Therapeutic effects of laser on psoriasis plaques: a systematic review

ABSTRACT Given the relevance of laser application, the objective of this study was to carry out a systematic review to verify the therapeutic effects of laser application on psoriasis plaques. The databases used were PubMED, Scopus, Embase, Cochrane, Web of Science, and in the gray literature: Google Scholar, Open Grey and LIVIVO. A total of 1,227 records were found, after removal of duplicates 851 studies remained for Phase 1 (reading titles and abstracts) and 31 for Phase 2 (reading the full studies) and finally 9 studies remained for this review, 7 randomized and 2 non-randomized. The risk of bias analysis had two studies with moderate risk and seven with high risk. The present study presented evidence that laser application has positive effects such as reduction of psoriasis plaques. However, due to the high risk of bias, there is a need for further studies.


Introduction
Psoriasis is a chronic, papulosquamous disease with variable morphology, distribution and severity on the skin, and can also affect joints, with a negative impact on the physical, emotional and psychosocial well-being of individuals with the disease.This disease has a strong genetic component, but environmental factors, such as infections, can play an important role in the presentation of the disease (1)(2)(3).With an abnormal interaction of the immune complex between T lymphocytes, dendritic cells, keratinocytes, neutrophils, and pro-inflammatory cytokines (4).
Psoriatic lesions usually present as chronic, symmetrical, erythematous, desquamative papules or plaques (1,5).Furthermore, they are generally symmetrically distributed on the scalp, elbows, knees, and lumbosacral region.Psoriasis can also develop at sites of trauma or injury, known as Koebner's phenomenon.Despite the classic presentation described above, the morphology can vary from small tear-shaped papules (guttate psoriasis) to pustules (pustular psoriasis), erythema, and generalized scaling (erythrodermic psoriasis).In addition, these different forms of psoriasis can be localized or generalized and can be disabling.Therefore, psoriasis can have a variable course, presenting as stable plaques, or it can present acutely, with rapid progression and generalized involvement, and it can be symptomatic, with patients complaining of intense itching or burning.In addition, if the psoriasis is progressive or uncontrolled, it can result in generalized exfoliative erythroderma, requiring the use of therapeutic and medication resources to control the condition.Phototherapy is the use of ultraviolet (UV) radiation or visible radiation for the treatment of different diseases and has long been used for the treatment of inflammatory skin diseases, such as psoriasis (5,6) The best spectrum for the treatment of psoriasis is believed to be between 300 and 313 nm, comprised within UVB (7).In general, the effects of UV radiation can be divided into two groups: immediate and late effects.The immediate effects, such as membrane and DNA damage, induction of cytoplasmic transcriptional factors, and isomerization of chromophores (such as urocanic acid), have been known since 1967, instantly inducing cell growth arrest and apoptosis.There is a direct molecular structure change in DNA due to photon absorption after UVB that inhibits DNA transcription and causes cell cycle arrest in human fibroblasts and epidermal cells.In addition, the late effects of UV radiation include inhibition of adaptive and innate immune cells that results in immunosuppression (5).The use of the 308 nm excimer laser, which is a mixture of gases, also produces monochromatic, coherent radiation within the UVB spectrum and has also shown excellent results for such disease (4).However, wavelengths within the visible field, such as 595 nm, have also been used in the form of pulsed dye laser (PDL), which presents a thermal effect and aims to alter local angiogenesis (8), in addition to photobiomodulation effects, with red or infrared laser, aiming to alter the inflammatory cascade and improve the reparative capacity of the tissue (9,10).
Given the relevance of the application of phototherapy, as well as the absence of up-to-date systematic reviews, the aim of this study was to conduct a systematic review to verify the therapeutic effects of laser application on the morphology of psoriasis plaques.

Eligibility criteria
The acronym PICOS was used to formulate the focused question in this study: P (population) -individuals with psoriasis; I (intervention) -laser; C (comparison) -no treatment, placebo or sham; O (outcome) -psoriatic plaques; and S (study)clinical trial.Clinical trials with laser intervention were included in people diagnosed with psoriasis of any form of presentation, in any anatomical region, without age or gender restriction.Case reports, studies that did not determine laser dosimetry, studies not fully available, and research involving animals were excluded.

Information sources
The initial search was conducted using keywords in the PubMed database with the Medical Subject Headings (MeSH) medical metadata system as well as free terms.Individual search strategies were developed for the databases: National Library of Medicine (PubMED), Scopus, Embase, Cochrane, Web of Science, and in the gray literature: Google Scholar, Open Grey and LIVIVO.
There was no limitation of publication period or language.The preliminary searches in all databases were performed on a single day, 3 May 2022, totaling 1,172 references.

Study selection and data collection process
EndNote Web and Rayyan Qatar Computing Research Institute (QCRI) reference managers were used.Articles were imported from the databases into the Endnote Web reference manager for automatic and manual removal of duplicate articles.Then, they were imported into Rayyan, and again the removal of duplicates was performed manually by the first reviewer and Phases 1 and 2 were performed by two blinded reviewers, R1 (CMG) and R2 (D.N.), disagreements were resolved by the third reviewer (RAS).In this way, the studies included in Phase 1 were defined, for reading of titles and abstracts, according to the eligibility criteria.The final selection, Phase 2 was based on reading the studies in their entirety.

Collected data
Data were collected on the characteristics of the studies (authors, year of publication, country), the population (sample size, mean age and sex), description of the intervention, results and conclusion (Table 1).

Individual assessment of risk of bias in studies
The risk of bias assessment was carried out using Cochrane tools, Rob 2 and ROBINS I, by two blinded reviewers R1 (CMG) and R2 (D.N.) and disagreements were resolved by the third reviewer R3 (RAS).Rob 2 was evaluated in five domains: bias in the randomization process; deviations from the intended intervention; bias due to missing data; bias in the measurement of outcomes and bias in the reporting of outcomes.Each domain can be assessed as low risk of bias, some concerns, or high risk of bias.ROBINS I was evaluated in seven domains: bias due to confounding; bias in participant selection; bias in classification of interventions; bias due to deviation from intended interventions; bias due to missing data; bias in measurement of outcomes; and bias in selection of reported outcomes.Each domain is rated as low, moderate, unclear, or high risk (11).

Assessment of the risk of publication bias
Initially, to prevent publication bias, a sensitive search was performed, without restriction as to period, language, and with a gray literature search.

Statistical analysis
Statistical analysis was performed using RevMan 5.4.1 (The Cochrane Collaboration, Software Update, Oxford, UK) (11).Continuous results were expressed as standard mean differences (with ninety-five percent confidence intervals (95% CI)).A p-value of < 0.05 was considered statistically significant.The I 2 statistical test value was calculated to test for heterogeneity between studies.An I 2 value ≥ 50% was considered significant heterogeneity.A random-effects model was adopted.

Study selection
During the search 1,227 records were found, of which 1,172 in the main databases and 155 in the gray literature.EndNote is identified in the indexed literature 406 duplicate studies automatically and 32 more manually; and from the gray literature 01 automatically and 06 manually.Then, in a new duplicate removal Rayyan identified 103 more duplicates, but after manual analysis only 32 studies were duplicates, 24 from the indexed literature and 8 from the gray literature.This left 851 studies for Phase 1 (reading titles and abstracts) and 31 for Phase 2 (reading the full studies) (Figure 1).

Risk of study bias
The results of the risk of bias analysis of the ROB-2 tool are shown in Figure 2 and the risk of bias of ROBINS-I in Figure 3.The two randomized clinical trials analyzed with ROB-2 were those of Almuslet & Osman (10) and Li et al (12).had a high risk of bias.Only the missing data outcome domain obtained a low risk of bias in both studies.The studies evaluated by ROBINS-I (9,14-17) were rated with high risk of overall bias, and the studies by Elwan et al (13).and Zerbinati et al (18).with moderate risk of bias.With this tool, it was possible to observe that the domain with the highest bias was in measuring outcomes, whereas, the domain with the lowest bias was in selecting reported outcomes.

Parameters used
Regarding the parameters of the laser therapy application, high variation was found among the nine included studies, with wavelengths ranging from 355 nm to 2940 nm.The highest wavelength (2940 nm) was applied in the study by Li et al (12).and the lowest (355 nm) by Zerbinati et al (18).In Ablon's study (9) the wavelength was from 830 nm to 633 nm.Almuslet & Osman's study (10) used 671 and 675 nm, while Elwan et al (13).used 595 nm.The wavelength 585 nm, on the other hand, was used in four studies (14)(15)(16)(17).
Li et al (12).obtained a sample of five people, which were treatment and control.The experiment used laser associated with topical medicine (calcipotriol) in the right knee and as control only topical medicine (calcipotriol) in the left knee.Er: YAG laser, 2940 nm, with pulse duration 500 μs, with dosimetry: 250-μm spot size, 11% dose and 100 μm energy depth was used.Topical medication was applied 2× per day in both groups, and the laser was applied 1×/week for 4 weeks.
In the quasi-experimental study by Noborio et al (15).PDL 585 nm, 450 µs, 10 mm beam diameter, and 8 J/cm 2 was used.One session/month/interval of 2 weeks between each session, on average 4.5 sessions.The study by Ros et al (16).with n = 10, used PDL, pulse duration 360-450 µs and 585 nm.With a treated area of 5-10 cm 2 and as a control, an area of the lesion was not treated.

Healing outcome
In Ablon's quasiexperimental study (9) the psoriasis area and severity index scores were not applied, only described as percent reduction to photographed area.The other studies used psoriasis area severity scale with a likert scale from 0 to 4, where 0 indicates no lesion and 4 severe lesion.

Meta-analysis
Two studies Erceg et al (14).and Ros et al (16).with 18 participants performed the outcome analysis of psoriatic plaques between the laser and control group.Both studies used the individual himself as the control, Erceg et al (14).used the contralateral limb as the control, and Ros et al (16).an area of the experimental lesion itself as the control (Figure 4).

Discussion
The present study aimed to analyze the literature on the use of radiation in the form of phototherapy in individuals with psoriasis, and they showed positive aspects as a therapeutic form, despite methodological biases observed in the studies.The pathogenesis is related to abnormal interactions between the immune system, keratinocytes and T cells, in which T cells release an excessive amount of pro-inflammatory factors, directing an activation of the immune system, the process resulting in hyperproliferation, inflammation and other clinical signs (21).
In psoriatic lesions there is increased surface area in the papillary dermis due to the development of new vessels (22).Therefore, the results of the study by Noborio et al (15).are important, in which it was observed that the application of PDL, 585 nm, was responsible for decreasing the diameter of the microvessels.That is also pointed out by Ros et al (16).as the differential of this therapy, with histopathology revealing a therapeutic benefit as early as the first week after the procedure, in spite of the formation of black crusts using fluences between 6.5 and 8 Jcm 2 .
An important point for therapy is its safety, and according to Elwan et al (13)., this technique has been shown to be safe, effective, and tolerable for localized, stable, and resistant psoriasis, with minimal side effects and a prolonged recurrence period.In addition, the authors reported clinical improvements on epidermal scaling and erythema, with histopathological findings demonstrating disappearance of parakeratosis and decreased inflammatory infiltrate.Corroborating with the results of the study by Zelickson et al (17).who demonstrated significant reduction in psoriatic plaques after treatment of patients receiving 585 nm PDL.They report that PDL is a good ally in the treatment of psoriasis, because in two sessions it allowed cutaneous lightening of the patients.Conversely, Erceg et al (14).after 4 weeks of PDL treatment combined with topical calcipotriol dipropionate/betamethasone treatment observed no reduction in plaque severity.However, limitations of this research included lack of blinding, small sample size and possible poor treatment compliance.Zerbinati et al (18)., also using UV laser, but at 355 nm, with moderate to high fluences, between 80 and 140 J/cm 2 , report improvement in patients with mild, moderate and severe psoriasis.
In the study by Li et al (12)., the application of the 2940 nm erbium:YAG infrared laser, which produces thermal effects, prior to the topical drug was better than using the drug alone; this is due to molecular arrangement changes in the tissue, forming channels to improve drug penetration.
For the low-level laser therapy, in Almuslet and Osman's study (10) the application of 671 nm diode laser with 100 mW power for 15 minutes was better than the application of 16 mW and 50 mW, for the same time of 15 minutes.In this study, five patients who were exposed to 100 mW power showed complete clearing of the psoriatic plaque after three sessions, besides that, one patient showed 75% reduction in the psoriasis area and severity index, and two patients showed 50% reduction after three sessions.Ablon's study ( 9) used an association of LEDs (830 and 633 nm), in  a small sample (n = 9), which is known to decrease the power of statistical analysis; in addition, in this same study, the psoriasis area and severity index scores were not applied, but a global medical evaluation, in any case, reports great satisfaction from the patients and anti-inflammatory effects.Thus, the results obtained indicate the importance of choosing both the ideal exposure time and laser power to achieve good results during treatment.The low-level laser generates increased energy production by mitochondria, which affects both anti-inflammatory and pro-tissue repair effects (23,24), which probably answers the findings of the above study.
In the present study, in order to avoid publication bias, a comprehensive and sensitive search was conducted, without restrictions as to period, language, and with a search in the gray literature, which is an important source of data, especially with regard to studies with null or negative results, which may be more difficult to publish in other ways (25).And given the heterogeneity of the studies with respect to the laser parameters and the outcomes analyzed, only two studies were included in the meta-analysis, making it impossible to use the funnel plot analysis to indicate publication bias (11).
In the present study, it should be noted that there was no study with a low risk of bias, i.e., even if the manuscripts show satisfactory clinical and statistically significant results, even in the metaanalysis performed (for PDL), caution should be exercised in interpreting these results.

Conclusion
The present study presented evidence that laser application has positive effects such as the reduction of psoriasis plaques, as well as the reduction of erythema, infiltration, and scaling.However, due to the high risk of bias, there is a need for further studies with low risk of bias and that seek to record an optimal parameter of application of this therapy.

Disclosure statement
No potential conflict of interest was reported by the author(s).

Funding
The author(s) reported there is no funding associated with the work featured in this article.

Figure 1 .
Figure 1.PRISMA 2020 flow diagram for new systematic reviews including searches of databases, registers and other sources.

Figure 3 .
Figure 3. Individual bias analysis of the ROBINS-I nonrandomised clinical trials.

Figure 4 .
Figure 4. Forest plot of comparison of laser 585 nm and control.

Table 1 .
Summary of the most important findings of the included randomized clinical trials (n = 9).