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Mayla Barbosa,1 Rebecca Perez de Amorim,1 Daniel Cassiano,2 Marina Dias,1 Ana Flávia de Abreu,1 Edileia Bagatin,2 Hélio Amante Miot,1 Ana Cláudia Cavalcante Espósito1 1Department of Dermatology, Faculdade de Medicina de Botucatu (UNESP), Botucatu, SP, Brazil; 2Department of Dermatology, Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, BrazilCorrespondence: Ana Cláudia Cavalcante Espósito, Department of Dermatology, Faculdade de Medicina de Botucatu, UNESP Medical School, Botucatu, SP, Brazil, Email anaclaudiaesposito@gmail.comBackground: Nicotinamide has demonstrated efficacy in the treatment of melasma. Topical antioxidants and humectants may enhance its performance. Currently, there is no controlled trial on the combination of 10% nicotinamide, 5% magnesium ascorbyl phosphate, and 5% hyaluronic acid, a dermo-cosmetic compound, in comparison to 4% hydroquinone for the treatment of melasma. This study aimed to explore the tolerability and efficacy of the association of the combined product versus hydroquinone.Methods: A randomized, double-blind trial involving women with facial melasma was conducted. Participants were instructed to apply the combined product (NIC group) twice daily or 4% hydroquinone for 60 days (HQ group) at night and placebo in the morning. Evaluations were performed at inclusion, after 14 and 60 days of treatment, measuring the modified Melasma Area and Severity Index (mMASI), Melasma Quality of Life Scale (MELASQoL), and colorimetric luminosity. The Global Aesthetic Improvement Scale (GAIS) was assessed by a blinded evaluator.Results: Both interventions led to a progressive improvement in mMASI, MELASQoL, and GAIS, without a difference between them on D14 and D60 (p> 0.2). For NIC, the mean reduction (95% CI) in mMASI was 16% (8– 24%) on D14 and 32% (23– 41%) on D60, while for HQ, it was 10% (7– 24%) on D14 and 43% (34– 52%) on D60. Reduction in colorimetric luminosity was greater in the HQ group at D60 (p=0.01). No serious side effects were identified. Of the initially included 50 patients, one was lost to follow-up in the HQ group on D60, and one withdrew consent from the NIC group, both unrelated to treatment.Conclusion: The association of 10% nicotinamide, 5% magnesium ascorbyl phosphate, and 5% hyaluronic acid was safe and well-tolerated, although its overall clinical efficacy was numerically inferior to 4% hydroquinone. This regimen can be considered for patients with poor tolerability to hydroquinone.Clinical Trial Registration: #RBR-4mkfmr8.Keywords: melasma, hyperpigmentation, nicotinamide, hydroquinone, antioxidants

Carolina Nunhez da Silva,1 Hélio Amante Miot,1 Tony Fernando Grassi,2 Luciane Alarcão Dias-Melício,2– 4 Leandro Santos,2,3 Ana Cláudia Cavalcante Espósito1 1Department of Dermatology, São Paulo State University (UNESP) - Medical School of Botucatu, Botucatu, São Paulo State, Brazil; 2UNIPEX - Experimental Research Unit, São Paulo State University (UNESP) - Medical School of Botucatu, Botucatu, São Paulo State, Brazil; 3Laboratory of Immunopathology and Infectious Agents – LIAI, São Paulo State University (UNESP) - Medical School of Botucatu, Botucatu, São Paulo State, Brazil; 4Department of Pathology, São Paulo State University (UNESP) - Medical School of Botucatu, Botucatu, São Paulo State, BrazilCorrespondence: Ana Cláudia Cavalcante Espósito, Division of Dermatology and Radiotherapy, São Paulo State University (UNESP) - Medical School of Botucatu, Botucatu, São Paulo State, Brazil, Email anaclaudiaesposito@gmail.comBackground/Objectives: Although melasma is highly prevalent, its pathogenesis is not yet fully understood. In the skin, endothelin-1 (ET-1) is primarily produced by keratinocytes in response to UVB exposure, which is mediated by an increase in IL-1α or reactive oxygen species. ET-1 plays a role in melanogenesis by binding to specific receptor B (ERB) or receptor A (ERA). However, the expression of ET-1, ERA, and ERB in melasma has not been systematically investigated. The objective of this study was to evaluate the expression of ET-1, ERA, and ERB in facial melasma compared to the adjacent unaffected skin.Methods: Cross-sectional study, with 40 skin samples (20: facial melasma; 20: adjacent unaffected skin) from women with facial melasma without treatment for 30 days except for sunscreen. A triple staining immunofluorescence technique was performed for anti-vimentin, DAPI, plus one of the following antibodies: (a) anti-ET1, (b) anti-ERA; (c) anti-ERB. Interfollicular areas on the slides of each topography (melasma; unaffected skin) were photographed in triplicate under confocal laser microscopy. The mean staining intensities of the image histograms (0– 255 pixels intensity) were estimated for different types of cells (suprabasal keratinocytes, basal layer, and upper dermis) and were blindly compared between topographies.Results: The mean (SD) age of the participants was 44.9 (9.2). The expression of ET-1 was increased in the whole epidermis with melasma when compared to the adjacent skin, being 32.8% (CI95% 14.7%– 52.6%) higher in the spinous layer (p=0.013), 30.4% (CI95% 13.7%– 47.9%) higher in the basal layer (p=0.014), and 29.7% (CI95% 11.4%– 49.7%) higher in the melanocytes (p=0.006). There was no noticeable expression of ET-1 within the cells on the upper dermis. Neither ERA nor ERB resulted in differential epidermal expression between melasma and unaffected skin (p≥ 0.1).Conclusion: ET-1 is expressed more intensely on the epidermis from the skin with facial melasma compared to the unaffected adjacent skin.Keywords: melasma, immunofluorescence technique, endothelin-1, endothelin receptor-A, endothelin receptor-B

Intervention studies require all participants to originate from the same population, with random allocation to intervention groups to ensure comparability. Randomization is crucial for minimizing confounding factors, allowing differences in outcomes to be attributed to the intervention. Simple randomization performs well for large samples (>100 per group), but smaller samples may require block or stratified randomization to balance group sizes and covariates. When randomization isn't feasible, quasi-randomized methods (e.g., based on dates or enrollment order) can help but must compensate with multivariate adjustments. Moreover, blinding and allocation concealment enhance internal validity and reproducibility. Allocation concealment (e.g., sealed envelopes) prevents bias during participant assignment while blinding mitigates detection and performance biases. Precise methodological descriptions in clinical trial registrations and publications enhance study reliability and reproducibility, highlighting the importance of rigorous planning and transparent reporting in intervention research. This article reviews the key concepts of randomization, blinding, and allocation concealment in interventional studies., Competing Interests: Conflicts of interest: No conflicts of interest declared concerning the publication of this article., (Copyright© 2024 The authors.)

Background Melasma is an acquired dyschromia with several histologic alterations in the epidermis, basement membrane and upper dermis. The treatment of melasma is challenging due to the irregular response and chronicity of the disease. To date, there are no curative strategies, largely due to the limited understanding of the intrinsic effects of each treatment. Objectives The objective of the study was to evaluate the histological changes promoted by triple combination cream, with or without complementary treatment with microneedling and oral tranexamic acid, in the treatment of melasma. Methods A factorial, randomised, controlled and evaluator-blinded clinical trial was performed involving 64 women with facial melasma, divided in four groups, who underwent 60 days of treatment with triple combination cream alone (control group) or combined with two monthly microneedling sessions (microneedling group), TA 250 mg twice daily (tranexamic acid group), or both tranexamic acid group and microneedling group. The participants underwent biopsy of the area with melasma at inclusion (D1) and D60. The primary outcomes were the variation (D1 × D60) between the variables: Thickness of the epidermis and stratum corneum, stratum corneum compaction and solar elastosis; melanin density in the epidermis and upper dermis; proportion between the extension of the nonintact and intact basement membrane zone; mast cell count in the upper dermis; melanocyte count in the basal layer, pendulum melanocyte count and melanocyte area; immunostaining density of vascular endothelial growth factor; stem cell factor and keratinocyte growth factor. Results One participant in the TG discontinued tranexamic acid due persistent headache; and herpes simplex occurred in three patients after microneedling. The groups showed a 24% (CI95%: 17-35%; P < 0.01) reduction in epidermal melanin density. There was no change in dermal melanin density or the area of melanocytes after treatment. There was an overall 25% (CI95%: 7-42%; P < 0.01) reduction in the number of pendulum melanocytes, especially in the microneedling and tranexamic acid group, that presented a 41% (CI95%: 7-73%; P < 0.01) reduction. The extension of the nonintact basal membrane relative to the intact basal membrane decreased after treatment, especially in microneedling group and microneedling and tranexamic acid group. There was an increase of 13% (CI95%: 5-21%; P = 0.02) in epidermal thickness and 6% (CI95%: 0-22%; P = 0.04) thinning of the stratum corneum in the groups. All groups showed stratum corneum compaction. Solar elastosis improved only in the microneedling group and microneedling and tranexamic acid group. Vascular endothelial growth factor immunostaining increased 14% (CI95%: 4-24%; P = 0.03) in the groups; and stem cell factor increased only in microneedling group. There was no change in the number of mast cells, CD34 and keratinocyte growth factor immunostaining. Limitations The site of biopsy may not represent all of the facial melasma and the immunohistochemical sensitivity of the cytokines does not have a stoichiometric relationship with proteins. Conclusion A greater thickness of the epidermis is associated with melasma bleaching. Dermal melanin seems to have no impact on melasma prognosis. Damage to the skin barrier and stimulus of angiogenesis should be avoided in the treatment of melasma. Microneedling complements the topical treatment of melasma by improving patterns of skin photoaging. Oral tranexamic acid complements the topical treatment of melasma by inhibiting the stem cell factor.

Background: In addition to melanocytic hyperfunction, changes are observed in the upper dermis of melasma, and fibroblasts play a central role in collagen synthesis and pigmentation induction., Objective: To explore the morphology, growth rate, and gene expression profile of fibroblasts from the skin with melasma in comparison to fibroblasts from the adjacent healthy skin., Methods: Ten women with facial melasma were biopsied (lesion and adjacent healthy skin), and the fragments were processed for fibroblast culture. Samples from five participants were seeded to evaluate growth (days 2, 5 and 8) and senescence (SA-β-gal) curves. The samples from the other participants were submitted to real-time PCR to comparatively evaluation of the expression of 39 genes., Results: Cultured fibroblasts from melasma skin were morphologically less fusiform in appearance and on average a 34% (95% CI 4%‒63%) greater proportion of cells labeled with SA-β-gal than the fibroblasts from the adjacent skin. The cell growth rate was lower for the melasma samples after eight days (p < 0.01). TheWNT3A, EDN3, ESR2, PTG2, MMP1, and SOD2 genes were up-regulated, whereas the COL4A1, CSF2, DKK3, COL7A1, TIMP4, CCL2, and CDH11 genes were down-regulated in melasma skin fibroblasts when compared to the ones from adjacent healthy skin., Study Limitations: Small sample size; absence of functional tests., Conclusions: Fibroblasts from the skin with melasma showed a lower growth rate, less fusiform morphology and greater accumulation of SA-β-gal than those from adjacent photo exposed skin. Moreover, their gene expression profile comprised factors that may contribute to upper dermis damage and sustained melanogenesis., (Copyright © 2022 Sociedade Brasileira de Dermatologia. Published by Elsevier España, S.L.U. All rights reserved.)

Melasma is a multifactorial dyschromia that results from exposure to external factors (such as solar radiation) and hormonal factors (such as sex hormones and pregnancy), as well as skin inflammation (such as contact dermatitis and esthetic procedures), in genetically predisposed individuals. Beyond hyperfunctional melanocytes, skin with melasma exhibits a series of structural and functional alterations in the epidermis, basement membrane, and upper dermis that interact to elicit and sustain a focal hypermelanogenic phenotype. Evolution in the knowledge of the genetic basis of melasma and the cutaneous response to solar radiation, as well as the roles of endocrine factors, antioxidant system, endothelium proliferation, fibroblast senescence, mast cell degranulation, autophagy deficits of the melanocyte, and the paracrine regulation of melanogenesis, will lead to the development of new treatments and preventive strategies. This review presents current knowledge on these aspects of the pathogenesis of melasma and discusses the effects of specific treatments and future research on these issues., (© 2022. The Author(s).)

Melasma is a prevalent chronic relapsing pigmentary disorder that affects photoexposed areas, especially in women of childbearing age. Although there is currently no curative treatment available for melasma, this manuscript critically reviews the knowledge regarding photoprotection, topical and oral therapies, and procedures such as peelings, laser, and microneedling that represent the main strategies for control and prevention of this disease. As the pathogenesis of melasma is not entirely understood, there are prospects for the development of new therapeutic strategies that might act on the pathways that promote sustained pigmentation rather than merely decreasing melanin synthesis and removing melanin from the epidermis., (© 2022. The Author(s).)

The pathogenesis of melasma is not fully understood, and the role of skin basement membrane zone (BMZ) alterations in disease development and the maintenance of hypermelanogenesis are also poorly known. We performed a comparative study to characterize the ultrastructural alterations that occur in BMZ in melasma and adjacent normal skin, as well as we discuss the implications of these changes in the physiopathology of the disease. Pairs of facial skin biopsies (2 mm) from 10 women with melasma and normal skin (< 2 cm apart) were processed by Transmission Electronic Microscopy or immunohistochemistry for Melan-A counterstained with Periodic acid-Schiff stain. Cytoplasmic organelles (from keratinocyte or melanocyte), BMZ damage were assessed and melanocyte counting (total and pendulous) was done. There was greater amount of cytoplasmic organelles inside basal keratinocytes and melanocytes in melasma, as well as structural damaged areas in the lamina densa (disruptions, gaps, lower density and thinning) and anchoring fibrils (lamina lucida), compared to healthy adjacent skin. Areas with pendulous melanocytes are characterized by discontinuity of BMZ ultrastructure. The prominence of cytoplasmic organelles from melanocytes and keratinocytes evidences the involvement of both cell groups in melasma. The damage in the lamina densa and lamina lucida suggest the role of upper dermis injury/repair process in the pathogenesis of the disease.

Background: Melasma is a chronic acquired focal hypermelanosis which pathogenesis has not been fully elucidated. Classical pathophysiologic studies have analysed the affected and perilesional areas, but little is known about the status of sun-protected skin, which is subjected to the same endogenous and genetic factors., Objective: To assess the histological characteristics of melasma compared to adjacent and retroauricular skin., Methods: Skin samples were collected from 10 female from: melasma, perilesional area and retroauricular. The samples were stained (haematoxylin-eosin, periodic acid-Schiff, Fontana-Masson, picrosirius red, toluidine blue and Verhoeff), immunolabelled for CD34 and Wnt1. The data from the skin sites were analysed simultaneously by a multivariate model., Results: Melasma skin exhibited noteworthy stratum corneum compaction, greater collagen heterogeneity, solar elastosis, higher number of mast cells, basement membrane zone (BMZ) damage, Wnt1 expression, pendulum melanocytes, higher cellularity and vascular proliferation at the superficial dermis. Stratum corneum compaction, collagen heterogeneity and BMZ abnormalities were variables associated to melasma that not follow a continuum through retroauricular to adjacent skin. Mast cell count was the variable that disclosed correlation with the most other abnormalities as well as had the greater contribution in the multivariate model., Conclusion: In addition to melanocyte hyperactivity, melasma skin exhibits alterations in the epidermal barrier, upper dermis and BMZ, which differ from the adjacent sun-exposed skin and retroauricular skin, indicating a distinct phenotype, rather than a mere extension of photoageing or intrinsic ageing. Mast cells appear to play a central role in the physiopathology of melasma., Competing Interests: CONFLICTS OF INTEREST: The authors have nothing to disclose., (Copyright © 2020 The Korean Dermatological Association and The Korean Society for Investigative Dermatology.)

Background: The physiopathology of epidermal hypermelanization in melasma is not completely understood. Several cytokines and growth factors are increased in skin with melasma, nevertheless, nor the pathways involved in the increased αMSH expression have been adequately evaluated, nor a model for sustained focal melanogenesis is available., Objective: To explore stimulatory pathways for epidermal pigmentation in facial melasma related to αMSH: those linked to ultraviolet radiation, oxidative stress, inflammation, neural crest pigmentation cell differentiation and antagonism of αMSH., Methods: Paired skin biopsies (3 mm) from 26 women with facial melasma and from normal adjacent skin (<2 cm far) were processed for immunofluorescence with markers for p53, p38, αMSH, MC1R, Melan-A, IL-1α, COX2, Wnt1, WIF-1 and ASIP., Results: The fluorescence intensity in the skin from melasma was higher for MC1R, αMSH at epidermis as at melanocytes (P < 0.05). There were no differences between the sites in epidermal protein expression of COX2, IL-1α, p53, WIF-1 and ASIP (P > 0.1). P53 was expressed only in epidermis, without difference between sites (P = 0.92). WNT1 was remarkable in the epidermis of melasma (P < 0.01), but not in dermis. Positive p38 cells were prominent in the upper dermis of melasma (P < 0.01), despite no marking in epidermis., Conclusion: Melanogenesis in melasma involves epithelial secretion of αMSH and activation of the Wnt pathway; nevertheless, it seems to be independent of the stimulation by ultraviolet radiation/p53, IL-1α, COX2/PgE 2 , WIF-1 and ASIP. Damaged cells at upper dermis suggest the role of senescence/autophagy in sustained pigmentation in melasma., (© 2018 Society of Cosmetic Scientists and the Société Française de Cosmétologie.)

Pigeon lice are insects that feed on feathers of these birds; their life cycle includes egg, nymph and adult and they may cause dermatoses in humans. Four persons of the same family, living in an urban area, presented with widespread intensely pruritic erythematous papules. A great number of lice were seen in their house, which moved from a nest of pigeons located on the condenser of the air-conditioning to the dormitory of one of the patients. Even in urban environments, dermatitis caused by parasites of birds is a possibility in cases of acute prurigo simplex. Pigeon lice are possible etiological agents of this kind of skin eruption, although they are often neglected, even by dermatologists.

Milker's nodule is an occupational dermatovirose caused by Parapoxvirus, which is self-limited and, due to the lack of information of health professionals, may lead to underdiagnosis. We present two cases with exuberant manifestations and classic histopathologic findings. Case 1: Male, 19 years of age, milker, presented nodules and blisters on his palm for 15 days. Case 2: Male, 33 years of age, administrative assistant, presented erythematous nodules on his palms with lymphangitis for 5 days. He had milked a cow one week before the onset of the lesions. In both cases, the histopathology was representative and coincident with the clinical hypothesis. The lesions have presented complete involution. Milker's nodule diagnosis is based on clinical presentation, epidemiology, and histopathology. The knowledge of this disease is essential for its correct diagnosis, as well as to guide the implementation of public health measures and the appropriate treatment of sick cattle.