Janus kinase inhibitors and the changing landscape of vitiligo management: a scoping review.

Vitiligo is a chronic skin condition caused by an autoimmune response that results in the progressive loss of melanocytes and recent studies have suggested that Janus kinase inhibitors (JAKi) are emerging as a promising new treatment modality. Therefore, to assess and understand the extent of knowledge in the emerging field of JAKi use in vitiligo, a scoping review of the literature was undertaken. The reviewed articles explored a wide variety of JAKi administered either orally or topically for vitiligo. There were no injectable JAKi studied. Tofacitinib was the most commonly studied oral JAKi in 16 of the 35 studies selected for review, followed by baricitinib (n = 3), and one study each with ritlecitinib, ruxolitinib, and upadacitinib. Ruxolitinib (n = 6) and tofacitinib (n = 6) were the most often studied topical JAKi, followed by delgocitinib (n = 1). Potential benefits may vary between JAKi based on their receptor selectivity profile and coexistent autoimmune diseases. A topical JAKi would be advantageous in limited body area involvement and in adolescents. Concurrent use of JAKi with phototherapy or sun exposure appears beneficial. Most studies permitted the use of other topical agents. Acne-related events, though frequent yet mild, were reported with both oral and topical JAKi. Nasopharyngitis, upper respiratory tract infections, and headaches were the most common adverse effects seen in the larger trials with JAKi. No serious or clinically meaningful hematology or thromboembolic events were detected. Treatment of vitiligo with oral or topical JAKi seems to be promising and the growing evidence shows a favorable risk-benefit profile.

A Malassezia pseudoprotease dominates the secreted hydrolase landscape and is a potential allergen on skin.

Malassezia globosa is abundant and prevalent on sebaceous areas of the human skin. Genome annotation reveals that M. globosa possesses a repertoire of secreted hydrolytic enzymes relevant for lipid and protein metabolism. However, the functional significance of these enzymes is uncertain and presence of these genes in the genome does not always translate to expression at the cutaneous surface. In this study we utilized targeted RNA sequencing from samples isolated directly from the skin to quantify gene expression of M. globosa secreted proteases, lipases, phospholipases and sphingomyelinases. Our findings indicate that the expression of these enzymes is dynamically regulated by the environment in which the fungus resides, as different growth phases of the planktonic culture of M. globosa show distinct expression levels. Furthermore, we observed significant differences in the expression of these enzymes in culture compared to healthy sebaceous skin sites. By examining the in situ gene expression of M. globosa's secreted hydrolases, we identified a predicted aspartyl protease, MGL_3331, which is highly expressed on both healthy and disease-affected dermatological sites. However, molecular modeling and biochemical studies revealed that this protein has a non-canonical active site motif and lacks measurable proteolytic activity. This pseudoprotease MGL_3331 elicits a heightened IgE-reactivity in blood plasma isolated from patients with atopic dermatitis compared to healthy individuals and invokes a pro-inflammatory response in peripheral blood mononuclear cells. Overall, our study highlights the importance of studying fungal proteins expressed in physiologically relevant environments and underscores the notion that secreted inactive enzymes may have important functions in influencing host immunity.

Safety and efficacy of eblasakimab, an interleukin 13 receptor α1 monoclonal antibody, in adults with moderate-to-severe atopic dermatitis: A phase 1b, multiple-ascending dose study.

BACKGROUND: Eblasakimab, an interleukin (IL)-13 receptor α1 antagonist, blocks IL-4 and IL-13 signaling through the type 2 receptor. OBJECTIVE: The safety and efficacy of eblasakimab was evaluated in adults with moderate-to-severe atopic dermatitis (AD). METHODS: In this phase 1b randomized, double-blinded study, 52 patients with moderate-to-severe AD received weekly subcutaneous injections of eblasakimab 200, 400, or 600 mg, or placebo for 8 weeks. Primary outcome was the incidence of treatment-emergent adverse events. Secondary outcomes included percentage change in the Eczema Area and Severity Index from baseline; Eczema Area and Severity Index improvement of at least 50%, 75%, or 90% from baseline; and percentage change in the peak-pruritus numeric rating scale score from baseline. RESULTS: Treatment-emergent adverse events were reported in 47% placebo and 71% eblasakimab patients; most were considered mild or moderate and did not lead to study discontinuation. At week 8 eblasakimab 600 mg showed statistically significant improvement in mean percentage change in Eczema Area and Severity Index versus placebo (-65% vs -27%, P = .014). Other key secondary physician- and patient-reported end points were met. LIMITATIONS: Longer studies are required to confirm eblasakimab safety and efficacy in AD patients. CONCLUSIONS: Treatment of adults with moderate-to-severe AD with eblasakimab was well-tolerated and associated with significant clinical improvements versus placebo.

Bridging the Gap Between Vitiligo Segmentation and Clinical Scores.

Quantitative evaluation of vitiligo is crucial for assessing treatment response. Dermatologists evaluate vitiligo regularly to adjust their treatment plans, which requires extra work. Furthermore, the evaluations may not be objective due to inter- and intra-assessor variability. Though automatic vitiligo segmentation methods provide an objective evaluation, previous methods mainly focus on patch-wise images, and their results cannot be translated into clinical scores for treatment adjustment. Thus, full-body vitiligo segmentation needs to be developed for recording vitiligo changes in different body parts of a patient and for calculating the clinical scores. To bridge this gap, the first full-body vitiligo dataset with 1740 images, following the international vitiligo photo standard, was established. Compared with patch-wise images, full-body images have more complicated ambient light conditions and larger variances in lesion size and distribution. Additionally, in some hand and foot images, skin can be fully covered by either vitiligo or healthy skin. Previous patch-wise segmentation studies completely ignore these cases, as they assume that the contrast between vitiligo and healthy skin is available in each image for segmentation. To address the aforementioned challenges, the proposed algorithm in this study exploits a tailor-made contrast enhancement scheme and long-range comparison. Furthermore, a novel confidence score refinement module is proposed to manage images fully covered by vitiligo or healthy skin. Our results can be converted to clinical scores and used by clinicians. Compared to the state-of-the-art method, the proposed algorithm reduces the average per-image vitiligo involvement percentage error from 3.69% to 1.81%, and the top 10% per-image errors from 23.17% to 8.29%. Our algorithm achieves 1.17% and 3.11% for the mean and max error for the per-patient vitiligo involvement percentage, which is better than an experienced dermatologist's naked-eye evaluation.

Worldwide expert recommendations for the diagnosis and management of vitiligo: Position statement from the International Vitiligo Task Force Part 1: towards a new management algorithm.

BACKGROUND: The treatment of vitiligo can be challenging and depends on several factors such as the subtype, disease activity, vitiligo extent, and treatment goals. Vitiligo usually requires a long-term approach. To improve the management of vitiligo worldwide, a clear and up-to-date guide based on international consensus with uniform stepwise recommendations is needed. OBJECTIVES: To reach an international consensus on the nomenclature and to develop a management algorithm for the diagnosis, assessment, and treatment of vitiligo. METHODS: In this consensus statement, a consortium of 42 international vitiligo experts and four patient representatives participated in online and live meetings to develop a consensus management strategy for vitiligo. At least two vitiligo experts summarized the evidence of topics included in the algorithms. A survey was utilized to resolve remaining issues among a core group of eight experts. Subsequently, the unanimous recommendations were finalized and validated based on further input from the entire group during two live meetings. RESULTS: The algorithms highlight the importance of shared decision-making. Dermatologists are encouraged to provide patients with detailed explanations of the prognosis and expected therapeutic outcomes based on clinical examination. The treatment goal should be discussed and clearly emphasized to patients given the different approaches for disease stabilization and repigmentation. The evaluation of disease activity remains a cornerstone in the tailor-made approach to vitiligo patients. CONCLUSIONS: These new treatment algorithms are intended to guide clinical decision-making in clinical practice. Promising novel therapies for vitiligo are on the horizon, further highlighting the need for reliable outcome measurement instruments and greater emphasis on shared decision-making.

Worldwide expert recommendations for the diagnosis and management of vitiligo: Position statement from the international Vitiligo Task Force-Part 2: Specific treatment recommendations.

BACKGROUND: The treatment of vitiligo can be challenging. Up-to-date agreed consensus recommendations on the use of topical and systemic therapies to facilitate the clinical management of vitiligo are currently lacking. OBJECTIVES: To develop internationally agreed-upon expert-based recommendations for the treatment of vitiligo. METHODS: In this consensus statement, a consortium of 42 international vitiligo experts and four patient representatives participated in different online and live meetings to develop a consensus management strategy for vitiligo. At least two vitiligo experts summarized the evidence for different topics included in the algorithms. A survey was then given to a core group of eight experts to resolve the remaining issues. Subsequently, the recommendations were finalized and validated based on further input from the entire group during two live meetings. RESULTS: The recommendations provided summarize the latest evidence regarding the use of topical therapies (steroids, calcineurin inhibitors and Jak-inhibitors) and systemic therapies, including steroids and other systemic immunomodulating or antioxidant agents. The different modalities of phototherapies (NB-UVB, photochemotherapy, excimer devices and home phototherapy), which are often combined with other therapies, are also summarized. Interventional approaches as well as depigmentation strategies are presented for specific indications. Finally, the status of innovative and targeted therapies under development is discussed. CONCLUSIONS: This international consensus statement culminated in expert-based clinical practice recommendations for the treatment of vitiligo. The development of new therapies is ongoing in vitiligo, and this will likely improve the future management of vitiligo, a disease that still has many unmet needs.

Non-invasive biochemical analysis and comparison of atopic dermatitis and psoriasis skin using handheld confocal Raman spectroscopy.

A handheld non-invasive confocal Raman system (CRS) was used to evaluate the differences in skin biochemicals between atopic dermatitis (AD) and psoriasis, which are inflammatory skin conditions. Raman spectral measurements in the fingerprint and high wavenumber region were acquired using a portable in-house CRS system with excitation lasers operating at 671 and 785 nm. It was deduced that relative amount of water decreases in the following sequence of skin: healthy, psoriasis and AD. Moreover, differential trends were observed for the subclasses of ceramides such that ceramide 3 is lower in the lesional AD and psoriasis skin as compared to healthy, while ceramide 2 showed a contrasting trend of decrease in lesional AD and increase in lesional psoriasis as opposed to healthy skin. Amount of cholesterol was significantly higher in lesional psoriasis as compared to lesional AD and healthy skin. These differences can aid in an objective classification of the skin conditions and in the formulation of new disease-specific topical treatments.

Investigating causal relationships between obesity and skin barrier function in a multi-ethnic Asian general population cohort.

BACKGROUND: Skin diseases impact significantly on the quality of life and psychology of patients. Obesity has been observed as a risk factor for skin diseases. Skin epidermal barrier dysfunctions are typical manifestations across several dermatological disturbances. OBJECTIVES: We aim to establish the association between obesity and skin physiology measurements and investigate whether obesity may play a possible causal role on skin barrier dysfunction. METHODS: We investigated the relationship of obesity with skin physiology measurements, namely transepidermal water loss (TEWL), skin surface moisture and skin pH in an Asian population cohort (n = 9990). To assess for a possible causal association between body mass index (BMI) and skin physiology measurements, we performed Mendelian Randomization (MR), along with subsequent additional analyses to assess the potential causal impact of known socioeconomic and comorbidities of obesity on TEWL. RESULTS: Every 1 kg/m2 increase in BMI was associated with a 0.221% (95%CI: 0.144-0.298) increase in TEWL (P = 2.82E-08), a 0.336% (95%CI: 0.148-0.524) decrease in skin moisture (P = 4.66E-04) and a 0.184% (95%CI: 0.144-0.224) decrease in pH (P = 1.36E-19), adjusting for age, gender, and ethnicity. Relationships for both TEWL and pH with BMI remained strong (Beta 0.354; 95%CI: 0.189-0.520 and Beta -0.170; 95%CI: -0.253 to -0.087, respectively) even after adjusting for known confounders, with MR experiments further supporting BMI's possible causal relationship with TEWL. Based on additional MR performed, none of the socioeconomic and comorbidities of obesity investigated are likely to have possible causal relationships with TEWL. CONCLUSION: We establish strong association of BMI with TEWL and skin pH, with MR results suggestive of a possible causal relationship of obesity with TEWL. It emphasizes the potential impact of obesity on skin barrier function and therefore opportunity for primary prevention.

Understanding Discordant Perceptions of Disease Severity Between Physicians and Patients With Eczema and Psoriasis Using Structural Equation Modeling.

Importance: Patients and physicians often have differing opinions on the patient's disease severity. This phenomenon, termed discordant severity grading (DSG), hinders the patient-physician relationship and is a source of frustration. Objective: To test and validate a model explaining the cognitive, behavioral, and disease factors associated with DSG. Design, Setting, and Participants: A qualitative study was first performed to derive a theoretical model. In this subsequent prospective cross-sectional quantitative study, the qualitatively derived theoretical model was validated using structural equation modeling (SEM). Recruitment was conducted between October 2021 and September 2022. This was a multicenter study in 3 Singapore outpatient tertiary dermatological centers. Dermatology patients and their attending physicians were recruited by convenience sampling. Patients were aged 18 to 99 years with psoriasis or eczema of at least 3 months' duration and recruited only once. The data were analyzed between October 2022 to May 2023. Main Outcomes and Measures: The outcome was the difference between global disease severity (0-10 numerical rating scale with a higher score indicating greater severity) as independently scored by the patient and the dermatologist. Positive discordance was defined as patient-graded severity more than 2 points higher (graded more severely) than physicians, and negative discordance if more than 2 points lower than physicians. Confirmatory factor analysis followed by SEM was used to assess the associations between preidentified patient, physician, and disease factors with the difference in severity grading. Results: Of the 1053 patients (mean [SD] age, 43.5 [17.5] years), a total of 579 (55.0%) patients were male, 802 (76.2%) had eczema, and 251 (23.8%) had psoriasis. Of 44 physicians recruited, 20 (45.5%) were male, 24 (54.5%) were aged between 31 and 40 years, 20 were senior residents or fellows, and 14 were consultants or attending physicians. The median (IQR) number of patients recruited per physician was 5 (2-18) patients. Of 1053 patient-physician pairs, 487 pairs (46.3%) demonstrated discordance (positive, 447 [42.4%]; negative, 40 [3.8%]). Agreement between patient and physician rating was poor (intraclass correlation, 0.27). The SEM analyses showed that positive discordance was associated with higher symptom expression (standardized coefficient B = 0.12; P = .02) and greater quality-of-life impairment (B = 0.31; P < .001), but not patient or physician demographics. A higher quality-of-life impairment was in turn associated with lower resilience and stability (B = -0.23; P < .001), increased negative social comparisons (B = 0.45; P < .001), lower self-efficacy (B = -0.11; P = .02), increased disease cyclicity (B = 0.47; P < .001), and greater expectation of chronicity (B = 0.18; P < .001). The model was well-fitted (Tucker-Lewis: 0.94; Root Mean Square Error of Approximation: 0.034). Conclusions and Relevance: This cross-sectional study identified various modifiable contributory factors to DSG, increased understanding of the phenomenon, and set a framework for targeted interventions to bridge this discordance.

Optimizing Melasma Management With Topical Tranexamic Acid: An Expert Consensus.

Because of its complex pathogenesis, chronicity, and high rates of recurrence, melasma is regarded as a challenging skin disorder. Topical treatments are often offered as first-line therapy. However, many patients are unaware that melasma is recurrent and requires long-term management. Hydroquinone is effective for controlling relapses and has become the standard of care for melasma in many countries. Nonetheless, it is limited by its side effect profile. Certain patient profiles who have had prior therapy and/or are refractory to treatment may be offered an alternative, that is topical tranexamic acid (TXA) alone or in combination with other modalities. This review provides a summary of current evidence on topical TXA as a treatment for certain case profiles. This paper aims to fill knowledge gaps in terms of currently available options, highlighting the role of topical TXA alone or in combination with other active ingredients (ie, topical TXA 2% with patented delivery technology). J Drugs Dermatol. 2023;22(4): doi:10.36849/JDD.7104 Citation: Desai SR, Chan LC, Handog E, et al. Optimizing melasma management with topical tranexamic acid: An expert consensus. J Drugs Dermatol. 2023;22(4):386-392. doi:10.36849/JDD.7104.

The human pathobiont Malassezia furfur secreted protease Mfsap1 regulates cell dispersal and exacerbates skin inflammation.

Malassezia form the dominant eukaryotic microbial community on the human skin. The Malassezia genus possesses a repertoire of secretory hydrolytic enzymes involved in protein and lipid metabolism which alter the external cutaneous environment. The exact role of most Malassezia secreted enzymes, including those in interaction with the epithelial surface, is not well characterized. In this study, we compared the expression level of secreted proteases, lipases, phospholipases, and sphingomyelinases of Malassezia globosa in healthy subjects and seborrheic dermatitis or atopic dermatitis patients. We observed upregulated gene expression of the previously characterized secretory aspartyl protease MGSAP1 in both diseased groups, in lesional and non-lesional skin sites, as compared to healthy subjects. To explore the functional roles of MGSAP1 in skin disease, we generated a knockout mutant of the homologous protease MFSAP1 in the genetically tractable Malassezia furfur. We observed the loss of MFSAP1 resulted in dramatic changes in the cell adhesion and dispersal in both culture and a human 3D reconstituted epidermis model. In a murine model of Malassezia colonization, we further demonstrated Mfsap1 contributes to inflammation as observed by reduced edema and inflammatory cell infiltration with the knockout mutant versus wildtype. Taken together, we show that this dominant secretory Malassezia aspartyl protease has an important role in enabling a planktonic cellular state that can potentially aid in colonization and additionally as a virulence factor in barrier-compromised skin, further highlighting the importance of considering the contextual relevance when evaluating the functions of secreted microbial enzymes.

Multispectral raster-scanning optoacoustic mesoscopy differentiate lesional from non-lesional atopic dermatitis skin using structural and functional imaging markers.

Atopic dermatitis (AD) is a chronic and pruritic skin inflammatory disease causing a significant burden to health care management and patient's quality of life. Seemingly healthy skin or non-lesional sites on AD patients still presents skin barrier defects and immune response, which can develop to AD at a later stage. To investigate further the balance between the epidermal barrier impairment and intrinsic immune dysregulation in AD, we exploited multispectral Raster-Scanning Optoacoustic Mesoscopy (ms-RSOM) to image lesional and non-lesional skin areas on AD patients of different severities non-invasively to elucidate their structural features and functional information. Herein, we demonstrate the objective assessment of AD severity using relative changes in oxygen saturation (δsO2) levels in microvasculature along with other structural parameters such as relative changes in epidermis thickness (δET) and total blood volume (δTBV) between the lesional and non-lesional areas of the skin. We could observe an increasing trend for δsO2 and δTBV, which correlated well with the subjective clinical Scoring Atopic Dermatitis (SCORAD) for evaluating the severity. Notably, δET showed a decreasing trend with AD severity, indicating that the difference in epidermal thickness between lesional and non-lesional area of the skin decreases with AD severity. Our results also correlated well with conventional metrics such as trans-epidermal water loss (TEWL) and erythrosine sedimentation rate (ESR). We quantified the δsO2 and δET changes to objectively evaluate the treatment response before and four months after treatment using topical steroids and cyclosporine in one severe AD patient. We observed reduced δsO2 and δET post treatment. We envision that in future, functional and structural imaging metrics derived from ms-RSOM can be translated as objective markers to assess and stratify the severity of AD and understand the function of skin barrier dysfunctions and immune dysregulation. It could also be employed to monitor the treatment response of AD in regular clinical settings.

Classification of Non-tumorous Facial Pigmentation Disorders Using Generative Adversarial Networks and Improved SMOTE.

The diagnosis of non-tumorous facial pigmentation disorders is crucial since facial pigmentations can serve as a health indicator for other more serious diseases. The computer-based classification of non-tumorous facial pigmentation disorders using images / photographs allows automated diagnosis of such disorders. However, the classification performance of existing methods is still not satisfactory due to the limited real-world images available for research. In this paper, we proposed a novel approach to applying generative adversarial network (GAN) with improved synthetic minority over-sampling technique (Improved SMOTE) to enhance the image dataset with more varieties. With the application of Improved SMOTE, more data is provided to train GAN models. By utilizing the GAN to perform data augmentation, more diverse and effective training images can be generated for developing classification model using deep neural networks via transfer learning. A significant increase in the classification accuracy (>4%) was achieved by the proposed method compared to the state-of-the-art method.

Model learning analysis of 3D optoacoustic mesoscopy images for the classification of atopic dermatitis.

Atopic dermatitis (AD) is a skin inflammatory disease affecting 10% of the population worldwide. Raster-scanning optoacoustic mesoscopy (RSOM) has recently shown promise in dermatological imaging. We conducted a comprehensive analysis using three machine-learning models, random forest (RF), support vector machine (SVM), and convolutional neural network (CNN) for classifying healthy versus AD conditions, and sub-classifying different AD severities using RSOM images and clinical information. CNN model successfully differentiates healthy from AD patients with 97% accuracy. With limited data, RF achieved 65% accuracy in sub-classifying AD patients into mild versus moderate-severe cases. Identification of disease severities is vital in managing AD treatment.

Microvascular imaging and monitoring of hemodynamic changes in the skin during arterial-venous occlusion using multispectral raster-scanning optoacoustic mesoscopy.

The ability to monitor oxygen delivery in microvasculature plays a vital role in measuring the viability of skin tissue and the probability of recovery. Using currently available clinical imaging tools, it is difficult to observe non-invasive hemodynamic regulation in the peripheral vessels. Here we propose the use of a novel multispectral raster-scanning optoacoustic mesoscopy (RSOM) system for noninvasive clinical monitoring of hemodynamic changes in the skin microvasculature's oxy- (HbO2) and deoxy-hemoglobin (Hb), total hemoglobin (HbT) and oxygen saturation (rsO2). High resolution images of hemoglobin distribution in the skin microvasculature from six healthy volunteers during venous and arterial occlusion, simulating systemic vascular diseases are presented. During venous occlusion, Hb and HbO2 optoacoustic signals showed an increasing trend with time, followed by a drop in the values after cuff deflation. During arterial occlusion, an increase in Hb value and decrease in HbO2 values was observed, followed by a drop in Hb and jump in HbO2 values after the cuff deflation. A decrease in rsO2 values during both venous and arterial occlusion was observed with an increase in value after occlusion release. Using this proof of concept study, hereby we propose multispectral RSOM as a novel tool to measure high resolution hemodynamic changes in microvasculature for investigating systemic vascular diseases on peripheral tissues and also for monitoring inflammatory skin diseases, and its therapeutic interventions.

Segmenting Vitiligo on Clinical Face Images Using CNN Trained on Synthetic and Internet Images.

Accurately diagnosing and describing the severity of vitiligo is crucial for prognostication, treatment selection and comparison. Currently, disease severity scores require dermatologists to estimate percentage area of involvement, which is subjected to inter and intra-assessor variability. Previous studies focus on pure skin but vitiligo on the face, which has a more serious impact on patients' quality of life, was completely neglected. Convolutional neural networks (CNNs) have good performance on many segmentation tasks. However, due to data privacy, it is hard to have a large clinical vitiligo face image dataset to train a CNN. To address this challenge, images from two different sources, the Internet and the proposed vitiligo face synthesis algorithm, are employed in training. 843 vitiligo images taken from different viewpoints were collected from the Internet. These images are hugely different from the target clinical images collected according to a newly established international standard. To have more vitiligo face images similar to the target clinical images to enhance segmentation performance, an image synthesis algorithm is proposed. Both synthetic and Internet images are used to train a CNN which is modified from the fully convolutional network (FCN) to segment face vitiligo lesions. The results show that 1) the synthetic images effectively improve segmentation performance; 2) the proposed algorithm achieves 1.06 % error for the face vitiligo area estimation and 3) it is more accurate than two dermatologists and all the previous automated vitiligo segmentation methods, which were designed for segmentation vitiligo on pure skin.