Case report

Pulsed-Dye Laser Efficacy in the Treatment of Psoriasis in Adult Patients: An Evidence-Based Case Report

Made Ananda Krisna, Hanny Nilasari*

Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia *Department of Dermatology and Venereology, Faculty of Medicine, Universitas Indonesia, dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia

Email: [email protected]

Abstract

Psoriasis is a chronic inflammatory skin disease known to be highly responsive to phototherapy. Narrow-band UVB (NBUVB) phototherapy has been one of the standard treatments for its moderate to severe form. However, its lack of efficacy in treating stable psoriatic plaques on extremities has lead researchers to find alternative treatments, one of which is pulsed-dye laser (PDL). Laser has been known to be effective in treating vascular lesions; in psoriasis, elongation of rete ridge along with tortuous dermal capillaries are one of the first pathologies identified early in the disease progression. Several in vivo and preliminary studies have found the molecular mechanism of action of laser on abnormal vessel growth. In this article, we report a psoriasis vulgaris case in adult whose lesions responded well to NBUVB phototherapy. The psoriatic plaques on her extremities were stable despite NBUVB therapy and some topical treatments afterwards. With knowledge of emerging role of PDL in inflammatory skin disease such as psoriasis, we conducted a literature search and critically appraised the resulting articles. The systematic review article found evaluates PDL efficacy as a treatment for inflammatory skin diseases, including psoriasis, and was appraised using a worksheet from British Medical Journal Evidence- Based Medicine Toolkit. Its validity, importance, and applicability aspects were evaluated, leading to a conclusion that PDL can be used as an alternative treatment for psoriasis plaques in trunks, extremities, hands, or feet (both stable and unstable), with minimal and transient side effects (hyperpigmentation, hypopigmentation, and blistering).

Keywords: psoriasis, treatment, pulsed-dye laser

Abstrak

Psoriasis merupakan penyakit peradangan kronis pada kulit yang memberikan respons sangat baik terhadap fototerapi. Oleh sebab itu, fototerapi dengan narrow-band UVB dijadikan terapi standar dalam pengobatan psoriasis sedang-berat. Namun, efektivitasnya dalam menangani lesi stabil pada ekstremitas masih dipertanyakan. Hal ini yang membuat peneliti mencari terapi alternatif, salah satunya adalah pulsed-dye laser (PDL). Selama ini, laser telah diketahui efektivitasnya dalam mengobati lesi vaskular. Pada tahap awal patogenesis psoriasis, pembuluh kapiler dermis pada papilla dermis diketahui mengalami pelebaran dan menunjukkan aktivitas abnormal. Beberapa studi in vivo dan studi pendahulu berhasil menemukan mekanisme kerja laser pada aktivitas pertumbuhan pembuluh darah yang abnormal. Pada tulisan ini, dilaporkan sebuah kasus psoriasis vulgaris pada orang dewasa yang seluruh lesinya memberikan respons baik terhadap fototerapi NBUVB, kecuali lesi pada ekstremitasnya. Lesi tersebut tidak menunjukkan perbaikan secara klinis, baik setelah fototerapi maupun setelah pemberian agen topikal. Berangkat dari pengetahuan mengenai peranan PDL dalam penyakit inflamasi kulit, dilakukan penelusuran pustaka dan telaah kritis artikel yang memenuhi kriteria. Ditemukan sebuah artikel systematic review yang bertujuan untuk evaluasi efikasi PDL sebagai terapi pada

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berbagai penyakit inflamasi kulit, termasuk psoriasis. Telaah kritis dilakukan sesuai dengan sistematika yang dianjurkan oleh British Medical Journal Evidence-Based Medicine Toolkit. Setelah penilaian validitas, importance, dan applicability artikel tersebut, didapatkan kesimpulan bahwa PDL dapat dijadikan sebagai terapi alternatif untuk penanganan lesi psoriasis pada batang tubuh, ekstremitas, telapak tangan, dan telapak kaki (baik yang bersifat stabil ataupun tidak). Efek samping minimal ditemukan, namun bersifat sementara (hiperpigmentasi, hipopigmentasi, dan lepuh).

Kata kunci: psoriasis, terapi, pulsed-dye laser

Introduction A few molecular in vivo studies have revealed that PDLs have additional mechanism of actions in Psoriasis is classified as a chronic inflammatory treating vascular excessive growths.9,10 One of the skin disease characterized by rapid growth and study depicting microscopic image of hamster abnormal differentiation of the epidermis, typical cheek pouch concluded that abnormal vascular vascularization, and dysfunctional immune system. growth remediation by laser was caused by physical Microscopically, one of the characteristic phenomenon.9 Meanwhile, a different in vivo study pathological changes in the skin prior to clinical had found that PDL was able to regulate manifestation of psoriasis skin lesion is dermal inflammatory processes, leading to apoptosis of capillaries abnormalities. The capillary pathologic endothelial cells of abnormal vessels. Due to the reaction start with perivascular mononuclear fact that these pathological endothelial cells secrete infiltrate, followed by capillary elongation with large amount of VEGF for its sustainability and prominent rete ridge, and finally end as tortuous expansion, its apoptosis causes decreased VEGF capillaries along with elongated rete ridges.1-3 level. Without enough concentration of VEGF, These pathologic capillaries are very close to the involution of abnormal vascular excessive growth 10 epidermal-dermal junction.4 will occur. A preliminary in vivo human study proved that a psoriasis plaque treated with PDL To date, there are three modalities of treatment for showed significant micro-vessel density, length, and psoriasis: topical therapies, systemic agents, and width reduction, which are correlated with the phototherapy. Phototherapy is chosen as an plaque severity score as a representative of 11 alternative, especially narrow-band UVB (NBUVB) psoriasis clinical aspects. Furthermore, PDL is phototherapy, due to its safer profile and more precisely targeted to each psoriasis plaque, even convenient administration.5 However, phototherapy preventing potential side effects such as erythema may induce non-melanoma skin cancer, especially if and blistering. This gives rise to a question whether the patient receive immunotherapy in the future.6 PDL can be used as an alternative treatment for psoriasis in an adult patient, especially for stable One of the alternative, more often than not psoriasis plaques on the extremities. neglected, psoriasis treatment modalities is laser modality.7 Vascular lasers are the most suitable Case Illustration lasers and the target is capillaries located high in the dermal papillae, using hemoglobin in the A 31-year old female patient came for her four- erythrocytes as a chromophore.8 Lasing material weekly follow up on phototherapy response for comes in different forms, such as solid, liquid, gas, psoriasis. Psoriasis was diagnosed six years before electromagnetic, or dye materials. Pulsed-dye current admission and has been partially controlled lasers (PDL) use ‘dyed’ materials known as with steroid, retinoic acid, and emollients. One year chromophores. This “selective photothermolysis”, before current admission, the intensity of psoriasis with the correct laser beam, has been proven to be patches worsened. The patient started NBUVB highly effective for treating skin lesions while the twice a week, and then reduced weekly after 20 target is heated in reaction to specific absorption of sessions, and further reduced to fortnightly after light (e.g. by hemoglobin within the capillaries) while additional sessions. By February 2015, she had not injurious to the surrounding normal tissue. 8, 9 completed a total of 54 NBUVB sessions and her condition had significantly improved, except for some persistent patches that she said to have

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minimal improvement, if any. The patient had a whether their results were valid, important, and history of dyslipidemia, controlled by diet. She was applicable for the patients in the predetermined then prescribed two different topical creams (0.05% clinical scenario. Betamethasone valerate cream twice daily and 0.005% calcipotriene cream twice daily) for three Search strategies months for plaques on the extremities, but no We searched through PubMed, Science Direct, and significant improvement was seen. Cochrane Library. The keywords used were ‘pulsed- dye laser’ and ‘psoriasis’ with a Boolean AND. They On physical examination, multiple post-inflammatory were already listed in PubMed Medical Subject well circumscribed hyperpigmented macules were Headings (MeSH). An article of systematic review found in various sizes (ranging from lenticular to and randomized controlled trial type was prioritized. palm-wide); scattered diffusely on the abdomen, Selection upper back, and bilateral limbs. No scales were observed. One well-circumscribed nummular plaque each on the lower legs and bilateral forearms, with minimal erythema and minimal white thin dry scales were also observed. Body surface area (BSA) involved was 2%. She then asked for a treatment other than topical and localized NBUVB treatment that could clear the persistent psoriatic patches on her legs and arms.

Clinical question

In order to investigate this further, we propose a research question: To what extent is pulsed-dye laser treatment Figure 1. Search Strategy Flowchart effective for psoriasis in adults? Due to the limited amount of systematic reviews We broke down the question into four parts, found regarding the subject of this study, an abbreviated as PICO (i.e. Patient/problem, expanded search was conducted in order to search Intervention, Comparison, and Outcome[s] of for articles with second highest level of evidence, interest): which are randomized-controlled trials with sufficient  Patient : Adult patients with psoriasis number of patients. Each article found was critically vulgaris appraised using three parameters: validity,  Intervention : Pulse-dye laser importance, and applicability. Each aspect of these  Comparison: N/A parameters were assessed using a worksheet from British Medical Journal Evidence-Based Medicine  Outcome : Psoriasis clinical severity scoring 12 reduction Toolkit.

Method Results

Type of study There were three RCTs found. Two of which had This study is an evidence-based case report been included and evaluated in the systematic (EBCR). An EBCR started from a relevant clinical review. while the other one was more of a scenario with corresponding clinical question pathogenesis study. Thus, the systematic review (PICO) regarding therapeutic options, diagnostic was the only article appraised for answering the value, prognosis, and etiology of the underlying clinical question in this evidence-based case report. disease. According to its PICO, several inclusion criteria are set to define what kind of previous The systematic review appraised aimed to evaluate original articles are most suitable. The article(s) PDL efficacy as a treatment of inflammatory skin found were then critically appraised to decide diseases, including psoriasis, acne vulgaris, lupus erythematosus, facial granuloma, sarcoidosis,

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chronic eczema, lichen sclerosis, granuloma expert consultation was not stated to have been annulare, Jessner lymphocytic infiltration of the skin, conducted. The studies included in the systematic reticular erythematous mucinosis, and review were also limited to those with full-texts papulopustular rosacea. Amongst them, psoriasis available in English, German, or Dutch.13 was the most studied inflammatory skin disease. These were all clearly stated in the article review, Inclusion criteria consist of: 1) patients with indicating the relevance of its research question to inflammatory skin disease which is psoriasis; and 2) the clinical question of this case report.13 treated with PDL. The systematic review included a wide range of study types (case reports, case There were a total of 13 clinical studies of psoriasis series, retrospective studies, open-label trials, and evaluated in the systematic review.13 Two of these RCTs) due to the limited available literatures studies strictly examined nail psoriasis, thus the regarding the topic being studied. However, the validity of which would not be considered any study did not mention in full details of the patient further. Amongst 11 studies of trunk and/or baseline or demographic criteria nor psoriasis extremities psoriatic plaques treated with PDL, the characteristics (location of lesions, severity, highest level of evidence (LOE) was 2B, which previous responsiveness to treatments, etc.). consists of individual cohort studies or low-quality Meanwhile, two exclusion criteria were noted: RCTs. There were only 2 studies with this LOE, 6 collateral use of local therapy other than keratolytic studies were of individual case-control studies (LOE pre-treatment and oral treatment started within six 3B), and 2 were only in the form of case series weeks prior to PDL therapy and/or during PDL (LOE 4). The maximum number of subjects included therapy. These inclusion and exclusion criteria were in the study was 41 patients14 and the minimum used as guidelines in filtering the studies. Three amount of subjects was eight patients.15, 16 dermatologists acted as a reviewer in filtering studies. How the three dermatologists coordinate PubMed was the only computerized bibliographic and their agreements in choosing the studies database through which the writer of the systematic included in the review were not explained further.13 review conducted a literature search. The keywords used were a combination of “pulsed dye laser(s)” All of the 11 trials included in the systematic review and a specific term of inflammatory diseases as produced significant results. A significant result was stated above. Any manual search, citation-indexing, defined as clinical improvement of psoriatic lesions evaluation through research registration to detect treated with PDL compared with either its before- possible unpublished studies or ongoing studies, or treatment degree of severity or other treatments.13

Table 1. Critical Appraisal of Validity

Validity Parameters Erceg, et al. (2013) Clear relevant research question Yes High-quality studies No Comprehensive search strategies No Assessment of the trials’ individual validity Clear inclusion criteria No Clear exclusion criteria Yes More than one investigators with good Yes interpersonal agreement Consistent trial results Clinically No Statistically Cannot be evaluated due to significant clinical heterogeneity

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The general patient characteristics are adult and 10 mm) all of which had been proven to be patients with psoriasis plaques existing either on the effective in inducing selective photothermolysis for trunk or extremities. There are some patient treating abnormal vascular growth. These small characteristics that would predictably affect the variations would be predicted to minimally impact results and therefore should have been considered the result.13 as either inclusion or exclusion criteria when recruiting subjects such as demographic profiles Pulse duration (age of onset, sex, comorbidities), genetic Pulse duration used was quite variable, ranging predisposition, psoriasis type, psoriasis severity, from 0.2 to 1.5 ms, with 0.45 ms being the most and previous response to other treatments. commonly applied.13 Decision regarding pulse Nevertheless, these features were not further duration to be applied is crucial in PDL therapy. mentioned in detail.13 Also known as pulse width, it influences thermal energy spatial confinement. Each vessel has one Discussion unique property known as thermal relaxation time, which is the time needed for the vessel to dissipate 17 Regarding psoriasis, some literature categorized it +63% of incident thermal energy. PDL pulse as erythro-papulo-squamous skin disorder, which duration should ideally be synchronized to this literally describes its classic lesion as well- property of vessel. Pulse duration exceeding demarcated erythematous papule or plaques with vessels’ thermal relaxation time could potentially white dry scales on the surface. These lesions are expose them to greater amount of incidental thermal usually symmetrical and easily recognized during energy, that rather than being dissipated to surrounding tissue, it would be absorbed, leading to physical examination (by the presence of Koebner 9 phenomenon, Auspitz sign, and Woronoff ring).1-3 unwanted side effect(s). In psoriatic plaques, the Approximately 90% of psoriasis cases are psoriasis abnormal capillaries in the dermal papillae are one vulgaris.4 of the main targets of a PDL therapy. There were no preliminary in vitro or in vivo studies examining In treating the disease, topical therapies are those vessels’ thermal relaxation time. However, indicated for mild localized psoriasis, while systemic one of the studies analyzed in the systematic review agents and phototherapy are the treatment for investigated the effects of different kinds of pulse severe psoriasis. However, there are limitations to duration on improvement (0.45 ms vs 1.5 ms) and revealed no significant difference. Difference in side systemic agents as they potentially have 13 unfavorable side effects such as hepatotoxicity, effects was not discussed any further. bone marrow suppression, hypertension, kidney failure, and teratogenicity.5 PDL fluence PDL fluence amongst the studies was varied, 2 2 Other modalities include lasers, which have already differing from 2.0 J/cm to 12.0 J/cm . Fluence is a measurement unit of energy delivered by PDL (in been studied in several countries. Based on critical 2 appraisal of the systematic review, pulsed-dye laser joule) per unit area (in cm ). It is the most common does play a role in psoriasis treatment. However, all quantitative endpoint previously determined by a of the 11 studies included in the systematic review pilot study. Different levels of fluence are applied to were small-scale studies consisting of less than 50 certain vessels and the level of exposure resulting subjects each: the biggest number of patients in permanent vessel damage/disappearance without enrolled in one study was 41 subjects14 while the leading to wall rupture will be considered as the smallest number was eight subjects16. Furthermore, ideal fluence, which is the endpoint of PDL therapy. there were several clinical heterogeneities among The previous study in hamster cheek pouches them that are further discussed below, including: the mentioned in the introduction section had revealed wavelength of light emitted by PDL, spot size that the fluence needed to accomplish vessel diameter, pulse duration, PDL fluence, and patients’ disappearance was in accordance with pulse 13 duration, where the longer the pulse duration is, a baseline and demographic characteristics. 9 higher fluence is needed. This finding is expected Light wavelength and can be explained logically in a sense that There were only two wavelength variations, 585 and longer pulse duration potentially exceeds the 595 nm, and three spot size diameters (five, seven, vessels’ thermal relaxation time and therefore more thermal energy dissipated into the surrounding

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tissue, rather than absorbed by the hemoglobin  Within 24 hours after PDL therapy in patients inside the vessels, which is a pivotal point leading to with stable psoriatic plaques, VEGFR and E- its (vessel) disappearance. Consequently, the PDL selectin expression were down-regulated. This is fluence has to be higher so that the energy lost due followed by reduced expression of IL-23 and to dissipation phenomenon is replaced and TNF-alpha after second PDL session; effectively absorbed by hemoglobin. In accordance normalization of epidermal activation markers with this deduction, the same study also discovered and dermal T-cell infiltrates after four times of that increasing fluence is correlated to more PDL therapy.19 abundance of intravascular cavitation, vessel wall Decreased epidermal activation markers and rupture, hemorrhage, and shrinkage of perivascular dermal T-cell infiltrates were also achieved by tissue during microscopic observation. One study in NBUVB, but only after 13 weeks of treatment. the systematic review applying the highest range of This means that PDL potentially induce earlier fluence, which is 10.0–12.0 J/cm2, showed blistering remission onset in psoriasis plaque.19 as a side effect of PDL treatment that was not found in other studies without improvement in psoriatic Conclusion severity exceeding excimer laser.12

This appraisal of the only systematic review Baseline characteristics regarding PDL therapy in psoriasis plaques Patients’ demographic and their psoriatic patches’ concludes that PDL can be used as an alternative baseline characteristics such as age of onset, sex, treatment for psoriasis plaques in trunks, comorbidities; genetic predisposition, psoriasis type, extremities, hands, or feet (both stable and psoriasis severity, and previous response to other unstable) in addition to NBUVB, an already treatments were possibly varied widely as no strict established treatment of choice for the same inclusion criteria were implemented regarding these indication. Clinically, psoriatic lesions were shown to components.12 be significantly improved after PDL therapy and it

was also proven to be at least as effective as Mechanism of Action NBUVB. Considering PDL’s small area coverage, Despite the need of careful interpretation of the this modality might be more convenient for small appraised systematic review, there is some psoriatic plaques. This is both an advantage and biological plausibility proven by researches which disadvantage; its smaller area coverage protects could explain the significant improvement of the healthy skin surrounding psoriatic lesion from psoriatic plaques treated with PDL: undesirable side effects. However, it requires more  Light energy, in the form of photon emitted by time for PDL to cover a larger psoriatic plaque. PDL devices, is almost exclusively absorbed by hemoglobin, leading to intravascular coagulation. There were only three noted side effects of PDL, This coagulum has underwent chemical structure namely: hyperpigmentation, hypopigmentation, and change resulting in splits, being in close blistering. Overall, they are transient in nature, proximity to the vessel walls, and retracts them. compared to more varied potential side effects of Observation via real-time microscopy shows NBUVB. vessel disappearance with neither rupture nor 9 haemorrhage. To date, there have not been any reports regarding  Endothelial cells exposed to PDL therapy PDL therapy remission rate when applied as showed ultrastructural changes consistent with treatment for psoriasis. Prospective studies with apoptosis phenomenon followed by a reduced high LOE are warranted in the future to firmly expression of VEGF mRNA, possibly secondary establish the utility of PDL therapy in psoriasis to apoptosis itself. However, what actually treatment. induced apoptotic cascade of events at the first time was still speculative: inflammatory process References is fairly probable.10

 Reduction in ICAM-1 expression in chronic 1. Wolff K, Lowel AG, Stephen IK, Barbara AG, psoriatic plaques was notable after 3 sessions of Amy SP, David JL. Fitzpatrick’s Dermatology in PDL treatment performed every 2 weeks.18 General Medicine. New York: McGraw-Hill; 2008. p.396-401.

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