[Nosogenic psychosomatic disorders in patients with skin diseases]. / Nozogennye psikhosomaticheskie rasstroistva u patsientov s kozhnymi zabolevaniyami.

OBJECTIVE: Development of a clinical typology of nosogenic psychosomatic disorders in patients with skin diseases. MATERIAL AND METHODS: The study was carried out in the interclinical psychosomatic department of the Clinical Center and the Clinic of Skin and Venereal Diseases named after. V.A. Rakhmanov Sechenov University in 2007 to 2022. Nine hundred and forty-two patients (253 males, 689 females, average age 37.3±12.4 years) with nosogenic psychosomatic disorders in chronic dermatoses, including ichen planus (n=143), psoriasis (n=137), atopic dermatitis (n=132), acne (n=118), rosacea (n=115), eczema n=10), seborrheic dermatitis (n=88), vitiligo (n=52), pemphigus (n=48), were studied. Index of clinical symptoms (ICS); the Dermatology Quality of Life Index (DQLI); itching severity questionnaire - Behavioral rating scores (BRS); the Hospital Anxiety and Depression Scale (HADS) and statistical methods were used. RESULTS: In patients with chronic dermatoses, nosogenic psychosomatic disorders were diagnosed according to ICD-10 criteria within adaptation disorders [F43.8] (n=465; 49.3%); hypochondriacal disorder [F45.2] (n=235; 24.9%); constitutionally determined and acquired (hypochondriac development) personality disorders [F60] (n=118; 12.5%); schizotypal disorder [F21] (n=65; 6.9%); recurrent depressive disorder [F33] (n=59; 6.2%). A typological model of nosogenic disorders in dermatology has been developed: hypochondriacal nosogenies in severe clinical forms of dermatosis (pemphigus, psoriasis, lichen planus, atopic dermatitis, eczema) and dysmorphic nosogenies in objectively mild, but cosmetically significant forms of dermatosis (acne, rosacea, seborrheic dermatitis, vitiligo). When analyzing socio-demographic and psychometric indicators, significant differences were revealed between the selected groups (p<0.001). In turn, the selected groups of nosogenic disorders demonstrate significant clinical heterogeneity and include various types of nosogenies that form a unique palette of the nosogenic spectrum in the structure of an extensive psychodermatological continuum. Along with the severity of the skin process, the dominant role in the formation of the clinical picture of nosogeny, including cases of paradoxical dissociation of the quality of life with the severity of dermatosis, amplification and somatization of itching, has a premorbid personality structure and somatoperceptive accentuation of the patient, as well as the presence of a comorbid mental disorder. CONCLUSION: The typology of nosogenic psychosomatic disorders in patients with skin diseases requires consideration of both the psychopathological structure of the disorders under discussion and the severity/clinical features of the skin process.

Leptin deficiency in CD8+ T cells ameliorates non-segmental vitiligo by reducing interferon-γ and Granzyme B.

Background: Vitiligo is an autoimmune skin disease mainly mediated by CD8+ T cells, which affects about 0.1%-2% population of the world. Leptin plays a critical role in regulating the activation of CD8+ T cells. However, the effect of Leptin on vitiligo remains unclear. Objectives: To explore the effect of leptin on CD8+ T cells and its influence on vitiligo. Methods: RNA sequencing and Quantitative Real-time PCR (RT-qPCR) were used to explore the differentially expressed genes. Immunofluorescence staining was performed on skin lesions. Leptin in serum was detected by enzyme linked immunosorbent assay (ELISA). The peripheral blood mononuclear cells were detected by flow cytometry after leptin stimulation for 72 hours. A vitiligo model was established by monobenzone on Leptin KO mice. Results: 557 differentially expressed genes were found, including 154 up-regulated and 403 down-regulated genes. Lipid metabolism pathways showed a close relationship to the pathogenesis of vitiligo, especially the PPAR signaling pathway. RT-qPCR (p = 0.013) and immunofluorescence staining (p = 0.0053) verified that LEPR expressed significantly higher in vitiligo. The serum leptin level of vitiligo patients was significantly lower than that of healthy controls (p = 0.0245). The interferon-γ subset of CD8+LEPR+ T cells from vitiligo patients was significantly higher (p = 0.0189). The protein level of interferon-γ was significantly increased after leptin stimulation in vitro (p = 0.0217). In mice, Leptin deficiency resulted in less severe hair depigmentation. Leptin deficiency also resulted in significantly lower expressed vitiligo-related genes, such as Cxcl9 (p = 0.0497), Gzmb (p < 0.001), Ifng (p = 0.0159), and Mx1 (p < 0.001) after modeling. Conclusion: Leptin could promote the progression of vitiligo by enhancing the cytotoxic function of CD8+ T cells. Leptin may become a new target for vitiligo treatment.

Quality of Life Index in Patients with Vitiligo.

OBJECTIVE: To ascertain the quality of life (QoL) impairment among the Pakistani population with vitiligo and to determine the relationship between sociodemographic and clinical characteristics. STUDY DESIGN: Cross-sectional study. Place and Duration of the Study: Dermatology Outpatients at the Aga Khan University in collaboration with outpatients of seven tertiary care hospitals of Sindh, Punjab, KPK, Balochistan, and AJK to collect data from March 2015 to April 2019. METHODOLOGY: All clinically diagnosed patients of vitiligo, who signed consent and assent forms, were included in the study. A validated 25-item, QoL scale for vitiligo was used. Socio-economic status of the patients, clinical assessment of the disease and patients' engagement in social and domestic lives was noted. RESULTS: Five hundred and seventy-three patients were enrolled in the study, having mean age 29.8 ± 16.2 years. In 306 (53.4%) males and 267 (46.65%) females; 21.8% were below 18 years. Mean vitiligo QoL index was 38.4 ± 11.8. Patients of vitiligo with disease duration 5-10 years, those affected on exposed parts, more than five body sites, rapidly progressing disease and of female gender had a higher impairment of quality of life. These scores were found significantly higher as compared to other levels of these parameters (p<0.05). CONCLUSION: Patients with vitiligo experience low self-esteem. The disease adversely affects their quality of life. The authors recommend the use of disease-specific instruments to assess the quality of life which enables the treating physician to devise best possible management plan individually. KEY WORDS: Vitiligo, Quality of life, Pakistan, Vitiligo life quality index.

The psychosocial impacts of vitiligo, psoriasis, and alopecia areata on pediatric patients.

Children and adolescents with chronic cutaneous conditions are at risk of experiencing adverse psychosocial effects such as anxiety, depression, and loneliness. The well-being of these children's families may also be impacted by their child's condition. It is important for the quality of life of patients and their families to better understand the psychosocial impact caused by pediatric dermatologic conditions and interventions that help mitigate these effects. This review summarizes the psychological impact of the common pediatric dermatological disorders, vitiligo, psoriasis, and alopecia areata, on children and their caregivers. Studies examining quality of life, psychiatric conditions, and other measures of psychosocial impact in children and caregivers, as well as those evaluating the effectiveness of interventions aimed at addressing psychosocial effects, were included. This review highlights the increased risk that children with these conditions have in experiencing adverse psychosocial effects including quality of life impairment, psychological pathology, and social stigmatization. In addition, the specific risk factors within this population that are associated with increased negative effect such as age and severity of disease are discussed. This review demonstrates a need for increased support of these patients and their families and additional research on the effectiveness of current interventions.

The impact of the COVID-19 surge on phototherapy in Taiwan: Focusing on the patient profile, adherence, and attitude before and after the surge.

BACKGROUND: Coronavirus disease 2019 (COVID-19) pandemic has caused changes in the medical practice. However, it is unclear whether the patients receiving phototherapy for their dermatoses have been affected. OBJECTIVES: This study aimed to identify the impact of the COVID-19 pandemic on phototherapy, focusing on the patient profile, adherence, and attitude before and after the surge. METHODS: The study encompassed the time 5 months prior to and after the surge of the COVID-19 pandemic (from May to July, 2021), resulting in the temporary closure of our phototherapeutic unit. RESULTS: Nine hundred eighty-one patients received phototherapy during this period. Vitiligo, psoriasis (Ps), and atopic dermatitis (AD) represented the groups with the highest patient numbers. For vitiligo, Ps and AD, 39.6%, 41.9%, and 28.4% of the patients resumed phototherapy after the pandemic-related shutdown (PRS). No significant difference was noted in age, gender, and number of weekly sessions between those who resumed or stopped phototherapy after PRS among three groups. Patients who resumed phototherapy after PRS tended to receive more weekly sessions of phototherapy than those who initiated after PRS. Additionally, patients who resumed phototherapy showed no significant difference in the number of weekly sessions before and after PRS. CONCLUSIONS: This study reveals a significant impact of the COVID-19 pandemic on patients undergoing phototherapy. Although the patient number remained similar before and after PRS, a significant portion of patients discontinued phototherapy after PRS. New strategies and continued education are needed to improve patient management in times of pandemic.

Optimization of Monobenzone-Induced Vitiligo Mouse Model by the Addition of Chronic Stress.

Vitiligo is a common primary, limited or generalized skin depigmentation disorder. Its pathogenesis is complex, multifactorial and unclear. For this reason, few animal models can simulate the onset of vitiligo, and studies of drug interventions are limited. Studies have found that there may be a pathophysiological connection between mental factors and the development of vitiligo. At present, the construction methods of the vitiligo model mainly include chemical induction and autoimmune induction against melanocytes. Mental factors are not taken into account in existing models. Therefore, in this study, mental inducement was added to the monobenzone (MBEH)-induced vitiligo model. We determined that chronic unpredictable mild stress (CUMS) inhibited the melanogenesis of skin. MBEH inhibited melanin production without affecting the behavioral state of mice, but mice in the MBEH combined with CUMS (MC) group were depressed and demonstrated increased depigmentation of the skin. Further analysis of metabolic differences showed that all three models altered the metabolic profile of the skin. In summary, we successfully constructed a vitiligo mouse model induced by MBEH combined with CUMS, which may be better used in the evaluation and study of vitiligo drugs.

Evaluation of CAT Variants A-89T, C389T, and C419T in Patients with Vitiligo in the Saudi Population.

Background and Objectives: Vitiligo is a chronic autoimmune and depigmentation disorder in humans that manifests as whitening lesions. Reactive oxygen species (ROS) are involved in cell damage. Catalase (CAT) is a well-known oxidative stress regulator and is primarily responsible for the catalytic decomposition of hydrogen peroxide into water and oxygen. Based on previous case-control and meta-analysis studies, we assessed the prevalence of three single-nucleotide polymorphisms (SNPs) of the CAT genes A-89T (rs7943316), C389T (rs769217) and C419T (rs11032709) in participants with vitiligo and healthy controls in the Saudi population. Materials and Methods: We recruited 152 participants with vitiligo and 159 healthy controls for A-89T, C389T, and C419T SNP genotyping studies using PCR and RFLP analysis. Additionally, we performed linkage disequilibrium and haplotype analyses between vitiligo cases and controls. Results: The rs7943316 and rs11032709 SNPs of the CAT genes showed a positive association with vitiligo for both heterozygous genotypes and dominant genetic models (TT + AT vs. AA in A-89T and TT + CT vs. CC in C389T), in the CAT gene. Linkage disequilibrium analysis revealed a moderate linkage between rs7943316 and rs11032709 SNPs in vitiligo cases and controls. Haplotype frequency estimation revealed a significant association (p = 0.003) among the three SNP alleles. Conclusions: The rs7943316 and rs11032709 SNPs of the CAT genes were strongly associated with susceptibility to vitiligo.

Generating Functional and Highly Proliferative Melanocytes Derived from Human Pluripotent Stem Cells: A Promising Tool for Biotherapeutic Approaches to Treat Skin Pigmentation Disorders.

Melanocytes are essential for skin homeostasis and protection, and their loss or misfunction leads to a wide spectrum of diseases. Cell therapy utilizing autologous melanocytes has been used for years as an adjunct treatment for hypopigmentary disorders such as vitiligo. However, these approaches are hindered by the poor proliferative capacity of melanocytes obtained from skin biopsies. Recent advances in the field of human pluripotent stem cells have fueled the prospect of generating melanocytes. Here, we have developed a well-characterized method to produce a pure and homogenous population of functional and proliferative melanocytes. The genetic stability and potential transformation of melanocytes from pluripotent stem cells have been evaluated over time during the in vitro culture process. Thanks to transcriptomic analysis, the molecular signatures all along the differentiation protocol have been characterized, providing a solid basis for standardizing the protocol. Altogether, our results promise meaningful, broadly applicable, and longer-lasting advances for pigmentation disorders and open perspectives for innovative biotherapies for pigment disorders.

The efficacy of bimatoprost ophthalmic solution combined with NB-UVB phototherapy in non-segmental and segmental vitiligo: a single-blind randomized controlled study.

Bimatoprost ophthalmic solution 0.03% (PGF2α analogues) combined with narrowband ultraviolet B (NB-UVB) was reported to be an effective treatment for vitiligo. To investigate the efficacy and safety of treatment for non-segmental/segmental vitiligo compared among bimatoprost ophthalmic solution 0.01% combined with NB-UVB phototherapy, bimatoprost monotherapy, and placebo. This single-blind randomized controlled study enrolled stable Thai vitiligo patients with at least three similarly sized lesions in the same anatomical area. The treatment duration was 6 months with 1- and 2-month post-treatment follow-ups. The 3 selected lesions on each patient were randomized to receive combination therapy, monotherapy, or placebo. The Vitiligo Area Scoring Index (VASI) was used to evaluate lesion response. Of the 25 initially enrolled subjects, 19 patients were analyzed. There were 13 and 6 non-segmental and segmental vitiligo cases, respectively. Eight and 11 cases had face/neck and non-face/neck lesions, respectively. Non-segmental vitiligo and non-face/neck vitiligo patients in the combination group had significant improvement in VASI score at 3 months, 6 months, and at the 2-month follow-up. No side effects were observed/reported. Bimatoprost combination therapy was shown to be safe and effective for treating Thai patients with non-segmental vitiligo in non-face/neck areas of the body.

Association of atopic dermatitis with autoimmune diseases: A bidirectional and multivariable two-sample mendelian randomization study.

Background: Observational studies have suggested the association between atopic dermatitis (AD) and the risks of autoimmune diseases. It is still unclear, however, whether or in which direction causal relationships exist, because these associations could be confounded. Objectives: Our study seeks to assess the possibility of AD as a cause of autoimmune diseases, and to estimate the magnitude of the causal effect. Methods: Two-sample mendelian randomization (MR) analyses were performed using genome-wide association study (GWAS) summary-level statistics. Specifically, bidirectional MR analyses were conducted to examine the direction of association of AD with autoimmune diseases; multivariable MR analyses (MVMR1) were used to test the independence of causal association of AD with autoimmune diseases after controlling other atopic disorders (asthma and allergic rhinitis), while MVMR2 analyses were conducted to account for potential confounding factors such as smoking, drinking, and obesity. Genetic instruments for AD (Ncases=22 474) were from the latest GWAS meta-analysis. The GWAS summary data for asthma and allergic rhinitis were obtained from UK Biobank. The GWAS summary data for smoking, alcohol consumption, obesity and autoimmune diseases (alopecia areata, vitiligo, systemic lupus erythematosus, ankylosing spondylitis, rheumatoid arthritis, and type 1 diabetes) were selected from the largest GWASs available. Causal estimates were derived by the inverse-variance weighted method and verified through a series of sensitivity analyses. Results: Genetically predicted AD linked to higher risks of rheumatoid arthritis (OR, 1.28; P=0.0068) (ORMVMR1, 1.65; P=0.0020) (ORMVMR2, 1.36; P<0.001), type 1 diabetes (OR, 1.37; P=0.0084) (ORMVMR1, 1.42; P=0.0155) (ORMVMR2, 1.45; P=0.002), and alopecia areata (OR, 1.98; P=0.0059) (ORMVMR1, 2.55; P<0.001) (ORMVMR2, 1.99; P=0.003) in both univariable and multivariable MR. These causal relationships were supported by sensitivity analyses. No causal effect of AD was identified in relation to systemic lupus erythematosus, vitiligo, and ankylosing spondylitis. Concerning the reverse directions, no significant association was noted. Conclusion: The results of this MR study provide evidence to support the idea that AD causes a greater risk of rheumatoid arthritis, type 1 diabetes and alopecia areata. Further replication in larger samples is needed to validate our findings, and experimental studies are needed to explore the underlying mechanisms of these causal effects.

Shining a Light on Vitiligo and Associated Comorbidities: What Is the Evidence?

CITATION: Desai S, McCormick E, Sodha P, et al. Shining a light on the vitiligo and associated comorbidities: What is the evidence? J Drugs Dermatol. 2023;22(4):428-430. doi:10.36849/JDD.NVRN0423.

Expression Signature of Immune-Related MicroRNAs in Autoimmune Skin Disease: Psoriasis and Vitiligo Insights.

BACKGROUND: Psoriasis and vitiligo are both chronic, skin-specific diseases classified as autoimmune diseases due to the involvement of several biochemical pathways in their pathogenesis, similar to those altered in other autoimmune diseases. The role of miRNAs in regulating skin autoimmune function has yet to be fully characterized. AIM: The aim of this study was to assess the expression profile of a panel of 11 circulating immune-related miRNAs in patients with autoimmune skin diseases, specifically psoriasis and vitiligo, and correlate their expression signature with the clinicopathological features of the diseases. SUBJECTS AND METHODS: Relative gene expression quantification for 11 immune-related circulating miRNAs in plasma was done for 300 subjects-100 patients with psoriasis, 100 patients with vitiligo and 100 normal healthy volunteers-followed by different modalities of bioinformatics analysis for the results. RESULTS: The expression levels of all the studied immune-related miRNAs were elevated in both autoimmune skin disorders, with much higher levels of expression in psoriasis than in vitiligo patients. There was a significant correlation between most of the studied miRNAs, suggesting shared target genes and/or pathways. Moreover, all the studied miRNAs showed significant results as biomarkers for autoimmune skin disease, with miRNA-145 being the best candidate. Regarding the clinicopathological data, miRNA-7, miRNA-9, miRNA-145, miRNA-148a, and miRNA-148b were positively correlated with age. All the miRNAs were inversely correlated with obesity and disease duration. CONCLUSION: This study highlights the critical role of miRNAs in skin-specific autoimmune diseases that proved to be potential biomarkers for autoimmune skin disorders, warranting their exploration as therapeutic targets.

MC1R Peptide Agonist Self-Assembles into a Hydrogel That Promotes Skin Pigmentation for Treating Vitiligo.

Vitiligo, a common skin disease that seriously affects 0.5-2.0% of the worldwide population, lacks approved therapeutics due to a wide range of adverse side effects. As a key regulator of skin pigmentation, MC1R may be an effective therapeutic target for vitiligo. Herein, we report an MC1R peptide agonist that directly self-assembles into nanofibrils that form a hydrogel matrix under normal physiological conditions. This hydrogel exhibits higher stability than free peptides, sustained release, rapid recovery from shear-thinning, and resistance to enzymatic proteolysis. Furthermore, this peptidal MC1R agonist upregulates tyrosinase, tyrosinase-related protein-1 (TYRP-1), and tyrosinase-related protein-2 (TYRP-2) to stimulate melanin synthesis. More importantly, MC1R agonist hydrogel promotes skin pigmentation in mice more potently than free MC1R agonist. This study supports the development of this MC1R agonist hydrogel as a promising pharmacological intervention for vitiligo.

The Role of Oxidative Stress in Vitiligo: An Update on Its Pathogenesis and Therapeutic Implications.

Vitiligo is an autoimmune skin disorder caused by dysfunctional pigment-producing melanocytes which are attacked by immune cells. Oxidative stress is considered to play a crucial role in activating consequent autoimmune responses related to vitiligo. Melanin synthesis by melanocytes is the main intracellular stressor, producing reactive oxygen species (ROS). Under normal physiological conditions, the antioxidative nuclear factor erythroid 2-related factor 2 (Nrf2) pathway functions as a crucial mediator for cells to resist oxidative stress. In pathological situations, such as with antioxidant defects or under inflammation, ROS accumulate and cause cell damage. Herein, we summarize events at the cellular level under excessive ROS in vitiligo and highlight exposure to melanocyte-specific antigens that trigger immune responses. Such responses lead to functional impairment and the death of melanocytes, which sequentially increase melanocyte cytotoxicity through both innate and adaptive immunity. This report provides new perspectives and advances our understanding of interrelationships between oxidative stress and autoimmunity in the pathogenesis of vitiligo. We describe progress with targeted antioxidant therapy, with the aim of providing potential therapeutic approaches.

Differences in the immune microenvironment between improved and non-improved cases of vitiligo after halo nevus excision.

BACKGROUND: Halo nevus, also called Sutton's nevus, is a nevus cell nevus surrounded by vitiligo thought to be caused by a T-cell mediated immune response to the nevus antigen. The immune microenvironment is mysterious, however, as vitiligo often does not improve even when the nevus cells are removed. OBJECTIVES: To analyze the clinical course and immune microenvironment of patients with halo nevus who had undergone nevus excision. METHODS: We collected 54 halo nevus patients and performed multivariate analysis and immunohistochemical analysis, including multiplexed immune cell phenotyping and spatial single-cell analyses using the PhenoCycler® assay. RESULTS: Multivariate analysis revealed that only the presence or absence of vitiligo vulgaris at the time of consultation was associated with improvement in the surrounding vitiligo following excision. Expression of programmed death-ligand 1 in nevus cells was significantly higher in non-improved cases compared with improved cases. The PhenoCycler® assay revealed that CD107a-positive and CD21-positive cells were more prevalent in improved cases than in non-improved cases. In the improved cases, active cell-cell interactions, centered on CD21-positive cells, were observed, whereas in the non-improved cases, cell-cell interactions were sparse. Instead, a dense infiltration of CD8-positive cells and CD3 and CD4-positive cells was observed in non-improved cases. CONCLUSION: Elucidation of the immune microenvironment of halo nevus is also relevant to melanoma-associated vitiligo and will contribute to our understanding of tumor immunity.

JAK inhibitors in dermatology: the road travelled and path ahead, a narrative review.

INTRODUCTION: Numerous cutaneous dermatoses mediated by cytokines depend on the JAK STAT pathway for intracellular signaling. JAK inhibitors form a useful therapeutic approach in treating these conditions. The literature on effectiveness of JAK inhibitors in treatment of alopecia areata, vitiligo, atopic dermatitis, psoriasis and several other inflammatory and autoimmune diseases is growing although very few conditions have sufficiently well performed studies to their credit and, barring a few indications, their use in rest remains empirical as yet. AREAS COVERED: A search of the PubMed database was made using the keywords Janus kinase inhibitors OR JAK inhibitors AND dermatology with the time duration limited to the last 5 years. Here, we review the JAK STAT pathway, the various conditions in which JAK inhibitors are currently used in dermatology, and other conditions their use is being explored in. EXPERT OPINION: The pathology of a large number of dermatological disorders is mediated via inflammatory cytokines which signal via the JAK STAT pathway. JAKinibs have shown great promise in treating cutaneous disorders refractory to conventional therapy. Their current clinical use in dermatology is based on robust evidence (for some), and anecdotal evidence for most other dermatoses.