Photodynamic Therapy Interventions in Facial Photodamage: A Systematic Review

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Sanclemente, V. Ruiz-Cañas, J.M. Miranda, A.P. Ferrín, P.A. Ramirez, G.N. Hernandez" "autores" => array:6 [ 0 => array:4 [ "nombre" => "G." "apellidos" => "Sanclemente" "email" => array:2 [ 0 => "sanclementegloria@gmail.com" 1 => "gsanclementem@gmail.com" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "V." "apellidos" => "Ruiz-Cañas" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "J.M." "apellidos" => "Miranda" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "A.P." "apellidos" => "Ferrín" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "P.A." 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"apellidos" => "Hernandez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Grupo de Investigación Dermatológica (GRID), Universidad de Antioquia, Medellín, Colombia" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "IPS Universitaria, Universidad de Antioquia, Medellín, Colombia" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Terapia fotodinámica en el fotodaño facial: revisión sistemática" ] ] "resumenGrafico" => array:2 [ "original" => 1 "multimedia" => array:5 [ "identificador" => "fig0045" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx1.jpeg" "Alto" => 750 "Ancho" => 1333 "Tamanyo" => 63409 ] ] ] ] "textoCompleto" => "IntroductionThe interplay of intrinsic (age-related decline of cutaneous cellular functions and/or genetic predisposition) and extrinsic factors (exposure to ultraviolet (UV) radiation, smoking or environmental changes) all lead to visible skin changes that result from an abnormal water distribution in tissue, (or a lack of hygroscopic substances), from an increase in skin pH, and from a prevailed oxidative cell metabolism that overwhelms local antioxidant activity. Those changes as a whole are usually referred as photodamage or actinic damage.<a class="elsevierStyleCrossRefs" href="#bib0280">1,2</a> Such disturbances result in a dry appearance of the skin, in an increase in skin surface pH and in a continuous production of reactive oxygen species (ROS) in mitochondria due to an oxidative cell metabolism and a decrease in antioxidant activity.<a class="elsevierStyleCrossRefs" href="#bib0290">3,4</a> Keratinocyte functional disturbances also occur due to a decreased mitotic activity and a 50%-increase in keratinocyte-migration time from the basal cell layer to the stratum corneum and an increase in cell-cycle duration.<a class="elsevierStyleCrossRefs" href="#bib0300">5,6</a> Skin aging is also accompanied by spinous cell layer atrophy and dermo-epidermal junction flattening which both contribute to skin fragility.<a class="elsevierStyleCrossRef" href="#bib0305">6</a>Aged skin is also characterized by an overall collagen synthesis reduction via the diminution of procollagen production, a down regulation of the transforming growth factor-b (TGF-b) type II receptor (a major regulator of dermal extracellular matrix (ECM) synthesis), and by a disturbed TGF-b activity that also stimulates fibroblast proliferation.<a class="elsevierStyleCrossRefs" href="#bib0310">7–10</a> Skin collagen is also affected by UV-induced matrix metalloproteinases (MMP)<a class="elsevierStyleCrossRef" href="#bib0330">11</a> such as MMP-1 (fibroblast collagenase), MMP-9 (gelatinase) and MMP-3 (stromelysin),<a class="elsevierStyleCrossRefs" href="#bib0325">10,12</a> and solar elastosis seems to be a consequence of an increased production of elastic fibers and elastin degradation by MMP-12 (human macrophage metalloelastase).<a class="elsevierStyleCrossRefs" href="#bib0325">10,13–15</a>Photodynamic therapy (PDT) is a selective therapeutic modality that combines an oxygen rich environment and a light source that stimulates a photosensitizing agent to produce singlet oxygen which is highly toxic to the cells.<a class="elsevierStyleCrossRefs" href="#bib0355">16,17</a> Porphyrins and particularly hematoporphyrins (e.g.: photofrin) were the first intravenous substances used for PDT, characterized by their long-term accumulation in target tissue that required rigorous photoprotection for several weeks after administration.<a class="elsevierStyleCrossRef" href="#bib0360">17</a>In 1990 new topical porphyrins such as 5-aminolevulinic acid (ALA) or its methyl ester (MAL) emerged, which could both easily penetrate the epidermis and produce short-term circumscribed photosensitivity.<a class="elsevierStyleCrossRef" href="#bib0365">18</a> More recently, hexylester 5-aminolevulinate (HAL) has been proposed to induce formation of high concentrations of PpIX in neoplastic tissue, but its use is still experimental.<a class="elsevierStyleCrossRef" href="#bib0370">19</a>These molecules intervene in heme biosynthesis intracellular pathway, by inducing the formation of a photoactive porphyrin known as protoporphyrin IX (PpIX), which is an efficient photosensitizer that accumulates particularly in photodamaged skin.<a class="elsevierStyleCrossRef" href="#bib0360">17</a>PDT requires either an incoherent/coherent light source that should be ideally specific to the chromophore/photosensitizer used. Incoherent light devices include a continuous-wave red light (635nm), blue light (417nm) and intense-pulsed light (IPL),<a class="elsevierStyleCrossRef" href="#bib0375">20</a> whereas lasers are among the most used coherent light equipment.<a class="elsevierStyleCrossRef" href="#bib0375">20</a>As photosensitizers can either localize in lysosomes, mitochondria, Golgi apparatus, endoplasmic reticulum, and plasma membranes, PDT effects are a consequence of how PS interact with cells within the target tissue/organ or tumor.<a class="elsevierStyleCrossRefs" href="#bib0380">21,22</a> Moreover, it seems that PDT direct DNA cellular damage can occur via modifications of guanine moiety and through strand breaks at uracil and thymine sites, whereas indirect DNA disruption is explained by deactivation of repairing enzymes by free radicals and singlet oxygen production.<a class="elsevierStyleCrossRef" href="#bib0390">23</a>In addition, skin effects of topical PDT include solar elastosis improvement and neocollagenesis via the induction of expression of collagen type I/III production, MMP-1,-3,-9 and-12 down-regulation, and TGF β up-regulation.<a class="elsevierStyleCrossRefs" href="#bib0325">10,24</a> Photodynamic therapy with MAL has also been reported to increase dermal thickness and to improve collagen, elastic tissue and perifollicular fibrosis in treated skin.<a class="elsevierStyleCrossRefs" href="#bib0400">25,26</a>Several procedures have been used for actinic damage treatment (e.g.: chemical exfoliation, topical retinoids, lasers, intense pulsed light (IPL) and LEDs (light emitting diodes)).<a class="elsevierStyleCrossRefs" href="#bib0395">24,27–34</a> However, and according to a systematic review, there is limited scientific evidence to support the preferential use of any of these therapies in photodamaged skin.<a class="elsevierStyleCrossRef" href="#bib0450">35</a>Up to know, topical PDT use in the treatment of photodamage is still off-label. Therefore, as uncertainty still remains in this field, this paper aims to assess published scientific evidence to establish the efficacy and safety of such therapy.MethodsSearch strategiesWe aimed to identify all relevant published or unpublished RCTs regardless of language. Searches were performed during the last 10 years, and updated up to 4 May 2016. Search terms with results are depicted in Supplementary Material 1. Trial registries were scanned up to December 15, 2015, using the search terms: “photodamage”, “photoaging”, “photodynamic therapy” and “photodynamic rejuvenation” (Supplementary Material 2). We also checked for relevant references in included and excluded studies. If full text of the articles was not available, we tried to contact authors.We did not perform a separate search for adverse effects of the specified intervention. However, we examined data on adverse effects from all included studies.Inclusion criteriaAll parallel randomized controlled trials (RCTs) of PDT for facial photodamage (dermatoheliosis)/photoaging and/or photodynamic rejuvenation that included adult participants diagnosed with facial photodamage (dermatoheliosis) or photoaging, and who have been treated with any PDT-based rejuvenation procedure, were included. Any photodynamic-based intervention for photodamage (dermatoheliosis) or photoaging was considered.Types of outcomes measuresPrimary endpoints included: (1) the proportion of participants who had an improvement/failure in global facial photodamage; (2) quality of life (QoL) changes measured through any validated and recognized generic or disease-specific instrument; (3) any adverse events, safety and tolerability.Secondary outcomes corresponded to: (1) the proportion of participants who had an improvement/failure in facial hyperpigmentation, wrinkles, sallowness, erythema or roughness according to a validated and/or recognized generic or disease-specific instrument; (2) change in facial cosmetic appearance; (3) participant satisfaction; (4) pain evaluation after the photodynamic-based procedure, and (5) cost effectiveness studies, if available.Data extraction and synthesisFour authors (V.R., J.M., A-P F., G. S.) checked the searched titles and abstracts. Potentially relevant studies were selected for full-text review. All authors independently assessed whether each study met the predefined selection criteria, and differences were resolved by discussion. The same four authors performed data extraction in pre-established data collection formats and independently assessed the risk of bias of included studies as low, high or unclear according to a domain-based evaluation described in the Cochrane Handbook for Systematic Reviews of Interventions<a class="elsevierStyleCrossRef" href="#bib0455">36</a> (e.g.: ‘sequence generation’; ‘allocation concealment’; ‘blinding’; ‘outcome data’; ‘selective reporting’ and other sources of bias) that could put it at high risk of bias (e.g. baseline imbalance).Statistical issuesWe planned to include only parallel designed trials. Dichotomous outcomes data were presented as reported in each individual study. However, if sufficient data were available, outcomes data were presented as relative risks (RR) with their associated 95% confidence intervals (CIs) and analyzed them in the Review Manager (RevMan) software, version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2014, Copenhagen, Denmark), using the Mantel–Haenszel test, unless we stated otherwise.We re-analyzed the data originally described according to an intention to treat (ITT) principle, whenever possible. If study authors conducted a per-protocol analysis, we evaluated potential imbalances in the dropout rate between the trial arms to determine bias. If treatment by allocation population was unavailable, we used an available case population and reported this accordingly.We planned to evaluate clinical, statistical, and methodological heterogeneity. Statistical heterogeneity was planned to be tested by using the I2 statistic.<a class="elsevierStyleCrossRef" href="#bib0455">36</a> If substantial heterogeneity (I2 greater than 60%) was found for the primary outcomes, we planned to explore reasons for heterogeneity. As at least ten studies suitable for meta-analysis were needed for funnel plot asymmetry testing,<a class="elsevierStyleCrossRef" href="#bib0460">37</a> we were unable to perform such test. Also, as we were unable to identify an adequate number of homogenous studies (n≥3),<a class="elsevierStyleCrossRef" href="#bib0465">38</a> we did not perform a meta-analysis but we summarized the data for each trial qualitatively. The number of studies was also inadequate to perform subgroup and sensitivity analysis.ResultsStudies descriptionAfter removal of duplicates our searches retrieved 1293 references. Further to titles and abstracts examination, we excluded 1235 references from the review. We obtained full-text copies of the remaining 51 records for further evaluation, and after evaluation, 39 studies were excluded. Reasons for their exclusion are depicted in Supplementary Material 3. Exclusions were made only after assessment of the full-text reports. The most frequent reason for exclusion was that they were non-RCTs. Regarding ongoing studies, we only identified one ongoing study, which is in the recruiting phase (Supplementary Material 3). Re-analysis of retrieved data was not necessary.All retrieved studies were published in English. Thirteen references to 12 studies were finally included, as one same trial had two reports<a class="elsevierStyleCrossRefs" href="#bib0400">25,39</a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). A total of 286 participants (135 patients from ALA studies and 151 from MAL studies) were evaluated. Among these, 30 were men and 212 women, but in 2 studies, gender of participants was not specified<a class="elsevierStyleCrossRefs" href="#bib0415">28,40</a> (Supplementary Material 4). The age of the participants ranged from 35 to 82 years.<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Among all 12 included randomized trials, 6 studies used ALA and 6 MAL, as chromophores. Only 2 studies used a placebo as control<a class="elsevierStyleCrossRefs" href="#bib0470">39,41</a> and 10 had an active control treatment arm. Studies were published from year 2004 until 2015. Four studies were conducted in the USA,<a class="elsevierStyleCrossRefs" href="#bib0415">28,42–44</a> four in South America,<a class="elsevierStyleCrossRefs" href="#bib0470">39–41,45</a> 2 in Spain,<a class="elsevierStyleCrossRefs" href="#bib0410">27,46</a> 1 in Denmark,<a class="elsevierStyleCrossRef" href="#bib0510">47</a> and one in China.<a class="elsevierStyleCrossRef" href="#bib0515">48</a>The range number of participants included in the individual studies varied from 4 to 60 participants. Ten studies had a split-face design whereas 2 had a full-face design. All patients were diagnosed with mild to severe facial photodamage.The included studies evaluated the following interventions: (1) IPL vs IPL+5-ALA in a split-face design<a class="elsevierStyleCrossRefs" href="#bib0415">28,44,48</a>; (2) laser fractional resurfacing alone vs laser fractional resurfacing+MAL+red light in a split-face design<a class="elsevierStyleCrossRef" href="#bib0505">46</a>; (3) MAL+red light with 1h incubation vs MAL+red light with 3h incubation in a split-face design<a class="elsevierStyleCrossRef" href="#bib0410">27</a>; (4) IPL waveband from 530 to 750nm and short pulse durations (J/cm2, 2–2.5ms, delay 10ms)+0.5% liposome encapsulated vs IPL (waveband from 400 to 720nm), three passes were performed (3.5J/cm2, 30ms pulse duration), also in a split-face design<a class="elsevierStyleCrossRef" href="#bib0510">47</a>; (5) blue light at different incubation times+5-ALA in a split-face design<a class="elsevierStyleCrossRef" href="#bib0485">42</a>; (6) IPL vs IPL+5-ALA in a full-face design<a class="elsevierStyleCrossRef" href="#bib0475">40</a>; (7) MAL+red light with 3h incubation vs placebo+red light with 3h incubation in a split-face design<a class="elsevierStyleCrossRef" href="#bib0470">39</a>; (8) MAL with 1h incubation+red light vs MAL with 1h incubation+blue light in a split-face design<a class="elsevierStyleCrossRef" href="#bib0490">43</a>; (9) MAL+red light vs MAL+red light+1.5mm length micro-needling in a split-face design<a class="elsevierStyleCrossRef" href="#bib0500">45</a>; and (10) MAL+2h daylight exposure vs placebo+2h daylight exposure in a full-face design.<a class="elsevierStyleCrossRef" href="#bib0480">41</a>The majority of included studies (except two<a class="elsevierStyleCrossRefs" href="#bib0470">39,41</a>) did not specify primary and secondary outcomes.Facial photodamage assessment was performed by the use of several original or modified scales such the Griffith's, Dover's, Fitzpatrick's, or arbitrary scales. Four studies reported that they had applied a “modified version” of another previous developed scale,<a class="elsevierStyleCrossRefs" href="#bib0470">39,41,45,48</a> but authors did not provide details of how and if their “modified version” was tested prior to its use. Only one study assessed intervention's effects on quality of life (QoL).<a class="elsevierStyleCrossRef" href="#bib0480">41</a>A large proportion of the trials (n=9) assessed intervention-associated adverse events a priori, either through questionnaires that rated the treatment tolerability, or as skin reactions, such as erythema, dryness, edema, oozing, vesiculation, crusting, pigmentation disturbances, skin atrophy, scarring and desquamation or scaling.<a class="elsevierStyleCrossRef" href="#bib0415">28</a> In addition, several included studies assessed secondary outcomes, but overall, the methods used for measurement and the timing of the assessments were not uniform or clear.Risk of bias AssessmentRisk of bias for each included study and graphs are depicted in Supplementary Material 4, and <a class="elsevierStyleCrossRefs" href="#fig0010">Figs. 2 and 3</a>, respectively. As one of the reviewers (GS) was the main author of 2 studies, both studies were assessed only by the other 3 assessors.<elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia>We assessed the global risk of bias for each included study, and we considered two studies to be at “low risk of bias” as both met all criteria across all domains in the Cochrane “Risk of bias” assessment tool (plausible bias unlikely to seriously alter the results).<a class="elsevierStyleCrossRefs" href="#bib0470">39,41</a> We rated the remaining 10 studies as at “unclear risk of bias” (plausible bias that raises some doubt about the result) because one or more criteria were assessed as unclear (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>).An important number of included studies (9) provided insufficient detail to enable us to make accurate judgements in respect to the domain “concealment of the allocation sequence”.<a class="elsevierStyleCrossRefs" href="#bib0410">27,28,40,42–44,46–48</a> Indeed, intervention allocations masking through sequentially numbered, opaque, sealed envelopes or pharmacy-controlled allocation was only performed in 2 studies.<a class="elsevierStyleCrossRefs" href="#bib0470">39,41</a> Similarly, the “blinding of outcome assessors” domain was unclear in 5 studies,<a class="elsevierStyleCrossRefs" href="#bib0410">27,40,42,47,48</a> and only two studies described blinding of study participants and personnel in sufficient detail.<a class="elsevierStyleCrossRefs" href="#bib0470">39,41</a> Also, baseline characteristics of patients or groups were only described in 3 studies.<a class="elsevierStyleCrossRefs" href="#bib0470">39,41,43</a>Incomplete data of patients lost to follow-up, and subsequent per-protocol analyses were other important sources of potential bias in a number of the included studies. In addition, trial protocol was provided in only two studies.<a class="elsevierStyleCrossRefs" href="#bib0470">39,41</a> Judgements were amended as required, after contact with trial investigator.<a class="elsevierStyleCrossRef" href="#bib0500">45</a> In some other studies authors replied that they no longer had information regarding trial methods<a class="elsevierStyleCrossRef" href="#bib0485">42</a> and for other studies, we did not obtain a reply from authors.Effects of interventions5-ALAAlthough 6 studies evaluated the effect of 5-ALA as chromophore, either insufficient data or just baseline vs post-treatment comparisons limited relative risks calculations which could be performed only for 3 studies<a class="elsevierStyleCrossRefs" href="#bib0415">28,47,48</a> (<a class="elsevierStyleCrossRefs" href="#fig0020">Figs. 4–6</a>).<elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia><elsevierMultimedia ident="fig0030"></elsevierMultimedia>In general, there was a tendency to less treatment failure in ALA-treated split-faces. Also, we were unable to determine primary and secondary endpoints in all 5-ALA studies.The effect of ALA in actinic keratosis, as well as in facial photodamage was assessed in 2 studies.<a class="elsevierStyleCrossRefs" href="#bib0475">40,42</a>Investigator assessment of changes in facial photodamage and participant's photodamage evaluation were performed through digital standardized photographs in 3 studies,<a class="elsevierStyleCrossRefs" href="#bib0475">40,44,47</a> and two studies,<a class="elsevierStyleCrossRefs" href="#bib0415">28,48</a> respectively.Partial or full sponsoring of ALA trials by the pharmaceutical industry was detected in 4 studies<a class="elsevierStyleCrossRefs" href="#bib0415">28,40,42,48</a> and in 2 studies,<a class="elsevierStyleCrossRefs" href="#bib0495">44,47</a> sponsoring information was lacking.Photodamage results according to the timeline at which outcomes were assessed in ALA studies varied from 1 month after last session<a class="elsevierStyleCrossRefs" href="#bib0415">28,42</a>, 2 months after last session,<a class="elsevierStyleCrossRef" href="#bib0475">40</a> 1–2 months after last session,<a class="elsevierStyleCrossRef" href="#bib0515">48</a> 3 months after last session,<a class="elsevierStyleCrossRef" href="#bib0510">47</a> and at 1, 3 and 6 months, after last session.<a class="elsevierStyleCrossRef" href="#bib0495">44</a>Regarding patient related outcomes, subject satisfaction was evaluated in 4 out of 6 ALA studies.<a class="elsevierStyleCrossRefs" href="#bib0415">28,42,47,48</a>In general, more erythema, edema and desquamation were reported in the ALA-treated side of the face.5-ALA-related adverse eventsHerpes simplex reactivation and post-inflammatory hyperpigmentation were reported in Touma et al.<a class="elsevierStyleCrossRef" href="#bib0485">42</a> and in Xi et al.<a class="elsevierStyleCrossRef" href="#bib0515">48</a> studies, respectively.A summary of findings table of 5-ALA results according to GRADE standards is depicted in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>MALAlthough 6 studies evaluated the effect of MAL as chromophore, the lack of contralateral comparisons or insufficient data allowed the calculation of relative risks only for 4 out of 6 studies (<a class="elsevierStyleCrossRefs" href="#fig0050">Figs. 7–10</a>).<elsevierMultimedia ident="fig0050"></elsevierMultimedia><elsevierMultimedia ident="fig0035"></elsevierMultimedia><elsevierMultimedia ident="fig0040"></elsevierMultimedia><elsevierMultimedia ident="fig0055"></elsevierMultimedia>We also were unable to differentiate primary and secondary endpoints in 4 out of 6 studies.<a class="elsevierStyleCrossRefs" href="#bib0410">27,43,45,46</a>The effect of MAL, actinic keratosis, and in facial photodamage simultaneously was assessed in 2 studies.<a class="elsevierStyleCrossRefs" href="#bib0490">43,45</a> Investigator assessment of photodamage outcomes was performed through digital standardized photographs in 1 study.<a class="elsevierStyleCrossRef" href="#bib0490">43</a>In general, timelines for photodamage outcome evaluation in MAL trials ranged from 1 to 3 months after last session.Partial or full sponsoring of trials by the pharmaceutical industry was detected in 3 studies.<a class="elsevierStyleCrossRefs" href="#bib0470">39,41,43</a> Sponsoring details were not described in 2 studies,<a class="elsevierStyleCrossRefs" href="#bib0410">27,46</a> and one study was developed without any sponsor.<a class="elsevierStyleCrossRef" href="#bib0500">45</a>In respect to patient satisfaction, such outcome was evaluated in 3 studies with better satisfaction scores in the MAL treated split-face.<a class="elsevierStyleCrossRefs" href="#bib0470">39,43,46</a> In addition, just 1 out of the 12 studies (ALA and MAL) included a quality of life outcome.<a class="elsevierStyleCrossRef" href="#bib0480">41</a>Overall, erythema, edema and desquamation were more frequently reported in the side of the face that included MAL as chromophore in all studies, except in one study<a class="elsevierStyleCrossRef" href="#bib0490">43</a> in which no statistical differences between the use of blue vs red light were found, but also mild discomfort was more frequent with red-light exposure.MAL-related adverse eventsHerpes simplex reactivation was reported in two studies whereas post-inflammatory hyperpigmentation was described in 3 studies.<a class="elsevierStyleCrossRefs" href="#bib0470">39,41,46</a> A severe infection related to the concomitant use of microdermabrasion+PDT was reported in 1 out of 10 patients in Torezan et al.’s<a class="elsevierStyleCrossRef" href="#bib0500">45</a> study and a severe allergic reaction not related to PDT was reported in another study.<a class="elsevierStyleCrossRef" href="#bib0470">39</a>A summary of findings table of MAL results according to GRADE standards is depicted in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>DiscussionTo the best of our knowledge, this is the first published systematic review (SR) to assess and examine the evidence for the efficacy and safety of PDT in facial photodamage, and although the full protocol of this SR was not published (just its abstract), it is available upon request to correspondence author.Two high quality studies suggest that MAL-PDT is effective in the treatment of facial photodamage, but low to moderate quality of evidence shows that PDT with ALA seems to be also effective. Although adverse events (AEs) were reported inadequately in most studies, non-serious reported AEs include herpes simplex recurrence and post-inflammatory hyperpigmentation, particularly in studies that included participants with darker skin (3 out of 4 studies with PIH reports).<a class="elsevierStyleCrossRefs" href="#bib0470">39,41,46,48</a>The main objectives of a randomized clinical trial are to assess efficacy and safety of an intervention. In this respect, concealment and blinding are key domains in the assessment of risk of bias.<a class="elsevierStyleCrossRefs" href="#bib0520">49–51</a> In particular, the methods used to generate the allocation sequence and how the sequence was concealed, are the most important and sensitive indicators that bias has been minimized in a clinical trial, as participants and investigators are masked to the upcoming assignment, and therefore could not “manipulate” it. Also, standardization of outcomes and objective measurement are key elements not only for clinical decision making, but also to establish health policies.<a class="elsevierStyleCrossRefs" href="#bib0535">52–54</a>Overall, the evidence provided by this review was limited mainly due to outcome inconsistencies, the lack of description of randomization methods/sequence generation, and a lack of a double-blind trial design. Moreover, the high heterogeneity of studies did not allow a quantitative synthesis of the evidence found. However, there was a tendency for having a better result when PDT with any chromophore was used, when compared to the use of a light source alone.Most of the included studies in this review were performed before the requirement of trial registration. As a result of insufficient data and the lack of reporting, we were “forced” to downgrade the quality of evidence to “unclear risk of bias”, as we appraised these studies according to the information contained within the full text of each article. However, more unbiased judgment elements could have been obtained if we were able to get a reply from all authors, but such information could only be gathered from one main author.In this review, it is unlikely that we have missed studies with an important sample size as we performed a rigorous systematic search of published and unpublished literature and we also tried to contact leading experts. Nonetheless, we cannot absolutely rule out the influence of publication bias. Unfortunately we were unable to reliably assess the presence of publication bias, given the small number of included studies. Also, we attempted to lower potential biases in the evaluation of two MAL trials<a class="elsevierStyleCrossRefs" href="#bib0470">39,41</a> performed by one of the reviewers of this systematic review by limiting their assessment only by the other 3 assessors.The applicability of evidence found by this review corresponds to what is usual in clinical practice,<a class="elsevierStyleCrossRefs" href="#bib0295">4,55</a> as included trials covered the usual age spectrum of participants who seek a dermatologist for photodamage therapeutic options. However, it is important to bear in mind that depending on the severity of facial photodamage, patients over 70 years old might not be the best candidates for PDT as they often require more invasive procedures such as resurfacing with ablational lasers and/or surgery. Also, as all included studies had participants with Fitzpatrick's SPT from I through IV, the applicability of the evidence in SPT V-VI is limited. Similarly, results applicability in men could be affected, as the majority of included participants, were women.In conclusion, the findings in our review showed that MAL PDT was effective for the treatment of facial photodamage, but also have highlighted that only a small number of published trials have followed the Consolidated Standards of Reporting Trials (CONSORT-Statement) and the criteria of evidence-based medicine. Such standards are necessary to heighten evidence strength and quality in future trials design. Also, as there is a relative paucity of long-term evaluations of the effect of PDT in facial photodamage and in quality of life, such knowledge gaps deserve further research.SponsoringThis work was supported by the Group of Investigative Dermatology-GRID of the Universidad de Antioquia, Medellin, Colombia and by the Fundacion Dermabase.Conflict of interestDr. Gloria Sanclemente has participated in advisory boards and has received honoraria and scientific meeting support from Galderma Laboratories.Dr. Veronica Ruiz Cañas has received scientific meeting support from Galderma Laboratories.Dr. Jenny Marcela Miranda Orozco has received scientific meeting support from Galderma Laboratories.Dr. Alba Patricia Ferrín Bastidas has received scientific meeting support from Galderma Laboratories.Paola Andrea Ramirez has nothing to discloseGilma Hernandez has nothing to disclose." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:3 [ "identificador" => "xres1011112" "titulo" => "Graphical abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:3 [ "identificador" => "xres1011113" "titulo" => "Abstract" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0010" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0015" "titulo" => "Aims" ] 2 => array:2 [ "identificador" => "abst0020" "titulo" => "Methods" ] 3 => array:2 [ "identificador" => "abst0025" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0030" "titulo" => "Discussion and conclusions" ] ] ] 2 => array:2 [ "identificador" => "xpalclavsec970505" "titulo" => "Keywords" ] 3 => array:3 [ "identificador" => "xres1011111" "titulo" => "Resumen" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0035" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0040" "titulo" => "Objetivo" ] 2 => array:2 [ "identificador" => "abst0045" "titulo" => "Métodos" ] 3 => array:2 [ "identificador" => "abst0050" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0055" "titulo" => "Discusión y conclusiones" ] ] ] 4 => array:2 [ "identificador" => "xpalclavsec970504" "titulo" => "Palabras clave" ] 5 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 6 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Search strategies" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Inclusion criteria" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Types of outcomes measures" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Data extraction and synthesis" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Statistical issues" ] ] ] 7 => array:3 [ "identificador" => "sec0040" "titulo" => "Results" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0045" "titulo" => "Studies description" ] 1 => array:2 [ "identificador" => "sec0050" "titulo" => "Risk of bias Assessment" ] 2 => array:3 [ "identificador" => "sec0055" "titulo" => "Effects of interventions" "secciones" => array:4 [ 0 => array:2 [ "identificador" => "sec0060" "titulo" => "5-ALA" ] 1 => array:2 [ "identificador" => "sec0065" "titulo" => "5-ALA-related adverse events" ] 2 => array:2 [ "identificador" => "sec0070" "titulo" => "MAL" ] 3 => array:2 [ "identificador" => "sec0075" "titulo" => "MAL-related adverse events" ] ] ] ] ] 8 => array:2 [ "identificador" => "sec0080" "titulo" => "Discussion" ] 9 => array:2 [ "identificador" => "sec0085" "titulo" => "Sponsoring" ] 10 => array:2 [ "identificador" => "sec0090" "titulo" => "Conflict of interest" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2016-12-07" "fechaAceptado" => "2017-05-07" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec970505" "palabras" => array:4 [ 0 => "Photodamage" 1 => "Rejuvenation" 2 => "Photoaging" 3 => "Photodynamic therapy" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec970504" "palabras" => array:4 [ 0 => "Fotodaño" 1 => "Rejuvenecimiento" 2 => "Fotoenvejecimiento" 3 => "Terapia fotodinámica" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:3 [ "titulo" => "Abstract" "resumen" => "IntroductionPhotodynamic therapy (PDT) involves the combination of a light source and a photosensitizing agent to induce tissue damage via the generation of singlet oxygen. Although topical PDT has been approved for other indications, its use in facial photodamage is uncertain. AimsTo assess the efficacy and safety of PDT in facial skin photoaging. MethodsAll randomized clinical trials (RCTs) evaluating the efficacy and safety of any form of topical PDT for the treatment of facial photodamage (dermatoheliosis) or photoaging in patients older than 18 years, were included. Photodynamic-therapy using any topical photosensitizing agent at any dose, and with any light-source, were considered. Comparators were chemical exfoliation, intense pulsed light (IPL), light emitting diodes (LED), dermabrasion or microdermabrasion, ablative or non-ablative lasers, injectables, surgery, placebo and/or no treatment.A systematic search in PubMed, Embase, Lilacs, Google Scholar and RCT's registry databases, was performed. ResultsSearch was conducted up to May 4th 2016. Four authors independently selected and assessed methodological quality of each RCT. According to inclusion criteria, twelve studies were included (6 aminolevulinate (ALA) trials and 6 methyl aminolevulinate (MAL) trials), but the majority of them had methodological constraints particularly in randomization description and patients/outcome assessors blindness. Discussion and conclusionsOverall results indicated that PDT either with ALA or with MAL was effective and safe for facial photodamage treatment, but high quality of evidence was found mainly for MAL studies." "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0010" "titulo" => "Introduction" ] 1 => array:2 [ "identificador" => "abst0015" "titulo" => "Aims" ] 2 => array:2 [ "identificador" => "abst0020" "titulo" => "Methods" ] 3 => array:2 [ "identificador" => "abst0025" "titulo" => "Results" ] 4 => array:2 [ "identificador" => "abst0030" "titulo" => "Discussion and conclusions" ] ] ] "es" => array:3 [ "titulo" => "Resumen" "resumen" => "IntroducciónLa terapia fotodinámica (TF) incluye una combinación de una fuente de luz y un agente fotosensibilizante para inducir daño tisular a través de la generación de oxígeno singlete. Aunque la TF se ha aprobado para otras indicaciones, su uso en el fotodaño facial resulta incierto. ObjetivoValorar la eficacia y seguridad de la TF en el fotoenvejecimiento de la piel del rostro. MétodosSe incluyeron todos los ensayos clínicos aleatorizados (ECA) que evalúan la eficacia y seguridad de cualquier forma de TF tópica para el tratamiento del fotodaño facial (dermatoheliosis) o fotoenvejecimiento en pacientes mayores de 18 años. Se consideró la TF que utiliza cualquier dosis de agente fotosensibilizante, así como cualquier fuente lumínica. Los comparadores fueron: exfoliación química, luz pulsada intensa (IPL), diodo emisor de luz (LED), dermoabrasión o microdermoabrasión, láseres ablativos o no ablativos, inyectables, cirugía, placebo y/o ausencia de tratamiento.Se llevó a cabo una búsqueda sistemática en las bases de datos de los registros de PubMed, Embase, Lilacs, Google Scholar y ECA. ResultadosLa búsqueda se realizó hasta el mes de mayo de 2016. Cuatro autores seleccionaron y valoraron de manera independiente la calidad metodológica de cada ECA. Con arreglo a los criterios de inclusión, se incluyeron 12 estudios (6 ensayos sobre aminolevulinato [ALA] y 6 sobre metiloaminolevulinato [MAL]), aunque la mayoría de ellos contenían limitaciones metodológicas, particularmente en cuanto a la descripción de la aleatorización y la valoración a ciegas de los asesores de los pacientes/resultados. Discusión y conclusionesLos resultados generales indicaron que la TF, tanto con ALA como con MAL, era una terapia efectiva y segura para el tratamiento del fotodaño facial, aunque se encontró evidencia de alta calidad principalmente en los estudios realizados sobre MAL." "secciones" => array:5 [ 0 => array:2 [ "identificador" => "abst0035" "titulo" => "Introducción" ] 1 => array:2 [ "identificador" => "abst0040" "titulo" => "Objetivo" ] 2 => array:2 [ "identificador" => "abst0045" "titulo" => "Métodos" ] 3 => array:2 [ "identificador" => "abst0050" "titulo" => "Resultados" ] 4 => array:2 [ "identificador" => "abst0055" "titulo" => "Discusión y conclusiones" ] ] ] ] "apendice" => array:1 [ 0 => array:1 [ "seccion" => array:1 [ 0 => array:4 [ "apendice" => "<elsevierMultimedia ident="upi0005"></elsevierMultimedia>" "etiqueta" => "Appendix A" "titulo" => "Supplementary data" "identificador" => "sec0100" ] ] ] ] "multimedia" => array:14 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2622 "Ancho" => 2337 "Tamanyo" => 304781 ] ] "descripcion" => array:1 [ "en" => "PRISMA flow diagram." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 928 "Ancho" => 2314 "Tamanyo" => 192382 ] ] "descripcion" => array:1 [ "en" => "Risk of bias graph. Review Manager (RevMan) software, version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2014, Copenhagen, Denmark)." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1093 "Ancho" => 2318 "Tamanyo" => 247778 ] ] "descripcion" => array:1 [ "en" => "Risk of bias summary graph. Review Manager (RevMan) software, version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2014, Copenhagen, Denmark)." ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 391 "Ancho" => 2336 "Tamanyo" => 104738 ] ] "descripcion" => array:1 [ "en" => "Forest plot of comparison: 5-ALA+IPL vs IPL alone, outcome: Global Photodamage failure to improve with n=20 subjects (40 split-faces). Review Manager (RevMan) software, version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2014, Copenhagen, Denmark)." ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Figure 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 424 "Ancho" => 2336 "Tamanyo" => 104978 ] ] "descripcion" => array:1 [ "en" => "5-ALA+IPL vs IPL alone, outcome: 3.1 Failure to improve according to a global score of photoaging (analysis was performed with n=26 patients (52 splitfaces)). The 2 patients that were excluded were labeled as not improved in the 5-ALA+IPL intervention group. Review Manager (RevMan) software, version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2014, Copenhagen, Denmark)." ] ] 5 => array:7 [ "identificador" => "fig0030" "etiqueta" => "Figure 6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr6.jpeg" "Alto" => 379 "Ancho" => 2336 "Tamanyo" => 109979 ] ] "descripcion" => array:1 [ "en" => "Forest plot of comparison: liposome encapsulated 5-ALA+IPL vs IPL alone, outcome: 5.1 Failure to improve periorbital wrinkles. n=37 subjects (74 splitfaces). Review Manager (RevMan) software, version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2014, Copenhagen, Denmark)." ] ] 6 => array:7 [ "identificador" => "fig0050" "etiqueta" => "Figure 7" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr7.jpeg" "Alto" => 385 "Ancho" => 2336 "Tamanyo" => 102723 ] ] "descripcion" => array:1 [ "en" => "Forest plot of comparison: MAL+red light+fractional laser vs fractional laser, outcome: 2.1 Failure to achieve good cosmetics results. Review Manager (RevMan) software, version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2014, Copenhagen, Denmark)." ] ] 7 => array:7 [ "identificador" => "fig0035" "etiqueta" => "Figure 8" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr8.jpeg" "Alto" => 340 "Ancho" => 2336 "Tamanyo" => 111530 ] ] "descripcion" => array:1 [ "en" => "Forest plot of comparison: 3h MAL incubation+red light vs 1h MAL incubation+red light, outcome: 4.1 Failure to improve fine lines. The excluded patient was labeled as a failure in the 1h MAL incubation group. n=10 subjects (20 split-faces). Review Manager (RevMan) software, version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2014, Copenhagen, Denmark)." ] ] 8 => array:7 [ "identificador" => "fig0040" "etiqueta" => "Figure 9" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr9.jpeg" "Alto" => 375 "Ancho" => 2336 "Tamanyo" => 112391 ] ] "descripcion" => array:1 [ "en" => "Forest plot of comparison: 6 MAL+red light vs placebo+red light, outcome: 6.1 Global Photodamage failure to improve. n=98 split-faces. The subject who discontinued treatment due to an adverse reaction was labeled as a failure in the MAL+red light group. Review Manager (RevMan) software, version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, 2014, Copenhagen, Denmark)." ] ] 9 => array:7 [ "identificador" => "fig0055" "etiqueta" => "Figure 10" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr10.jpeg" "Alto" => 366 "Ancho" => 2336 "Tamanyo" => 114460 ] ] "descripcion" => array:1 [ "en" => "Forest plot of comparison: MAL+daylight vs Placebo+daylight, outcome: 7.1 Global Photodamage failure to improve. n=60 subjects (60 whole faces). Review Manager (RevMan) software, version 5.3 (The Nordic Cochrane Center, The Cochrane Collaboration, 2014, Copenhagen, Denmark)." ] ] 10 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:2 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">5-ALA for facial photodamage? \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient or population: Facial Photodamage \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Setting: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Intervention: 5-ALA \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Comparison: Any intervention \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1712371.png" ] ] 1 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Outcomes \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Anticipated absolute effects<a class="elsevierStyleCrossRef" href="#tblfn0025">*</a> (95% CI)</th><th class="td" title="table-head " align="left" valign="top" scope="col">Relative effect (95% CI) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">No. of participants (studies) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Quality of the evidence (GRADE) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Comments \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk with any intervention \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk with 5-ALA \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Failure to improve according to a Global Photodamage scale \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">550 per 1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">198 per 1000 (77–523) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RR 0.36 (0.14–0.95) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">40 (1 RCT) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">–<a class="elsevierStyleCrossRef" href="#tblfn0005">a</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed, a full recommendation cannot be made. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Failure to improve according to a global score of photoaging \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">154 per 1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">115 per 1000 (29–466) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RR 0.75 (0.19–3.03) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">52 (1 RCT) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">–<a class="elsevierStyleCrossRef" href="#tblfn0010">b</a>,<a class="elsevierStyleCrossRef" href="#tblfn0015">c</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed, a full recommendation cannot be made. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Failure to improve periorbital wrinkles \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">378 per 1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">299 per 1000 (155–568) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RR 0.79 (0.41–1.50) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">74 (1 RCT) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">–<a class="elsevierStyleCrossRef" href="#tblfn0020">d</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed, a full recommendation cannot be made. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1712372.png" ] ] ] "notaPie" => array:5 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "The method of sequence generation was not reported. The method used for allocation concealment was not described. It was a single-blinded (investigator) study. Patient's satisfaction outcome could have been influenced by participants unblinding. A blinded investigator evaluated photodamage improvement but tolerability assessment was performed by an unblinded investigator. All split-faces were included in the analysis and follow-ups were performed in all patients. Patient's satisfaction through photographs evaluation was not specified in the methods section, but was included in the abstract and in the discussion section of the manuscript. Telangiectasia and erythema results were only depicted in the discussion section. Sample size calculation was not specified. The power of the study might have led to non-statistical significant differences in some outcomes at different time-points. Fluence changes might have influenced the results. Baseline characteristics of groups were not included." ] 1 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "b" "nota" => "The method of sequence generation was not reported. The method used for allocation concealment was not described. Although the study was labeled as double-blind, it was unclear who was also blinded besides the outcome assessors. A blinded “independent” investigator evaluated outcomes but it was unclear if assessments were performed clinically or through the photographs taken. Measures used to assure outcome assessor's blinding were not included in the article. An ITT analysis was not performed. Two patients withdrew from the study: one due to an allergy to IPL, but it was unclear which side of the face (or whole face) was affected. In the other excluded patient, it was unclear if not meeting study requirements was related to the type of intervention received. The exclusion of these 2 patients in the analysis might have influenced the results due to the low power of the study. Selective reporting was not detected. This was an industry-sponsored trial with positive results, with scarce specific data on potential conflicts of interest. Sample size calculation was not specified. Variations in IPL parameters according to individual features might have influenced final results. Baseline characteristics of groups were not included." ] 2 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "c" "nota" => "An ITT analysis was not performed. Two patients withdrew from the study. The exclusion of these 2 patients in the analysis might have influenced the results due to the low power of the study." ] 3 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "d" "nota" => "Sample size calculation was not specified. The low power of the study might have led to non-statistical significant differences in outcomes when contralateral comparisons were made." ] 4 => array:3 [ "identificador" => "tblfn0025" "etiqueta" => "*" "nota" => "The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: confidence interval; RR: risk ratio. GRADE Working Group grades of evidence: High quality: we are very confident that the true effect lies close to that of the estimate of the effect. Moderate quality: we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. Low quality: our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect. Very low quality: we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect." ] ] ] "descripcion" => array:1 [ "en" => "Summary of findings." ] ] 11 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:2 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">MAL for Facial Photodamage \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient or population: Facial Photodamage \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Setting: \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Intervention: MAL \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Comparison: any intervention \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1712374.png" ] ] 1 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Outcomes \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Anticipated absolute effects<a class="elsevierStyleCrossRef" href="#tblfn0050">*</a> (95% CI)</th><th class="td" title="table-head " align="left" valign="top" scope="col">Relative effect (95% CI) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">No. of participants (studies) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Quality of the evidence (GRADE) \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col">Comments \t\t\t\t\t\t\n \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk with Any intervention \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk with MAL \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="" valign="top" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Failure to achieve good cosmetics results \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">500 per 1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">100 per 1000 (5–1000) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RR 0.20 (0.01–3.20) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">8 (1 study) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">–<a class="elsevierStyleCrossRef" href="#tblfn0030">a</a>,<a class="elsevierStyleCrossRef" href="#tblfn0035">b</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed, a full recommendation cannot be made. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Failure to improve fine lines \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">300 per 1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">99 per 1000 (12–807) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RR 0.33 (0.04–2.69) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">20 (1 study) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">–<a class="elsevierStyleCrossRef" href="#tblfn0040">c</a>,<a class="elsevierStyleCrossRef" href="#tblfn0045">d</a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed, a full recommendation cannot be made. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Global Photodamage failure to improve \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">980 per 1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">39 per 1000 (10–157) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RR 0.04 (0.01–0.16) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">98 (1 study) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed, a full recommendation cannot be made. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Global Photodamage failure to improve \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">900 per 1000 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">171 per 1000 (72–378) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RR 0.19 (0.08–0.42) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">60 (1 study) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed, a full recommendation cannot be made. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab1712373.png" ] ] ] "notaPie" => array:5 [ 0 => array:3 [ "identificador" => "tblfn0030" "etiqueta" => "a" "nota" => "The method of sequence generation was not reported. The method used for allocation concealment was not described. Measures used for blinding were not specified. It was not clear if patients were blinded for satisfaction assessment. Quote: “A blinded investigator evaluated each side of the perioral area”. All split-faces were included in the analysis. Safety outcome was not specified in the methods section, but was included in the analysis. Only superficial wrinkles were evaluated but other photodamage features were not included. Baseline characteristics of groups were not included. Potential conflicts of interests and financial support were not described." ] 1 => array:3 [ "identificador" => "tblfn0035" "etiqueta" => "b" "nota" => "Neither sample size calculation nor statistical tests used in analysis, were specified. The low power of the study might have led to non-statistical significant differences." ] 2 => array:3 [ "identificador" => "tblfn0040" "etiqueta" => "c" "nota" => "The method of sequence generation was not reported. The method used for allocation concealment was not described. It was unclear if the study was single or double-blinded. A blinded investigator evaluated photodamage improvement through baseline vs post-treatment patient's photographs but blinding of side effects assessment was not specified. Measures used to assure outcome assessor's blinding were not described. Nine out of ten patients completed follow-ups. No intention to treat analysis (ITT) was specified. Safety outcome was not specified in the methods section, but was included in the results section of the manuscript. Side-effects outcomes were measured as ordinal variables but in the analysis section these were treated statistically as quantitative variables. A qualitative comparison of clinical facial photodamage improvement was performed from baseline vs post-treatment in the same split-face, but there were neither contralateral comparisons, nor statistical comparisons for this outcome. 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Photodynamic Therapy Interventions in Facial Photodamage: A Systematic Review

Terapia fotodinámica en el fotodaño facial: revisión sistemática

G. Sanclementea,b,

Corresponding author

sanclementegloria@gmail.com
gsanclementem@gmail.com

Corresponding author.

, V. Ruiz-Cañasa, J.M. Mirandaa, A.P. Ferrína, P.A. Ramireza, G.N. Hernandeza

a Grupo de Investigación Dermatológica (GRID), Universidad de Antioquia, Medellín, Colombia

b IPS Universitaria, Universidad de Antioquia, Medellín, Colombia

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">The interplay of intrinsic &#40;age-related decline of cutaneous cellular functions and&#47;or genetic predisposition&#41; and extrinsic factors &#40;exposure to ultraviolet &#40;UV&#41; radiation&#44; smoking or environmental changes&#41; all lead to visible skin changes that result from an abnormal water distribution in tissue&#44; &#40;or a lack of hygroscopic substances&#41;&#44; from an increase in skin pH&#44; and from a prevailed oxidative cell metabolism that overwhelms local antioxidant activity&#46; Those changes as a whole are usually referred as photodamage or actinic damage&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">1&#44;2</span></a> Such disturbances result in a dry appearance of the skin&#44; in an increase in skin surface pH and in a continuous production of reactive oxygen species &#40;ROS&#41; in mitochondria due to an oxidative cell metabolism and a decrease in antioxidant activity&#46;<a class="elsevierStyleCrossRefs" href="#bib0290"><span class="elsevierStyleSup">3&#44;4</span></a> Keratinocyte functional disturbances also occur due to a decreased mitotic activity and a 50&#37;-increase in keratinocyte-migration time from the basal cell layer to the stratum corneum and an increase in cell-cycle duration&#46;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">5&#44;6</span></a> Skin aging is also accompanied by spinous cell layer atrophy and dermo-epidermal junction flattening which both contribute to skin fragility&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">6</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Aged skin is also characterized by an overall collagen synthesis reduction via the diminution of procollagen production&#44; a down regulation of the transforming growth factor-b &#40;TGF-b&#41; type II receptor &#40;a major regulator of dermal extracellular matrix &#40;ECM&#41; synthesis&#41;&#44; and by a disturbed TGF-b activity that also stimulates fibroblast proliferation&#46;<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">7&#8211;10</span></a> Skin collagen is also affected by UV-induced matrix metalloproteinases &#40;MMP&#41;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">11</span></a> such as MMP-1 &#40;fibroblast collagenase&#41;&#44; MMP-9 &#40;gelatinase&#41; and MMP-3 &#40;stromelysin&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">10&#44;12</span></a> and solar elastosis seems to be a consequence of an increased production of elastic fibers and elastin degradation by MMP-12 &#40;human macrophage metalloelastase&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">10&#44;13&#8211;15</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">Photodynamic therapy &#40;PDT&#41; is a selective therapeutic modality that combines an oxygen rich environment and a light source that stimulates a photosensitizing agent to produce singlet oxygen which is highly toxic to the cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">16&#44;17</span></a> Porphyrins and particularly hematoporphyrins &#40;e&#46;g&#46;&#58; photofrin&#41; were the first intravenous substances used for PDT&#44; characterized by their long-term accumulation in target tissue that required rigorous photoprotection for several weeks after administration&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">17</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">In 1990 new topical porphyrins such as 5-aminolevulinic acid &#40;ALA&#41; or its methyl ester &#40;MAL&#41; emerged&#44; which could both easily penetrate the epidermis and produce short-term circumscribed photosensitivity&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">18</span></a> More recently&#44; hexylester 5-aminolevulinate &#40;HAL&#41; has been proposed to induce formation of high concentrations of PpIX in neoplastic tissue&#44; but its use is still experimental&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">19</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">These molecules intervene in heme biosynthesis intracellular pathway&#44; by inducing the formation of a photoactive porphyrin known as protoporphyrin IX &#40;PpIX&#41;&#44; which is an efficient photosensitizer that accumulates particularly in photodamaged skin&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">17</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">PDT requires either an incoherent&#47;coherent light source that should be ideally specific to the chromophore&#47;photosensitizer used&#46; Incoherent light devices include a continuous-wave red light &#40;635<span class="elsevierStyleHsp" style=""></span>nm&#41;&#44; blue light &#40;417<span class="elsevierStyleHsp" style=""></span>nm&#41; and intense-pulsed light &#40;IPL&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">20</span></a> whereas lasers are among the most used coherent light equipment&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">20</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">As photosensitizers can either localize in lysosomes&#44; mitochondria&#44; Golgi apparatus&#44; endoplasmic reticulum&#44; and plasma membranes&#44; PDT effects are a consequence of how PS interact with cells within the target tissue&#47;organ or tumor&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">21&#44;22</span></a> Moreover&#44; it seems that PDT direct DNA cellular damage can occur via modifications of guanine moiety and through strand breaks at uracil and thymine sites&#44; whereas indirect DNA disruption is explained by deactivation of repairing enzymes by free radicals and singlet oxygen production&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">23</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">In addition&#44; skin effects of topical PDT include solar elastosis improvement and neocollagenesis via the induction of expression of collagen type I&#47;III production&#44; MMP-1&#44;-3&#44;-9 and-12 down-regulation&#44; and TGF &#946; up-regulation&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">10&#44;24</span></a> Photodynamic therapy with MAL has also been reported to increase dermal thickness and to improve collagen&#44; elastic tissue and perifollicular fibrosis in treated skin&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">25&#44;26</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Several procedures have been used for actinic damage treatment &#40;e&#46;g&#46;&#58; chemical exfoliation&#44; topical retinoids&#44; lasers&#44; intense pulsed light &#40;IPL&#41; and LEDs &#40;light emitting diodes&#41;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0395"><span class="elsevierStyleSup">24&#44;27&#8211;34</span></a> However&#44; and according to a systematic review&#44; there is limited scientific evidence to support the preferential use of any of these therapies in photodamaged skin&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">35</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Up to know&#44; topical PDT use in the treatment of photodamage is still off-label&#46; Therefore&#44; as uncertainty still remains in this field&#44; this paper aims to assess published scientific evidence to establish the efficacy and safety of such therapy&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Methods</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Search strategies</span><p id="par0055" class="elsevierStylePara elsevierViewall">We aimed to identify all relevant published or unpublished RCTs regardless of language&#46; Searches were performed during the last 10 years&#44; and updated up to 4 May 2016&#46; Search terms with results are depicted in Supplementary Material 1&#46; Trial registries were scanned up to December 15&#44; 2015&#44; using the search terms&#58; &#8220;photodamage&#8221;&#44; &#8220;photoaging&#8221;&#44; &#8220;photodynamic therapy&#8221; and &#8220;photodynamic rejuvenation&#8221; &#40;Supplementary Material 2&#41;&#46; We also checked for relevant references in included and excluded studies&#46; If full text of the articles was not available&#44; we tried to contact authors&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">We did not perform a separate search for adverse effects of the specified intervention&#46; However&#44; we examined data on adverse effects from all included studies&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Inclusion criteria</span><p id="par0065" class="elsevierStylePara elsevierViewall">All parallel randomized controlled trials &#40;RCTs&#41; of PDT for facial photodamage &#40;dermatoheliosis&#41;&#47;photoaging and&#47;or photodynamic rejuvenation that included adult participants diagnosed with facial photodamage &#40;dermatoheliosis&#41; or photoaging&#44; and who have been treated with any PDT-based rejuvenation procedure&#44; were included&#46; Any photodynamic-based intervention for photodamage &#40;dermatoheliosis&#41; or photoaging was considered&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Types of outcomes measures</span><p id="par0070" class="elsevierStylePara elsevierViewall">Primary endpoints included&#58; &#40;1&#41; the proportion of participants who had an improvement&#47;failure in global facial photodamage&#59; &#40;2&#41; quality of life &#40;QoL&#41; changes measured through any validated and recognized generic or disease-specific instrument&#59; &#40;3&#41; any adverse events&#44; safety and tolerability&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">Secondary outcomes corresponded to&#58; &#40;1&#41; the proportion of participants who had an improvement&#47;failure in facial hyperpigmentation&#44; wrinkles&#44; sallowness&#44; erythema or roughness according to a validated and&#47;or recognized generic or disease-specific instrument&#59; &#40;2&#41; change in facial cosmetic appearance&#59; &#40;3&#41; participant satisfaction&#59; &#40;4&#41; pain evaluation after the photodynamic-based procedure&#44; and &#40;5&#41; cost effectiveness studies&#44; if available&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Data extraction and synthesis</span><p id="par0080" class="elsevierStylePara elsevierViewall">Four authors &#40;V&#46;R&#46;&#44; J&#46;M&#46;&#44; A-P F&#46;&#44; G&#46; S&#46;&#41; checked the searched titles and abstracts&#46; Potentially relevant studies were selected for full-text review&#46; All authors independently assessed whether each study met the predefined selection criteria&#44; and differences were resolved by discussion&#46; The same four authors performed data extraction in pre-established data collection formats and independently assessed the risk of bias of included studies as low&#44; high or unclear according to a domain-based evaluation described in the <span class="elsevierStyleItalic">Cochrane Handbook for Systematic Reviews of Interventions</span><a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">36</span></a> &#40;e&#46;g&#46;&#58; &#8216;sequence generation&#8217;&#59; &#8216;allocation concealment&#8217;&#59; &#8216;blinding&#8217;&#59; &#8216;outcome data&#8217;&#59; &#8216;selective reporting&#8217; and other sources of bias&#41; that could put it at high risk of bias &#40;e&#46;g&#46; baseline imbalance&#41;&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Statistical issues</span><p id="par0085" class="elsevierStylePara elsevierViewall">We planned to include only parallel designed trials&#46; Dichotomous outcomes data were presented as reported in each individual study&#46; However&#44; if sufficient data were available&#44; outcomes data were presented as relative risks &#40;RR&#41; with their associated 95&#37; confidence intervals &#40;CIs&#41; and analyzed them in the Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Centre&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#44; using the Mantel&#8211;Haenszel test&#44; unless we stated otherwise&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">We re-analyzed the data originally described according to an intention to treat &#40;ITT&#41; principle&#44; whenever possible&#46; If study authors conducted a per-protocol analysis&#44; we evaluated potential imbalances in the dropout rate between the trial arms to determine bias&#46; If treatment by allocation population was unavailable&#44; we used an available case population and reported this accordingly&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">We planned to evaluate clinical&#44; statistical&#44; and methodological heterogeneity&#46; Statistical heterogeneity was planned to be tested by using the <span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span> statistic&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">36</span></a> If substantial heterogeneity &#40;<span class="elsevierStyleItalic">I</span><span class="elsevierStyleSup">2</span> greater than 60&#37;&#41; was found for the primary outcomes&#44; we planned to explore reasons for heterogeneity&#46; As at least ten studies suitable for meta-analysis were needed for funnel plot asymmetry testing&#44;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">37</span></a> we were unable to perform such test&#46; Also&#44; as we were unable to identify an adequate number of homogenous studies &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>3&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">38</span></a> we did not perform a meta-analysis but we summarized the data for each trial qualitatively&#46; The number of studies was also inadequate to perform subgroup and sensitivity analysis&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Results</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Studies description</span><p id="par0100" class="elsevierStylePara elsevierViewall">After removal of duplicates our searches retrieved 1293 references&#46; Further to titles and abstracts examination&#44; we excluded 1235 references from the review&#46; We obtained full-text copies of the remaining 51 records for further evaluation&#44; and after evaluation&#44; 39 studies were excluded&#46; Reasons for their exclusion are depicted in Supplementary Material 3&#46; Exclusions were made only after assessment of the full-text reports&#46; The most frequent reason for exclusion was that they were non-RCTs&#46; Regarding ongoing studies&#44; we only identified one ongoing study&#44; which is in the recruiting phase &#40;Supplementary Material 3&#41;&#46; Re-analysis of retrieved data was not necessary&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">All retrieved studies were published in English&#46; Thirteen references to 12 studies were finally included&#44; as one same trial had two reports<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">25&#44;39</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; A total of 286 participants &#40;135 patients from ALA studies and 151 from MAL studies&#41; were evaluated&#46; Among these&#44; 30 were men and 212 women&#44; but in 2 studies&#44; gender of participants was not specified<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">28&#44;40</span></a> &#40;Supplementary Material 4&#41;&#46; The age of the participants ranged from 35 to 82 years&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">Among all 12 included randomized trials&#44; 6 studies used ALA and 6 MAL&#44; as chromophores&#46; Only 2 studies used a placebo as control<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41</span></a> and 10 had an active control treatment arm&#46; Studies were published from year 2004 until 2015&#46; Four studies were conducted in the USA&#44;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">28&#44;42&#8211;44</span></a> four in South America&#44;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#8211;41&#44;45</span></a> 2 in Spain&#44;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">27&#44;46</span></a> 1 in Denmark&#44;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">47</span></a> and one in China&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">48</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">The range number of participants included in the individual studies varied from 4 to 60 participants&#46; Ten studies had a split-face design whereas 2 had a full-face design&#46; All patients were diagnosed with mild to severe facial photodamage&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">The included studies evaluated the following interventions&#58; &#40;1&#41; IPL vs IPL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>5-ALA in a split-face design<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">28&#44;44&#44;48</span></a>&#59; &#40;2&#41; laser fractional resurfacing alone vs laser fractional resurfacing<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light in a split-face design<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">46</span></a>&#59; &#40;3&#41; MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light with 1<span class="elsevierStyleHsp" style=""></span>h incubation vs MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light with 3<span class="elsevierStyleHsp" style=""></span>h incubation in a split-face design<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">27</span></a>&#59; &#40;4&#41; IPL waveband from 530 to 750<span class="elsevierStyleHsp" style=""></span>nm and short pulse durations &#40;J&#47;cm<span class="elsevierStyleSup">2</span>&#44; 2&#8211;2&#46;5<span class="elsevierStyleHsp" style=""></span>ms&#44; delay 10<span class="elsevierStyleHsp" style=""></span>ms&#41;<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>0&#46;5&#37; liposome encapsulated vs IPL &#40;waveband from 400 to 720<span class="elsevierStyleHsp" style=""></span>nm&#41;&#44; three passes were performed &#40;3&#46;5<span class="elsevierStyleHsp" style=""></span>J&#47;cm<span class="elsevierStyleSup">2</span>&#44; 30<span class="elsevierStyleHsp" style=""></span>ms pulse duration&#41;&#44; also in a split-face design<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">47</span></a>&#59; &#40;5&#41; blue light at different incubation times<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>5-ALA in a split-face design<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">42</span></a>&#59; &#40;6&#41; IPL vs IPL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>5-ALA in a full-face design<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">40</span></a>&#59; &#40;7&#41; MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light with 3<span class="elsevierStyleHsp" style=""></span>h incubation vs placebo<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light with 3<span class="elsevierStyleHsp" style=""></span>h incubation in a split-face design<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">39</span></a>&#59; &#40;8&#41; MAL with 1<span class="elsevierStyleHsp" style=""></span>h incubation<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light vs MAL with 1<span class="elsevierStyleHsp" style=""></span>h incubation<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>blue light in a split-face design<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">43</span></a>&#59; &#40;9&#41; MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light vs MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>1&#46;5<span class="elsevierStyleHsp" style=""></span>mm length micro-needling in a split-face design<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">45</span></a>&#59; and &#40;10&#41; MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>h daylight exposure vs placebo<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>2<span class="elsevierStyleHsp" style=""></span>h daylight exposure in a full-face design&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">41</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The majority of included studies &#40;except two<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41</span></a>&#41; did not specify primary and secondary outcomes&#46;</p><p id="par0130" class="elsevierStylePara elsevierViewall">Facial photodamage assessment was performed by the use of several original or modified scales such the Griffith&#39;s&#44; Dover&#39;s&#44; Fitzpatrick&#39;s&#44; or arbitrary scales&#46; Four studies reported that they had applied a &#8220;modified version&#8221; of another previous developed scale&#44;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41&#44;45&#44;48</span></a> but authors did not provide details of how and if their &#8220;modified version&#8221; was tested prior to its use&#46; Only one study assessed intervention&#39;s effects on quality of life &#40;QoL&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">41</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">A large proportion of the trials &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>9&#41; assessed intervention-associated adverse events <span class="elsevierStyleItalic">a priori</span>&#44; either through questionnaires that rated the treatment tolerability&#44; or as skin reactions&#44; such as erythema&#44; dryness&#44; edema&#44; oozing&#44; vesiculation&#44; crusting&#44; pigmentation disturbances&#44; skin atrophy&#44; scarring and desquamation or scaling&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">28</span></a> In addition&#44; several included studies assessed secondary outcomes&#44; but overall&#44; the methods used for measurement and the timing of the assessments were not uniform or clear&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Risk of bias Assessment</span><p id="par0140" class="elsevierStylePara elsevierViewall">Risk of bias for each included study and graphs are depicted in Supplementary Material 4&#44; and <a class="elsevierStyleCrossRefs" href="#fig0010">Figs&#46; 2 and 3</a>&#44; respectively&#46; As one of the reviewers &#40;GS&#41; was the main author of 2 studies&#44; both studies were assessed only by the other 3 assessors&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0145" class="elsevierStylePara elsevierViewall">We assessed the global risk of bias for each included study&#44; and we considered two studies to be at &#8220;low risk of bias&#8221; as both met all criteria across all domains in the Cochrane &#8220;Risk of bias&#8221; assessment tool &#40;plausible bias unlikely to seriously alter the results&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41</span></a> We rated the remaining 10 studies as at &#8220;unclear risk of bias&#8221; &#40;plausible bias that raises some doubt about the result&#41; because one or more criteria were assessed as unclear &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">An important number of included studies &#40;9&#41; provided insufficient detail to enable us to make accurate judgements in respect to the domain &#8220;concealment of the allocation sequence&#8221;&#46;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">27&#44;28&#44;40&#44;42&#8211;44&#44;46&#8211;48</span></a> Indeed&#44; intervention allocations masking through sequentially numbered&#44; opaque&#44; sealed envelopes or pharmacy-controlled allocation was only performed in 2 studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41</span></a> Similarly&#44; the &#8220;blinding of outcome assessors&#8221; domain was unclear in 5 studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">27&#44;40&#44;42&#44;47&#44;48</span></a> and only two studies described blinding of study participants and personnel in sufficient detail&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41</span></a> Also&#44; baseline characteristics of patients or groups were only described in 3 studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41&#44;43</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">Incomplete data of patients lost to follow-up&#44; and subsequent per-protocol analyses were other important sources of potential bias in a number of the included studies&#46; In addition&#44; trial protocol was provided in only two studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41</span></a> Judgements were amended as required&#44; after contact with trial investigator&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">45</span></a> In some other studies authors replied that they no longer had information regarding trial methods<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">42</span></a> and for other studies&#44; we did not obtain a reply from authors&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Effects of interventions</span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">5-ALA</span><p id="par0160" class="elsevierStylePara elsevierViewall">Although 6 studies evaluated the effect of 5-ALA as chromophore&#44; either insufficient data or just baseline vs post-treatment comparisons limited relative risks calculations which could be performed only for 3 studies<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">28&#44;47&#44;48</span></a> &#40;<a class="elsevierStyleCrossRefs" href="#fig0020">Figs&#46; 4&#8211;6</a>&#41;&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><elsevierMultimedia ident="fig0025"></elsevierMultimedia><elsevierMultimedia ident="fig0030"></elsevierMultimedia><p id="par0165" class="elsevierStylePara elsevierViewall">In general&#44; there was a tendency to less treatment failure in ALA-treated split-faces&#46; Also&#44; we were unable to determine primary and secondary endpoints in all 5-ALA studies&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">The effect of ALA in actinic keratosis&#44; as well as in facial photodamage was assessed in 2 studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">40&#44;42</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">Investigator assessment of changes in facial photodamage and participant&#39;s photodamage evaluation were performed through digital standardized photographs in 3 studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0475"><span class="elsevierStyleSup">40&#44;44&#44;47</span></a> and two studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">28&#44;48</span></a> respectively&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">Partial or full sponsoring of ALA trials by the pharmaceutical industry was detected in 4 studies<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">28&#44;40&#44;42&#44;48</span></a> and in 2 studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">44&#44;47</span></a> sponsoring information was lacking&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">Photodamage results according to the timeline at which outcomes were assessed in ALA studies varied from 1 month after last session<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">28&#44;42</span></a>&#44; 2 months after last session&#44;<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">40</span></a> 1&#8211;2 months after last session&#44;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">48</span></a> 3 months after last session&#44;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">47</span></a> and at 1&#44; 3 and 6 months&#44; after last session&#46;<a class="elsevierStyleCrossRef" href="#bib0495"><span class="elsevierStyleSup">44</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">Regarding patient related outcomes&#44; subject satisfaction was evaluated in 4 out of 6 ALA studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">28&#44;42&#44;47&#44;48</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">In general&#44; more erythema&#44; edema and desquamation were reported in the ALA-treated side of the face&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">5-ALA-related adverse events</span><p id="par0200" class="elsevierStylePara elsevierViewall">Herpes simplex reactivation and post-inflammatory hyperpigmentation were reported in Touma et al&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">42</span></a> and in Xi et al&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">48</span></a> studies&#44; respectively&#46;</p><p id="par0205" class="elsevierStylePara elsevierViewall">A summary of findings table of 5-ALA results according to GRADE standards is depicted in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">MAL</span><p id="par0210" class="elsevierStylePara elsevierViewall">Although 6 studies evaluated the effect of MAL as chromophore&#44; the lack of contralateral comparisons or insufficient data allowed the calculation of relative risks only for 4 out of 6 studies &#40;<a class="elsevierStyleCrossRefs" href="#fig0050">Figs&#46; 7&#8211;10</a>&#41;&#46;</p><elsevierMultimedia ident="fig0050"></elsevierMultimedia><elsevierMultimedia ident="fig0035"></elsevierMultimedia><elsevierMultimedia ident="fig0040"></elsevierMultimedia><elsevierMultimedia ident="fig0055"></elsevierMultimedia><p id="par0215" class="elsevierStylePara elsevierViewall">We also were unable to differentiate primary and secondary endpoints in 4 out of 6 studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">27&#44;43&#44;45&#44;46</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">The effect of MAL&#44; actinic keratosis&#44; and in facial photodamage simultaneously was assessed in 2 studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">43&#44;45</span></a> Investigator assessment of photodamage outcomes was performed through digital standardized photographs in 1 study&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">43</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">In general&#44; timelines for photodamage outcome evaluation in MAL trials ranged from 1 to 3 months after last session&#46;</p><p id="par0230" class="elsevierStylePara elsevierViewall">Partial or full sponsoring of trials by the pharmaceutical industry was detected in 3 studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41&#44;43</span></a> Sponsoring details were not described in 2 studies&#44;<a class="elsevierStyleCrossRefs" href="#bib0410"><span class="elsevierStyleSup">27&#44;46</span></a> and one study was developed without any sponsor&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">45</span></a></p><p id="par0235" class="elsevierStylePara elsevierViewall">In respect to patient satisfaction&#44; such outcome was evaluated in 3 studies with better satisfaction scores in the MAL treated split-face&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;43&#44;46</span></a> In addition&#44; just 1 out of the 12 studies &#40;ALA and MAL&#41; included a quality of life outcome&#46;<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">41</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">Overall&#44; erythema&#44; edema and desquamation were more frequently reported in the side of the face that included MAL as chromophore in all studies&#44; except in one study<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">43</span></a> in which no statistical differences between the use of blue vs red light were found&#44; but also mild discomfort was more frequent with red-light exposure&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">MAL-related adverse events</span><p id="par0245" class="elsevierStylePara elsevierViewall">Herpes simplex reactivation was reported in two studies whereas post-inflammatory hyperpigmentation was described in 3 studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41&#44;46</span></a> A severe infection related to the concomitant use of microdermabrasion<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>PDT was reported in 1 out of 10 patients in Torezan et al&#46;&#8217;s<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">45</span></a> study and a severe allergic reaction not related to PDT was reported in another study&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">39</span></a></p><p id="par0250" class="elsevierStylePara elsevierViewall">A summary of findings table of MAL results according to GRADE standards is depicted in <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span></span></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Discussion</span><p id="par0255" class="elsevierStylePara elsevierViewall">To the best of our knowledge&#44; this is the first published systematic review &#40;SR&#41; to assess and examine the evidence for the efficacy and safety of PDT in facial photodamage&#44; and although the full protocol of this SR was not published &#40;just its abstract&#41;&#44; it is available upon request to correspondence author&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">Two high quality studies suggest that MAL-PDT is effective in the treatment of facial photodamage&#44; but low to moderate quality of evidence shows that PDT with ALA seems to be also effective&#46; Although adverse events &#40;AEs&#41; were reported inadequately in most studies&#44; non-serious reported AEs include herpes simplex recurrence and post-inflammatory hyperpigmentation&#44; particularly in studies that included participants with darker skin &#40;3 out of 4 studies with PIH reports&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41&#44;46&#44;48</span></a></p><p id="par0265" class="elsevierStylePara elsevierViewall">The main objectives of a randomized clinical trial are to assess efficacy and safety of an intervention&#46; In this respect&#44; concealment and blinding are key domains in the assessment of risk of bias&#46;<a class="elsevierStyleCrossRefs" href="#bib0520"><span class="elsevierStyleSup">49&#8211;51</span></a> In particular&#44; the methods used to generate the allocation sequence and how the sequence was concealed&#44; are the most important and sensitive indicators that bias has been minimized in a clinical trial&#44; as participants and investigators are masked to the upcoming assignment&#44; and therefore could not &#8220;manipulate&#8221; it&#46; Also&#44; standardization of outcomes and objective measurement are key elements not only for clinical decision making&#44; but also to establish health policies&#46;<a class="elsevierStyleCrossRefs" href="#bib0535"><span class="elsevierStyleSup">52&#8211;54</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">Overall&#44; the evidence provided by this review was limited mainly due to outcome inconsistencies&#44; the lack of description of randomization methods&#47;sequence generation&#44; and a lack of a double-blind trial design&#46; Moreover&#44; the high heterogeneity of studies did not allow a quantitative synthesis of the evidence found&#46; However&#44; there was a tendency for having a better result when PDT with any chromophore was used&#44; when compared to the use of a light source alone&#46;</p><p id="par0275" class="elsevierStylePara elsevierViewall">Most of the included studies in this review were performed before the requirement of trial registration&#46; As a result of insufficient data and the lack of reporting&#44; we were &#8220;forced&#8221; to downgrade the quality of evidence to &#8220;unclear risk of bias&#8221;&#44; as we appraised these studies according to the information contained within the full text of each article&#46; However&#44; more unbiased judgment elements could have been obtained if we were able to get a reply from all authors&#44; but such information could only be gathered from one main author&#46;</p><p id="par0280" class="elsevierStylePara elsevierViewall">In this review&#44; it is unlikely that we have missed studies with an important sample size as we performed a rigorous systematic search of published and unpublished literature and we also tried to contact leading experts&#46; Nonetheless&#44; we cannot absolutely rule out the influence of publication bias&#46; Unfortunately we were unable to reliably assess the presence of publication bias&#44; given the small number of included studies&#46; Also&#44; we attempted to lower potential biases in the evaluation of two MAL trials<a class="elsevierStyleCrossRefs" href="#bib0470"><span class="elsevierStyleSup">39&#44;41</span></a> performed by one of the reviewers of this systematic review by limiting their assessment only by the other 3 assessors&#46;</p><p id="par0285" class="elsevierStylePara elsevierViewall">The applicability of evidence found by this review corresponds to what is usual in clinical practice&#44;<a class="elsevierStyleCrossRefs" href="#bib0295"><span class="elsevierStyleSup">4&#44;55</span></a> as included trials covered the usual age spectrum of participants who seek a dermatologist for photodamage therapeutic options&#46; However&#44; it is important to bear in mind that depending on the severity of facial photodamage&#44; patients over 70 years old might not be the best candidates for PDT as they often require more invasive procedures such as resurfacing with ablational lasers and&#47;or surgery&#46; Also&#44; as all included studies had participants with Fitzpatrick&#39;s SPT from I through IV&#44; the applicability of the evidence in SPT V-VI is limited&#46; Similarly&#44; results applicability in men could be affected&#44; as the majority of included participants&#44; were women&#46;</p><p id="par0290" class="elsevierStylePara elsevierViewall">In conclusion&#44; the findings in our review showed that MAL PDT was effective for the treatment of facial photodamage&#44; but also have highlighted that only a small number of published trials have followed the Consolidated Standards of Reporting Trials &#40;CONSORT-Statement&#41; and the criteria of evidence-based medicine&#46; Such standards are necessary to heighten evidence strength and quality in future trials design&#46; Also&#44; as there is a relative paucity of long-term evaluations of the effect of PDT in facial photodamage and in quality of life&#44; such knowledge gaps deserve further research&#46;</p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Sponsoring</span><p id="par0295" class="elsevierStylePara elsevierViewall">This work was supported by the Group of Investigative Dermatology-GRID of the <span class="elsevierStyleGrantSponsor" id="gs1">Universidad de Antioquia</span>&#44; Medellin&#44; Colombia and by the <span class="elsevierStyleGrantSponsor" id="gs2">Fundacion Dermabase</span>&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Conflict of interest</span><p id="par0300" class="elsevierStylePara elsevierViewall">Dr&#46; Gloria Sanclemente has participated in advisory boards and has received honoraria and scientific meeting support from Galderma Laboratories&#46;</p><p id="par0305" class="elsevierStylePara elsevierViewall">Dr&#46; Veronica Ruiz Ca&#241;as has received scientific meeting support from Galderma Laboratories&#46;</p><p id="par0310" class="elsevierStylePara elsevierViewall">Dr&#46; Jenny Marcela Miranda Orozco has received scientific meeting support from Galderma Laboratories&#46;</p><p id="par0315" class="elsevierStylePara elsevierViewall">Dr&#46; Alba Patricia Ferr&#237;n Bastidas has received scientific meeting support from Galderma Laboratories&#46;</p><p id="par0320" class="elsevierStylePara elsevierViewall">Paola Andrea Ramirez has nothing to disclose</p><p id="par0325" class="elsevierStylePara elsevierViewall">Gilma Hernandez has nothing to disclose&#46;</p></span></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Photodynamic therapy &#40;PDT&#41; involves the combination of a light source and a photosensitizing agent to induce tissue damage via the generation of singlet oxygen&#46; Although topical PDT has been approved for other indications&#44; its use in facial photodamage is uncertain&#46;</p></span> <span id="abst0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Aims</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">To assess the efficacy and safety of PDT in facial skin photoaging&#46;</p></span> <span id="abst0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Methods</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">All randomized clinical trials &#40;RCTs&#41; evaluating the efficacy and safety of any form of topical PDT for the treatment of facial photodamage &#40;dermatoheliosis&#41; or photoaging in patients older than 18 years&#44; were included&#46; Photodynamic-therapy using any topical photosensitizing agent at any dose&#44; and with any light-source&#44; were considered&#46; Comparators were chemical exfoliation&#44; intense pulsed light &#40;IPL&#41;&#44; light emitting diodes &#40;LED&#41;&#44; dermabrasion or microdermabrasion&#44; ablative or non-ablative lasers&#44; injectables&#44; surgery&#44; placebo and&#47;or no treatment&#46;</p><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">A systematic search in PubMed&#44; Embase&#44; Lilacs&#44; Google Scholar and RCT&#39;s registry databases&#44; was performed&#46;</p></span> <span id="abst0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Results</span><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Search was conducted up to May 4th 2016&#46; Four authors independently selected and assessed methodological quality of each RCT&#46; According to inclusion criteria&#44; twelve studies were included &#40;6 aminolevulinate &#40;ALA&#41; trials and 6 methyl aminolevulinate &#40;MAL&#41; trials&#41;&#44; but the majority of them had methodological constraints particularly in randomization description and patients&#47;outcome assessors blindness&#46;</p></span> <span id="abst0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Discussion and conclusions</span><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Overall results indicated that PDT either with ALA or with MAL was effective and safe for facial photodamage treatment&#44; but high quality of evidence was found mainly for MAL studies&#46;</p></span>"
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          0 => array:2 [
            "identificador" => "abst0010"
            "titulo" => "Introduction"
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          1 => array:2 [
            "identificador" => "abst0015"
            "titulo" => "Aims"
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          2 => array:2 [
            "identificador" => "abst0020"
            "titulo" => "Methods"
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          3 => array:2 [
            "identificador" => "abst0025"
            "titulo" => "Results"
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          4 => array:2 [
            "identificador" => "abst0030"
            "titulo" => "Discussion and conclusions"
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        "titulo" => "Resumen"
        "resumen" => "<span id="abst0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Introducci&#243;n</span><p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">La terapia fotodin&#225;mica &#40;TF&#41; incluye una combinaci&#243;n de una fuente de luz y un agente fotosensibilizante para inducir da&#241;o tisular a trav&#233;s de la generaci&#243;n de ox&#237;geno singlete&#46; Aunque la TF se ha aprobado para otras indicaciones&#44; su uso en el fotoda&#241;o facial resulta incierto&#46;</p></span> <span id="abst0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Objetivo</span><p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Valorar la eficacia y seguridad de la TF en el fotoenvejecimiento de la piel del rostro&#46;</p></span> <span id="abst0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">M&#233;todos</span><p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Se incluyeron todos los ensayos cl&#237;nicos aleatorizados &#40;ECA&#41; que eval&#250;an la eficacia y seguridad de cualquier forma de TF t&#243;pica para el tratamiento del fotoda&#241;o facial &#40;dermatoheliosis&#41; o fotoenvejecimiento en pacientes mayores de 18 a&#241;os&#46; Se consider&#243; la TF que utiliza cualquier dosis de agente fotosensibilizante&#44; as&#237; como cualquier fuente lum&#237;nica&#46; Los comparadores fueron&#58; exfoliaci&#243;n qu&#237;mica&#44; luz pulsada intensa &#40;IPL&#41;&#44; diodo emisor de luz &#40;LED&#41;&#44; dermoabrasi&#243;n o microdermoabrasi&#243;n&#44; l&#225;seres ablativos o no ablativos&#44; inyectables&#44; cirug&#237;a&#44; placebo y&#47;o ausencia de tratamiento&#46;</p><p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">Se llev&#243; a cabo una b&#250;squeda sistem&#225;tica en las bases de datos de los registros de PubMed&#44; Embase&#44; Lilacs&#44; Google Scholar y ECA&#46;</p></span> <span id="abst0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Resultados</span><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">La b&#250;squeda se realiz&#243; hasta el mes de mayo de 2016&#46; Cuatro autores seleccionaron y valoraron de manera independiente la calidad metodol&#243;gica de cada ECA&#46; Con arreglo a los criterios de inclusi&#243;n&#44; se incluyeron 12 estudios &#40;6 ensayos sobre aminolevulinato &#91;ALA&#93; y 6 sobre metiloaminolevulinato &#91;MAL&#93;&#41;&#44; aunque la mayor&#237;a de ellos conten&#237;an limitaciones metodol&#243;gicas&#44; particularmente en cuanto a la descripci&#243;n de la aleatorizaci&#243;n y la valoraci&#243;n a ciegas de los asesores de los pacientes&#47;resultados&#46;</p></span> <span id="abst0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Discusi&#243;n y conclusiones</span><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">Los resultados generales indicaron que la TF&#44; tanto con ALA como con MAL&#44; era una terapia efectiva y segura para el tratamiento del fotoda&#241;o facial&#44; aunque se encontr&#243; evidencia de alta calidad principalmente en los estudios realizados sobre MAL&#46;</p></span>"
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            "titulo" => "Introducci&#243;n"
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            "titulo" => "Objetivo"
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          2 => array:2 [
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            "titulo" => "M&#233;todos"
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            "titulo" => "Resultados"
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            "titulo" => "Discusi&#243;n y conclusiones"
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            "apendice" => "<p id="par0335" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="upi0005"></elsevierMultimedia></p>"
            "etiqueta" => "Appendix A"
            "titulo" => "Supplementary data"
            "identificador" => "sec0100"
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          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Risk of bias graph&#46; Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Centre&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#46;</p>"
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          "en" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Forest plot of comparison&#58; 5-ALA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>IPL vs IPL alone&#44; outcome&#58; Global Photodamage failure to improve with <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>20 subjects &#40;40 split-faces&#41;&#46; Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Centre&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#46;</p>"
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        "etiqueta" => "Figure 5"
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          "en" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">5-ALA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>IPL vs IPL alone&#44; outcome&#58; 3&#46;1 Failure to improve according to a global score of photoaging &#40;analysis was performed with <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>26 patients &#40;52 splitfaces&#41;&#41;&#46; The 2 patients that were excluded were labeled as not improved in the 5-ALA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>IPL intervention group&#46; Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Centre&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#46;</p>"
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        "etiqueta" => "Figure 6"
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          "en" => "<p id="spar0095" class="elsevierStyleSimplePara elsevierViewall">Forest plot of comparison&#58; liposome encapsulated 5-ALA<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>IPL vs IPL alone&#44; outcome&#58; 5&#46;1 Failure to improve periorbital wrinkles&#46; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>37 subjects &#40;74 splitfaces&#41;&#46; Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Centre&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#46;</p>"
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        "identificador" => "fig0050"
        "etiqueta" => "Figure 7"
        "tipo" => "MULTIMEDIAFIGURA"
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        "descripcion" => array:1 [
          "en" => "<p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">Forest plot of comparison&#58; MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>fractional laser vs fractional laser&#44; outcome&#58; 2&#46;1 Failure to achieve good cosmetics results&#46; Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Centre&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#46;</p>"
        ]
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        "etiqueta" => "Figure 8"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">Forest plot of comparison&#58; 3<span class="elsevierStyleHsp" style=""></span>h MAL incubation<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light vs 1<span class="elsevierStyleHsp" style=""></span>h MAL incubation<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light&#44; outcome&#58; 4&#46;1 Failure to improve fine lines&#46; The excluded patient was labeled as a failure in the 1<span class="elsevierStyleHsp" style=""></span>h MAL incubation group&#46; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>10 subjects &#40;20 split-faces&#41;&#46; Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Centre&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#46;</p>"
        ]
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        "etiqueta" => "Figure 9"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
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        "descripcion" => array:1 [
          "en" => "<p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">Forest plot of comparison&#58; 6 MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light vs placebo<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light&#44; outcome&#58; 6&#46;1 Global Photodamage failure to improve&#46; n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>98 split-faces&#46; The subject who discontinued treatment due to an adverse reaction was labeled as a failure in the MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>red light group&#46; Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Centre&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#46;</p>"
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        "etiqueta" => "Figure 10"
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        "mostrarFloat" => true
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          "en" => "<p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">Forest plot of comparison&#58; MAL<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>daylight vs Placebo<span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span>daylight&#44; outcome&#58; 7&#46;1 Global Photodamage failure to improve&#46; <span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>60 subjects &#40;60 whole faces&#41;&#46; Review Manager &#40;RevMan&#41; software&#44; version 5&#46;3 &#40;The Nordic Cochrane Center&#44; The Cochrane Collaboration&#44; 2014&#44; Copenhagen&#44; Denmark&#41;&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">5-ALA for facial photodamage&#63;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient or population&#58; Facial Photodamage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Setting&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Intervention&#58; 5-ALA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Comparison&#58; Any intervention&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Outcomes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Anticipated absolute effects<a class="elsevierStyleCrossRef" href="#tblfn0025"><span class="elsevierStyleSup">&#42;</span></a> &#40;95&#37; CI&#41;</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Relative effect &#40;95&#37; CI&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">No&#46; of participants &#40;studies&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Quality of the evidence &#40;GRADE&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Comments&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk with any intervention&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk with 5-ALA&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Failure to improve according to a Global Photodamage scale&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">550 per 1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">198 per 1000 &#40;77&#8211;523&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RR 0&#46;36 &#40;0&#46;14&#8211;0&#46;95&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">40 &#40;1 RCT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed&#44; a full recommendation cannot be made&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Failure to improve according to a global score of photoaging&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">154 per 1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">115 per 1000 &#40;29&#8211;466&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RR 0&#46;75 &#40;0&#46;19&#8211;3&#46;03&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">52 &#40;1 RCT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed&#44; a full recommendation cannot be made&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Failure to improve periorbital wrinkles&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">378 per 1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">299 per 1000 &#40;155&#8211;568&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RR 0&#46;79 &#40;0&#46;41&#8211;1&#46;50&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">74 &#40;1 RCT&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed&#44; a full recommendation cannot be made&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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              "identificador" => "tblfn0005"
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">The method of sequence generation was not reported&#46; The method used for allocation concealment was not described&#46; It was a single-blinded &#40;investigator&#41; study&#46; Patient&#39;s satisfaction outcome could have been influenced by participants unblinding&#46; A blinded investigator evaluated photodamage improvement but tolerability assessment was performed by an unblinded investigator&#46; All split-faces were included in the analysis and follow-ups were performed in all patients&#46; Patient&#39;s satisfaction through photographs evaluation was not specified in the methods section&#44; but was included in the abstract and in the discussion section of the manuscript&#46; Telangiectasia and erythema results were only depicted in the discussion section&#46; Sample size calculation was not specified&#46; The power of the study might have led to non-statistical significant differences in some outcomes at different time-points&#46; Fluence changes might have influenced the results&#46; Baseline characteristics of groups were not included&#46;</p>"
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            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">The method of sequence generation was not reported&#46; The method used for allocation concealment was not described&#46; Although the study was labeled as double-blind&#44; it was unclear who was also blinded besides the outcome assessors&#46; A blinded &#8220;independent&#8221; investigator evaluated outcomes but it was unclear if assessments were performed clinically or through the photographs taken&#46; Measures used to assure outcome assessor&#39;s blinding were not included in the article&#46; An ITT analysis was not performed&#46; Two patients withdrew from the study&#58; one due to an allergy to IPL&#44; but it was unclear which side of the face &#40;or whole face&#41; was affected&#46; In the other excluded patient&#44; it was unclear if not meeting study requirements was related to the type of intervention received&#46; The exclusion of these 2 patients in the analysis might have influenced the results due to the low power of the study&#46; Selective reporting was not detected&#46; This was an industry-sponsored trial with positive results&#44; with scarce specific data on potential conflicts of interest&#46; Sample size calculation was not specified&#46; Variations in IPL parameters according to individual features might have influenced final results&#46; Baseline characteristics of groups were not included&#46;</p>"
            ]
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              "identificador" => "tblfn0015"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0015">An ITT analysis was not performed&#46; Two patients withdrew from the study&#46; The exclusion of these 2 patients in the analysis might have influenced the results due to the low power of the study&#46;</p>"
            ]
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              "identificador" => "tblfn0020"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Sample size calculation was not specified&#46; The low power of the study might have led to non-statistical significant differences in outcomes when contralateral comparisons were made&#46;</p>"
            ]
            4 => array:3 [
              "identificador" => "tblfn0025"
              "etiqueta" => "&#42;"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0025">The risk in the intervention group &#40;and its 95&#37; confidence interval&#41; is based on the assumed risk in the comparison group and the relative effect of the intervention &#40;and its 95&#37; CI&#41;&#46; CI&#58; confidence interval&#59; RR&#58; risk ratio&#46;</p> <p class="elsevierStyleNotepara" id="npar0030">GRADE Working Group grades of evidence&#58;</p> <p class="elsevierStyleNotepara" id="npar0035">High quality&#58; we are very confident that the true effect lies close to that of the estimate of the effect&#46;</p> <p class="elsevierStyleNotepara" id="npar0040">Moderate quality&#58; we are moderately confident in the effect estimate&#58; the true effect is likely to be close to the estimate of the effect&#44; but there is a possibility that it is substantially different&#46;</p> <p class="elsevierStyleNotepara" id="npar0045">Low quality&#58; our confidence in the effect estimate is limited&#58; the true effect may be substantially different from the estimate of the effect&#46;</p> <p class="elsevierStyleNotepara" id="npar0050">Very low quality&#58; we have very little confidence in the effect estimate&#58; the true effect is likely to be substantially different from the estimate of effect&#46;</p>"
            ]
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        ]
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          "en" => "<p id="spar0120" class="elsevierStyleSimplePara elsevierViewall">Summary of findings&#46;</p>"
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                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">MAL for Facial Photodamage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Patient or population&#58; Facial Photodamage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Setting&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Intervention&#58; MAL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Comparison&#58; any intervention&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="table-head ; entry_with_role_rowhead " align="left" valign="top" scope="col">Outcomes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " colspan="2" align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Anticipated absolute effects<a class="elsevierStyleCrossRef" href="#tblfn0050"><span class="elsevierStyleSup">&#42;</span></a> &#40;95&#37; CI&#41;</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Relative effect &#40;95&#37; CI&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">No&#46; of participants &#40;studies&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Quality of the evidence &#40;GRADE&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col">Comments&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr><tr title="table-row"><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk with Any intervention&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Risk with MAL&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th><th class="td" title="table-head  " align="" valign="top" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Failure to achieve good cosmetics results&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">500 per 1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">100 per 1000 &#40;5&#8211;1000&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RR 0&#46;20 &#40;0&#46;01&#8211;3&#46;20&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">8 &#40;1 study&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;<a class="elsevierStyleCrossRef" href="#tblfn0030"><span class="elsevierStyleSup">a</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#tblfn0035"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed&#44; a full recommendation cannot be made&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Failure to improve fine lines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">300 per 1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">99 per 1000 &#40;12&#8211;807&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RR 0&#46;33 &#40;0&#46;04&#8211;2&#46;69&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">20 &#40;1 study&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;<a class="elsevierStyleCrossRef" href="#tblfn0040"><span class="elsevierStyleSup">c</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#tblfn0045"><span class="elsevierStyleSup">d</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed&#44; a full recommendation cannot be made&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Global Photodamage failure to improve&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">980 per 1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">39 per 1000 &#40;10&#8211;157&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RR 0&#46;04 &#40;0&#46;01&#8211;0&#46;16&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">98 &#40;1 study&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed&#44; a full recommendation cannot be made&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="table-entry ; entry_with_role_rowhead " align="left" valign="top">Global Photodamage failure to improve&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">900 per 1000&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">171 per 1000 &#40;72&#8211;378&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">RR 0&#46;19 &#40;0&#46;08&#8211;0&#46;42&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">60 &#40;1 study&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="table-entry  " align="left" valign="top">As this review assessed the quality of evidence of individual trials and a meta-analysis could not be performed&#44; a full recommendation cannot be made&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "nota" => "<p class="elsevierStyleNotepara" id="npar0055">The method of sequence generation was not reported&#46; The method used for allocation concealment was not described&#46; Measures used for blinding were not specified&#46; It was not clear if patients were blinded for satisfaction assessment&#46; Quote&#58; &#8220;A blinded investigator evaluated each side of the perioral area&#8221;&#46; All split-faces were included in the analysis&#46; Safety outcome was not specified in the methods section&#44; but was included in the analysis&#46; Only superficial wrinkles were evaluated but other photodamage features were not included&#46; Baseline characteristics of groups were not included&#46; Potential conflicts of interests and financial support were not described&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0035"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0060">Neither sample size calculation nor statistical tests used in analysis&#44; were specified&#46; The low power of the study might have led to non-statistical significant differences&#46;</p>"
            ]
            2 => array:3 [
              "identificador" => "tblfn0040"
              "etiqueta" => "c"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0065">The method of sequence generation was not reported&#46; The method used for allocation concealment was not described&#46; It was unclear if the study was single or double-blinded&#46; A blinded investigator evaluated photodamage improvement through baseline vs post-treatment patient&#39;s photographs but blinding of side effects assessment was not specified&#46; Measures used to assure outcome assessor&#39;s blinding were not described&#46; Nine out of ten patients completed follow-ups&#46; No intention to treat analysis &#40;ITT&#41; was specified&#46; Safety outcome was not specified in the methods section&#44; but was included in the results section of the manuscript&#46; Side-effects outcomes were measured as ordinal variables but in the analysis section these were treated statistically as quantitative variables&#46; A qualitative comparison of clinical facial photodamage improvement was performed from baseline vs post-treatment in the same split-face&#44; but there were neither contralateral comparisons&#44; nor statistical comparisons for this outcome&#46; Baseline characteristics of groups were not included&#46;</p>"
            ]
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              "identificador" => "tblfn0045"
              "etiqueta" => "d"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0070">Sample size calculation was not specified&#46; The lack of an ITT analysis could have an impact in efficacy results due to the small sample size of the study&#46; Similarly&#44; the low power of the study might have led to non-statistical significant differences in all outcomes&#46;</p>"
            ]
            4 => array:3 [
              "identificador" => "tblfn0050"
              "etiqueta" => "&#42;"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0075">The risk in the intervention group &#40;and its 95&#37; confidence interval&#41; is based on the assumed risk in the comparison group and the relative effect of the intervention &#40;and its 95&#37; CI&#41;&#46; CI&#58; confidence interval&#59; RR&#58; risk ratio&#46;</p> <p class="elsevierStyleNotepara" id="npar0080">GRADE Working Group grades of evidence&#58;</p> <p class="elsevierStyleNotepara" id="npar0085">High quality&#58; we are very confident that the true effect lies close to that of the estimate of the effect&#46;</p> <p class="elsevierStyleNotepara" id="npar0090">Moderate quality&#58; we are moderately confident in the effect estimate&#58; the true effect is likely to be close to the estimate of the effect&#44; but there is a possibility that it is substantially different&#46;</p> <p class="elsevierStyleNotepara" id="npar0095">Low quality&#58; our confidence in the effect estimate is limited&#58; the true effect may be substantially different from the estimate of the effect&#46;</p> <p class="elsevierStyleNotepara" id="npar0100">Very low quality&#58; we have very little confidence in the effect estimate&#58; the true effect is likely to be substantially different from the estimate of effect&#46;</p>"
            ]
          ]
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        "descripcion" => array:1 [
          "en" => "<p id="spar0150" class="elsevierStyleSimplePara elsevierViewall">Summary of findings&#46;</p>"
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    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:55 [
            0 => array:3 [
              "identificador" => "bib0280"
              "etiqueta" => "1"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Mechanisms of photoaging and chronological skin aging"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46;J&#46; Fisher"
                            1 => "S&#46; Kang"
                            2 => "J&#46; Varani"
                            3 => "Z&#46; Bata-Csorgo"
                            4 => "Y&#46; Wan"
                            5 => "S&#46; Datta"
                          ]
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Article information

ISSN: 15782190
Original language: English

DOI:10.1016/j.adengl.2017.05.026

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2023 November	70	49	119
2023 October	53	24	77
2023 September	66	35	101
2023 August	46	12	58
2023 July	79	37	116
2023 June	75	23	98
2023 May	63	27	90
2023 April	39	19	58
2023 March	44	22	66
2023 February	66	20	86
2023 January	61	40	101
2022 December	67	34	101
2022 November	17	22	39
2022 October	23	46	69
2022 September	28	36	64
2022 August	20	37	57
2022 July	24	38	62
2022 June	34	25	59
2022 May	47	42	89
2022 April	52	49	101
2022 March	62	55	117
2022 February	55	31	86
2022 January	67	38	105
2021 December	50	45	95
2021 November	55	58	113
2021 October	47	65	112
2021 September	38	38	76
2021 August	28	45	73
2021 July	39	45	84
2021 June	40	34	74
2021 May	78	62	140
2021 April	151	96	247
2021 March	116	41	157
2021 February	86	56	142
2021 January	66	49	115
2020 December	66	51	117
2020 November	45	48	93
2020 October	34	17	51
2020 September	50	24	74
2020 August	40	31	71
2020 July	49	22	71
2020 June	30	34	64
2020 May	19	10	29
2020 April	21	16	37
2020 March	19	17	36
2020 February	2	0	2
2020 January	2	0	2
2019 December	8	0	8
2019 November	4	0	4
2019 September	10	0	10
2019 August	4	0	4
2019 July	3	0	3
2019 June	4	0	4
2019 May	6	0	6
2019 April	2	0	2
2019 March	2	0	2
2019 February	2	0	2
2018 December	4	0	4
2018 November	4	0	4
2018 September	3	0	3
2018 June	0	1	1
2018 April	2	2	4

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