enrolled four patients with chronic plaque psoriasis to receive weekly treatment of a single entire plaque with topical 20% ALA, 630 nm light, and a dose of 10 J/cm2 at 120 m/W/cm2. Three times weekly, every patient also underwent whole body narrow-band therapy with the PDT treatment plaque covered by a UV light opaque card. By 12 weeks of treatment, the SEI index of the PDT treated plaques reduced by 50% in two patients, 17% in one, and was unchanged in the fourth patient. These results were significantly inferior to the NB-UVB-treated
J Dermatolog Treat, Early Online: 1–6
plaques, which achieved clearance or minimal residual activity in the same amount of time. The PDT-treated plaques were also noted to have increased in area, possibly due to Koebnerization. Another study by Fransson et al. (18) enrolled 12 patients with chronic plaque psoriasis to receive topical ALA-PDT on a single entire plaque. Patients were scheduled to receive 3 weekly treatments with topical 20% ALA, red light, a variable dose between 10 and 30 J/cm2, and a power density between 20 and 315 m/W/cm2. One patient received two treatment sessions before clearance was achieved, and two patients received five sessions due to unsatisfactory response. Four patients withdrew from the study due to pain. In all of the remaining patients, improvement of the psoriatic plaques was observed. The median SEI index decreased from 7 (range 5–9) to 1.5 (range 0–3) (p50.0001). In the first randomized, observer-blinded study, RadakovicFijan et al. (19) assessed the efficacy of topical ALA-PDT on 29 patients with chronic plaque psoriasis. For each patient, three comparable plaques were selected, followed by a computergenerated randomization to determine the irradiation dose for each plaque. Before initiation of PDT, all plaques were pretreated with a keratolytic preparation containing 10% salicylic acid. Treatment sessions occurred twice weekly until complete clearance or up to 12 irradiations using topical 1% ALA, 600–740 nm light, power density of 60 m/W/cm2, and the randomly allocated dose of 5, 10, or 20 J/cm2. Eight patients withdrew from the study (four due to time constraints, two due to poor compliance, one due to slow response, and one due to pain). Of the remaining 63 treatment plaques, 8 (13%) completely cleared, 4 (6%) substantially improved, 21 (33%) moderately improved, 28 (45%) showed slight or minimal response, and 2 (3%) increased in severity. There was a 59% final reduction in the mean psoriasis severity index (PSI) for the 20 J/cm2 treated plaques, a statistically significant difference compared to those treated with 10 J/cm2 (46% reduction, p ¼ 0.003) and 5 J/cm2 (49% reduction, p ¼ 0.02). A follow-up prospective, randomized, double-blind, phase I/II study was performed by Schleyer et al. (20) in 2006. Twelve patients with chronic plaque psoriasis were enrolled, and every patient had three plaques randomly assigned to 0.1%, 1%, or 5% topical ALA. Prior to beginning therapy, every patient underwent keratolytic pretreatment with 10% salicylic acid. Treatment sessions occurred twice weekly until complete clearance or up to 12 irradiations using 600–740 nm light and a dose of 20 J/cm2 at 60 m/W/cm2. One patient withdrew from the study, and two patients discontinued therapy at the higher ALA concentrations due to pain. Therefore, the last three patients enrolled only received treatment with 0.1% and 1% ALA. The mean PSI improvement from baseline was 37.5% in the 0.1% ALA-treated plaques, 45.6% in the 1% ALA-treated plaques, and 51.2% in the 5% ALA-treated plaques, clearly demonstrating a dose-dependent relationship. No plaques achieved complete clearance in the study. Smits et al. (21) performed a placebo-controlled, randomized study of topical ALA-PDT for psoriasis. Eight patients with chronic plaque psoriasis were enrolled, and in every patient two comparable contralateral plaques were randomized to receive topical 10% ALA or the placebo vehicle. Prior to therapy, lesions were pretreated with 10% salicylic acid for 1 week. Treatment sessions occurred weekly for 4 weeks using 600–750 nm light and power density of 40 m/W/cm2. The plaques were first treated with a dose of 2 J/cm2 followed by another dose of 8 J/cm2. There was a statistically significant decrease in the mean plaque severity score of the ALA-treated plaques versus placebo (p ¼ 0.009), but minimal or completely clear results were not achieved. Two ALAtreated plaques increased in total psoriatic surface area. Kleinpenning et al. (22) performed a study to assess the effect of keratolytic pretreatment on PDT for psoriasis. Seven patients
PDT for psoriasis
J Dermatolog Treat Downloaded from informahealthcare.com by University of Melbourne on 10/27/14 For personal use only.
DOI: 10.3109/09546634.2014.927816
with chronic plaque psoriasis were enrolled. Two comparable contralateral plaques were selected from each patient; one plaque was assigned to receive 10% salicylic acid pretreatment for 1 week prior to PDT, while the other plaque was covered with hydrocolloid occlusive dressing. After pretreatment, PDT was performed on both plaques with topical 10% ALA, 600–750 nm light, and a dose of 10 J/cm2 at 40 m/W/cm2. Treatment sessions occurred weekly for 6 weeks, with the aforementioned pretreatment regimen applied in between sessions. Following PDT, the final reduction in the total psoriasis severity score was 37% in the hydrocolloid dressing group (p50.001) and 43% in the 10% salicylic acid group (p50.001). However, the difference between the groups was not statistically significant. In 2012, Maytin et al. (23) performed a pilot study assessing the use of Vitamin D combined with ALA-PDT. Seven patients with chronic plaque psoriasis were enrolled, and two symmetric, comparable plaques were chosen from each patient. In a doubleblind manner, each plaque was treated with topical 0.005% calcipotriol (cream or ointment) or a matched vehicle control twice daily for 6 d. On day 7, patients underwent one PDT session with topical 20% ALA, red or blue light, and a power density of 100 m/W/cm2. Each study plaque was divided into three areas, which separately received light doses of 10, 20, or 40 J/cm2. For plaques treated with calcipotriol cream, no clinical improvement in psoriasis was observed, either with or without calcipotriol. In the calcipotriol ointment-treated plaques, there was a greater decline in PSI and reported itching with calcipotriol versus vehicle control. Efficacy of non-ALA-PDT for psoriasis In 1997, Schick et al. (24) reported treating three patients with chronic plaque psoriasis with PDT using ALA and methylene blue (MB) as photosensitizers. To comparable regions of psoriatic involvement, either 10% ALA or 10% MB was applied topically. Treatment sessions occurred twice weekly with 600–700 nm light and a dose of 5 J/cm2 at 70 m/W/cm2. On the contralateral side, lesions were treated with 0.1–2% topical dithranol based on clinical response. Similar to the findings of Boehncke et al. (13), both ALA-PDT and MB-PDT-treated plaques paralleled the clinical response of dithranol treatment. All plaques achieved clearance within 5–6 weeks of therapy. Boehncke et al. (25) tested a systemic photosensitizer called verteporfin. Twenty patients with chronic plaque psoriasis were treated with intravenous verteporfin, 600–700 nm light, and a dose of 60 J/cm2 at 5.5 m/W/cm2. Treatment sessions occurred weekly for a total of 5 weeks. Five patients were terminated prematurely from the study (thrombophlebitis, non-compliance, infection, two cases of acute dermatitis from verteporfin extravasation). In the remaining 15 patients, by 2 weeks into therapy, lesions improved in erythema and elevation in all cases compared to control lesions. The use of MB-PDT for psoriasis was addressed again by Salah et al. (26) in 2009. Sixteen patients with chronic plaque psoriasis were treated with topical 0.1% MB, 570 nm light, and a dose of 5 J/cm2 at 565 m/W/cm2. Results showed that 68% of patients achieved at least a 75% reduction in their psoriasis severity score after a mean of nine treatments. All sixteen patients eventually achieved complete clearance. Rook et al. (27) tested topical hypericin, another known photodynamic compound. Eleven patients with chronic plaque psoriasis were enrolled into a multi-center, phase II, open-label, placebo-controlled study. One site administered topical hypericin at concentrations of 0.05% and 0.1%, while the other sites utilized concentrations of 0.1% and 0.25%. In each patient, comparable plaques were selected and treated with one of the hypericin
3
preparations or a placebo preparation. Treatment sessions occurred twice weekly for 6 weeks using 590–650 nm light, a light dose ranging from 8 to 20 J/cm2, and irradiation periods not exceeding 15 min. Patients were considered responsive to therapy if there was a 50% or greater improvement in the lesional area. Plaques that received topical 0.1% hypericin demonstrated a 36.4% response rate and those that received topical 0.25% hypericin had a 45.4% response rate (p50.02). Lesions treated with 0.05% hypericin did not show a statistically significant difference compared to placebo. It was also shown that liquid-based hypericin was far superior with an 80% response rate (p50.02), while the ointment-based hypericin did not produce statistically significant results compared to placebo (Table 1). Side effects By far the most common side effect experienced with topical ALA-PDT was pain at the irradiation site, lasting up to 2 d in some patients (14). The pain was described as a stinging or burning sensation in nearly all of the studies we reviewed. In five studies, the pain was severe enough to cause patients to discontinue further treatment (15,18–20,22). Robinson et al. (15) reported that the severity of discomfort increased with the calculated photodynamic dose (the product of the tissue concentration of photosensitizer and light dose). However, studies that utilized lower photodynamic doses still reported stinging and burning sensations as well as pain severe enough to cause discontinuation (19). On the contrary, the use of systemic ALA-PDT was welltolerated with only mild burning in one patient (16). Other photosensitizers were also better tolerated than ALA. Systemic verteporfin (25) and topical hypericin (27) caused only mild burning in some patients. Two studies addressing topical MB-PDT did not report any discomfort with this modality (24,26). Skin erosions were seen in early studies due to very high photodynamic doses (14,15). In some cases, patients experienced worsening of plaque psoriasis in PDT-treated areas, possibly due to Koebnerization (17,19,21) (Table 2).
Conclusion Early reports on the complete clearance of plaques after topical ALA-PDT were promising for the birth of a new phototherapeutic modality for psoriasis. However, as more research was performed, including randomized, blinded, and placebo-controlled studies, the clinical efficacy of topical ALA-PDT was underwhelming and inconsistent. There was no clear correlation between the photodynamic dose and clinical response (15), nor was there a predictable relationship between the mean fluorescence and treatment outcome (17). Biopsy studies showed an inhomogeneous distribution of PpIX in the epidermis of sections from the same biopsy sample, as well as from different patients (15). As this variability may be attributed to differential hyperkeratosis within psoriatic plaques, more recent studies included keratolytic pretreatment to improve topical ALA absorption into the skin. The results of these studies were also variable and largely unremarkable (20–22). Compounding the relatively unimpressive clinical results, the painful side effect of topical ALA-PDT is another major drawback to its use. Even with lower photodynamic doses, burning and stinging sensations were still prevalent enough to cause significant discomfort to patients (19). Pain associated with ALA-PDT has been well documented in the treatment of other cutaneous diseases as well, such as acne vulgaris, benign growths, and skin cancers (28). In their review, Warren et al. (28) concluded that the use of topical anesthetics such as EMLA,
Comparison of topical ALA-PDT versus narrowband UVB photo- therapy for chronic plaque psoriasis
Clinical evaluation of the response of plaque psoriasis to multiple treatments of topical ALA-PDT at varying light parameters Randomized, observer-blinded study of topical ALA-PDT on keratolyticpretreated psoriatic plaques randomly allocated to different light doses
Prospective, randomized, double- blind phase I/II study of different topical ALA concentrations in PDT of keratolytic-pretreated psoriatic plaques
Randomized, placebo-controlled study of topical ALA-PDT on keratolyticpretreated psoriatic plaques
Clinical evaluation of the effect of keratolytic pretreatment of psoriatic plaques on the efficacy of topical ALA-PDT
Pilot study on the use of vitamin D combined with topical ALA-PDT for chronic plaque psoriasis
Beattie et al. (17)
Fransson et al. (18)
Schleyer et al. (20)
Smits et al. (21)
Kleinpenning et al. (22)
Maytin et al. (23)
Radakovic-Fijan et al. (19)
Clinical evaluation of the response of plaque psoriasis to a single treatment of systemic ALA-PDT at varying light parameters
Clinical evaluation of the response of plaque psoriasis to a single treatment of topical ALA-PDT at varying light dosages Clinical evaluation of the response of plaque psoriasis to multiple treatments of topical ALA-PDT at fixed light parameters
Study design
Bissonnette et al. (16)
Robinson et al. (15)
Collins et al. (14)
References 20% ALA
20% ALA
5, 10, or 15 mg/kg ALA
20% ALA
20% ALA
1% ALA
0.1%, 1%, or 5% ALA
10% ALA
10% ALA
20% ALA
10
12
4
12
29
12
8
7
7
Photosensitizer
22
n
Table 1. Clinical studies assessing the efficacy of photodynamic therapy for psoriasis.
Topical
Red or Blue light
600–750
600–750
600–740
600–740
Red light
630
Blue light
Broadband light
400–650
Wavelength (nm)
1
Max. 12
Max. 5
Max. 12
Max. 12
4
6
1
10 J/cm2 at 120 m/W/cm2
10–30 J/cm2 at 20–315 m/W/cm2 5, 10, or 20 J/cm2 at 60 m/W/cm2
20 J/cm2 at 60 m/W/cm2
2 J/cm2 followed by 8 J/cm2 at 40 m/W/cm2 10 J/cm2 at 40 m/W/cm2
10, 20, or 40 J/cm2 at 100 m/W/cm2
12
1
No. of sessions
1,3,6,12,20 J/cm2 or 1,2,4,8,10 J/cm2 at 9-11 m/W/cm2
2,4,8,16 J/cm2 at 25 m/W/cm2 or 8,16 J/cm2 at 10,40 m/W/cm2 8 J/cm2 at 15 m/W/cm2
Treatment parameters Results
Eighty treatment sites: 14 (18%) cleared, six (8%) had a 30–50% reduction in SEI index, and 60 (75%) had minimal or no improvement Nineteen treatment sites: four (22%) cleared, five (26%) had a greater than 50% reduction in SEI index, five (26%) had 30–50% reduction, and five (26%) had minimal or no improvement The 5 or 10 mg/kg ALA recipients did not show a statistically significant improvement. The 15 mg/kg ALA recipients did improve, with a best response of 42% in one patient. SEI index of PDT-treated plaques reduced by 50% in two patients, 17% in one patient, and was unchanged in the fourth patient. These results were significantly inferior to NB-UVB Improvement in psoriatic plaques was observed in all eight remaining patients. The median SEI index decreased from 7 (range 5–9) to 1.5 (range 0–3) (p50.0001) Sixty-three treatment plaques: eight (13%) cleared, four (6%) substantially improved, 21 (33%) moderately improved, 28 (45%) showed slight or minimal response, and two (3%) increased in severity The mean PSI improvement was 37.5% in the 0.1% ALA-treated plaques, 45.6% in the 1% ALA-treated plaques, and 51.2% in the 5% ALA-treated plaques. No plaques achieved complete clearance There was a statistically significant decrease in the mean plaque severity score of ALAtreated plaques versus placebo (p ¼ 0.009), but minimal or completely clear results were not achieved Total psoriasis severity score decreased by 43% in the 10% salicylic acid group (p50.001) versus 37% in the control group (p50.001), but the difference between the groups was not statistically significant No clinical improvement in psoriasis was observed with calcipotriol cream treatment. Calcipotriol ointment-treated
Y. M. Choi et al.
Topical
Topical
Topical
Topical
Topical
Topical
PO
Topical
Topical
Mode of delivery
J Dermatolog Treat Downloaded from informahealthcare.com by University of Melbourne on 10/27/14 For personal use only.
4 J Dermatolog Treat, Early Online: 1–6
PDT for psoriasis
12
After a mean of nine treatments, 68% of patients achieved at least a 75% reduction in psoriasis severity score. All 16 patients eventually achieved complete clearance Topical 0.1% hypericin demonstrated a 45.4% response rate and 0.25% hypericin had a 36.4% response rate (p50.02). Liquid-based hypericin was far superior to ointment-based hypericin –
5
Max. 12
References Collins et al. (14) Robinson et al. (15)
Bissonnette et al. (16) Beattie et al. (17) Fransson et al. (18)
8–20 J/cm2 not exceeding 15 min
5 J/cm2 at 565 m/W/cm2
60 J/cm2 at 5.5 m/W/cm2
5 J/cm2 at 70 m/W/cm2
Schleyer et al. (20)
590–650
570
600–700
600–700
Smits et al. (21)
Salah et al. (26)
Topical 0.05%, 0.1%, or 0.25% hypericin 11 Multicenter, phase II, open-label, placebo-controlled study on the efficacy of topical hypericin-PDT for chronic plaque psoriasis Rook et al. (27)
Topical 0.1% MB 16
IV 8 mg/m2 verteporfin 20
Open, non-randomized, phase I/II study on the use of systemic verteporfin for PDT in the treatment of plaque psoriasis Clinical evaluation of the response of chronic plaque psoriasis to MB-PDT Boehncke et al. (25)
3
10% ALA or 10% MB
Topical
Kleinpenning et al. (22)
Comparison of dithranol and topical ALA-PDT and MB-PDT for chronic plaque psoriasis
5
Table 2. Side effects noted in clinical trials of PDT for psoriasis.
Radakovic-Fijan et al. (19)
Schick et al. (24)
J Dermatolog Treat Downloaded from informahealthcare.com by University of Melbourne on 10/27/14 For personal use only.
plaques demonstrated a decline in PSI and itching versus control Both ALA-PDT and MB-PDT-treated plaques paralleled the clinical response of dithranol-treated lesions. All plaques achieved clearance within five to 6 weeks of therapy By 2 weeks into therapy, all treated lesions demonstrated improvement in erythema and elevation compared to control lesions
DOI: 10.3109/09546634.2014.927816
Maytin et al. (23) Schick et al. (24) Boehncke et al. (25) Rook et al. (27)
Side effects Four patients developed erosions Stinging or burning sensation lasting from a few hours to 2 d Two patients developed erosions Eight patients experienced a sensation during irradiation, ranging from tingling to stinging to burning Three patients had very severe pain, causing one patient to discontinue the study One patient had mild burning sensation One patient experienced nausea Plaque area increased in three patients Pain scores ranged from mild to moderate in all four patients Median VAS score was 7 Four patients discontinued the study due to severe pain All patients experienced stinging or burning One patient discontinued the study due to severe pain Two plaques increased in severity score Three patients experienced severe pain and burning One patient discontinued the study after the first treatment due to unbearable pain Generally well-tolerated with some patients experiencing mild burning and stinging Two plaques increased in surface area Mean pain score of 6.5 (range 0–10) One patient discontinued the study due to severe pain Tolerable pain and stinging Slight burning sensation experienced by all patients in areas treated with ALA-PDT Mild burning sensation Mild to moderate burning and itching
lidocaine hydrochloride cream, and capsaicin cream have not shown any benefit for pain from ALA-PDT. However, cooling measures with ice water or a high-airflow cooling device did show promise as an effective means of analgesia (28). One study of topical ALA-PDT for psoriasis applied intense cooling measures with liquid nitrogen and laser cooler without much avail, as severe pain still occurred in several cases (20). Based on the variable clinical response and poor tolerability, the British Association of Dermatologists guidelines (29) in 2008 did not support the use of topical ALA-PDT ‘‘as a practical therapy for psoriasis’’. Nevertheless, the long-term carcinogenic effects of PUVA therapy, as well as the favorability of visible light over UV radiation, make further exploration of PDT a worthwhile endeavor (30). In our review, the use of systemic ALA (16) and verteporfin (25) for PDT was well-tolerated and efficacious for psoriasis, warranting further studies. Other topical photosensitizers such as hypericin (27) and MB (24,26) were also very promising. The two studies assessing MB-PDT demonstrated excellent tolerability as well as eventual complete clearance of all treated lesions (24,26). As future studies explore these potential opportunities as well as emerging novel photosensitizers (31,32), more comparative studies between PDT, PUVA, and NB-UVB will need to be executed to assess the role of PDT in the light-based treatment of psoriasis.
6
Y. M. Choi et al.
J Dermatolog Treat, Early Online: 1–6
J Dermatolog Treat Downloaded from informahealthcare.com by University of Melbourne on 10/27/14 For personal use only.
Declaration of interest J. J. W. received research funding from AbbVie, Amgen, Coherus Biosciences, Eli Lilly, Merck, Pfizer, and Sandoz; he is a consultant for Eli Lilly. Y. M. C. and L. A. do not have any potential conflicts of interest.
18.
References
19.
1. Flatz L, Conrad C. Role of T-cell-mediated inflammation in psoriasis: pathogenesis and targeted therapy. Psoriasis: Targets Therap. 2013;3:1–10. 2. Villasen˜or-Park J, Wheeler D, Grandinetti L. Psoriasis: evolving treatment for a complex disease. Cleve Clin J Med. 2012;79:413–23. 3. Gladman DD, Antoni C, Mease P, et al. Psoriatic arthritis: epidemiology, clinical features, course, and outcome. Ann Rheum Dis. 2005;64:il 14–17. 4. Miller IM, Ellervik C, Yazdanyar S, Jemec GB. Meta-analysis of psoriasis, cardiovascular disease, and associated risk factors. J Am Acad Dermatol. 2013;69:1014–24. 5. Pardasani AG, Feldman SR, Clark AR. Treatment of psoriasis: an algorithm-based approach for primary care physicians. Am Fam Physician. 2000;61:725–33. 6. Ra´cz E, Prens EP, Kurek D, et al. Effective treatment of psoriasis with narrow-band UVB phototherapy is linked to suppression of the IFN and Th17 pathways. J Invest Dermatol. 2011;131:1547–58. 7. Inzinger M, Heschl B, Weger W, et al. Efficacy of psoralen plus ultraviolet A therapy vs. biologics in moderated to severe chronic plaque psoriasis: retrospective data analysis of a patient registry. Br J Dermatol. 2011;165:640–5. 8. Lee Y, Baron ED. Photodynamic therapy: current evidence and applications in dermatology. Semin Cutan Med Surg. 2011;30: 199–209. 9. Boehncke WH, Sterry W, Kaufmann R. Treatment of psoriasis by topical photodynamic therapy with polychromatic light. Lancet. 1994;343:801. 10. Calzavara-Pinton PG, Venturini M, Sala R. Photodynamic therapy: update 2006. Part 1: photochemistry and photobiology. J Eur Acad Dermatol Venereol. 2007;21:293–302. 11. Kurwa HA, Barlow RJ. The role of photodynamic therapy in dermatology. Clin Exp Dermatol. 1999;24:143–8. 12. Josefsen LB, Boyle RW. Photodynamic therapy and the development of metal-based photosensitisers. Met Based Drugs. 2008;2008:1–24. 13. Tandon YK, Yang MF, Baron ED. Role of photodynamic therapy in psoriasis: a brief review. Photodermatol Photoimmunol Photomed. 2008;24:222–30. 14. Collins P, Robinson DJ, Stringer MR, et al. The variable response of plaque psoriasis after a single treatment with topical 5-aminolaevulinic acid photodynamic therapy. Br J Dermatol. 1997;137:743–9. 15. Robinson DJ, Collins P, Stringer MR, et al. Improved response of plaque psoriasis after multiple treatments with topical 5-aminolaevulinic acid photodynamic therapy. Acta Derm Venereol. 1999;79: 451–5. 16. Bissonnette R, Tremblay JF, Juzenas P, et al. Systemic photodynamic therapy with aminolevulinic acid induced apoptosis in lesional T lymphocytes of psoriatic plaques. J Invest Dermatol. 2002;119:77–83. 17. Beattie PE, Dawe RS, Ferguson J, Ibbotson SH. Lack of efficacy and tolerability of topical PDT for psoriasis in comparison
20.
21.
22.
23.
24. 25. 26. 27.
28. 29. 30.
31.
32.
with narrowband UVB phototherapy. Clin Exp Dermatol. 2004;29: 560–2. Fransson J, Ros AM. Clinical and immunohistochemical evaluation of psoriatic plaques treated with topical 5-aminolaevulinic acid photodynamic therapy. Photodermatol Photoimmunol Photomed. 2005;21:326–32. Radakovic-Fijan S, Blecha-Thalhammer U, Schleyer V, et al. Topical aminolaevulinic acid-based photodynamic therapy as a treatment option for psoriasis? Results of a randomized, observer-blinded study. Br J Dermatol. 2005;152:279–83. Schleyer V, Radakovic-Fijan S, Karrer S, et al. Disappointing results and low tolerability of photodynamic therapy with topical 5-aminolaevulinic acid in psoriasis. A randomized, double-blind phase I/II study. J Eur Acad Dermatol Venereol. 2006:20:823–8. Smits T, Kleinpenning MM, van Erp PEJ, et al. A placebocontrolled randomized study on the clinical effectiveness, immunohistochemical changes and protoporphyrin IX accumulation in fractionated 5-aminolaevulinic acid-photodynamic therapy in patients with psoriasis. Br J Dermatol. 2006;155:429–36. Kleinpenning MM, Kanis JH, Smits T, et al. The effects of keratolytic pretreatment prior to fluorescence diagnosis and photodynamic therapy with aminolevulinic acid-induced porphyrins in psoriasis. J Dermatolog Treat. 2010;21:245–51. Maytin EV, Honari G, Khachemoune A, et al. Vitamin D combined with aminolevulinate (ALA)-mediated photodynamic therapy (PDT) for human psoriasis: a proof-of-principle study. Isr J Chem. 2012;52: 767–75. Schick E, Ru¨ck A, Boehncke WH, Kaufmann R. Topical photodynamic therapy using methylene blue and 5-aminolaevulinic acid in psoriasis. J Dermatol Treat. 1997;8:17–19. Boehncke WH, Elshorst-Schmidt T, Kaufmann R. Systemic photodynamic therapy is a safe and effective treatment for psoriasis. Arch Dermatol. 2000;136:271–2. Salah M, Samy N, Fadel M. Methylene blue mediated photodynamic therapy for resistant plaque psoriasis. J Drugs Dermatol. 2009;8: 42–9. Rook AH, Wood GS, Duvic M, et al. A phase II placebo-controlled study of photodynamic therapy with topical hypericin and visible light irradiation in the treatment of cutaneous T-cell lymphoma and psoriasis. J Am Acad Dermatol. 2010;63:984–90. Warren CB, Karai LJ, Vidimos A, Maytin EV. Pain associated with aminolevulinic acid-photodynamic therapy of skin disease. J Am Acad Dermatol. 2009;61:1033–43. Morton CA, McKenna KE, Rhodes LE. Guidelines for topical photodynamic therapy: update. Br J Dermatol. 2008;159:1245–66. Archier E, Devaux S, Castela E, et al. Carcinogenic risks of psoralen UV-A therapy and narrowband UV-B therapy in chronic plaque psoriasis: a systematic literature review. J Eur Acad Dermatol Venereol. 2012;26:22–31. Takahashi H, Nakajima S, Sakata I, et al. Photodynamic therapy using a novel photosensitizer, ATX-S10(Na): comparative effect with 5-aminolevulinic acid on squamous cell carcinoma line, SCC15, ultraviolet B-induced skin tumor, and phorbol ester-induced hyperproliferative skin. Arch Dermatol Res. 2005;296:496–502. Baron ED, Malbasa CL, Santo-Domingo D, et al. Silicon phthalocyanine (Pc4) photodynamic therapy is a safe modality for cutaneous neoplasms: results of a phase 1 clinical trial. Laser Surg Med. 2010;42:728–35.
