Evidence of a possible therapeutic role of vitamin D in a cohort of adult Caucasian vitiligo patients.

Reduced serum 25(OH)D levels have been largely reported in vitiligo, which is an autoimmune skin disorder characterized by the appearance of achromic macules. Since vitamin D can positively modulate immune function and stimulate melanogenesis in vitro, a possible role of sufficient vitamin D levels in promoting the stability of the disease and repigmentation process might be hypothesized in vitiligo. Hence, we conducted an observational study on medical records related to 101 vitiligo patients, in order to correlate baseline 25(OH)D levels with the baseline vitiligo activity and repigmentation of vitiligo macules on a 6-month follow-up. According to our results, at baseline we found that active vitiligo was significantly associated with 25(OH)D deficiency (≤20 ng/mL) (P = 0.036) or insufficiency (21-29 ng/mL) (P = 0.041), while stable disease was significantly associated with sufficient 25(OH)D levels (30-100 ng/mL) (P = 0.043). After 6 months, vitiligo patients with sufficient 25(OH)D levels (30-100 ng/mL) achieved a significantly higher degree of repigmentation. In conclusion, our study provides a novel evidence of a significant positive association of sufficient 25(OH)D levels with the stability of the disease and a satisfactory repigmentation process in Caucasian adult vitiligo patients and strengthen the need to assess vitamin D status in vitiligo. The correlation between sufficient vitamin D levels and a satisfactory course of the disease opens the way for future randomized controlled trials assessing a possible beneficial role of vitamin D supplementation on vitiligo.

No Association between Vitiligo and Obesity: A Case-Control Study.

OBJECTIVE: The purpose of this study was to investigate the relationship between vitiligo and body mass index (BMI) to assess the possible association between vitiligo and obesity. SUBJECTS AND METHODS: This was a case-control study on a total of 400 participants, i.e., 200 patients with vitiligo and 200 healthy volunteers. Medical assessments were performed by dermatologists using the modified Vitiligo European Task Force form. The height and weight of all of the participants were measured and used to calculate the BMI. Data were analyzed using multivariate logistic regression models. Adjustment for age and gender was carried out preliminarily in the case-control analysis, whereas a forward stepwise selection algorithm was used to assess which independent factors were associated with a BMI ≥30 or a BMI ≤18.5. RESULTS: Comparison of the vitiligo and control groups revealed the absence of a significant association. The multivariate analysis of factors associated with a high BMI (≥30) in vitiligo patients showed a significant association between a high BMI and a sudden onset of vitiligo (p = 0.021; OR = 3.83; 95% CI 1.22-11.99) and the presence of inflammation and pruritus (p = 0.031; OR = 3.26; 95% CI 1.11-9.57). No significant association was observed in the analysis of factors associated with a low BMI (≤18.5) in vitiligo patients. CONCLUSION: In this study, vitiligo did not appear to be associated with a high BMI; obesity might not be a risk factor for vitiligo, in contrast to most autoimmune diseases which are significantly associated with obesity.

Hair and Scalp Disorders in a Tuscan Pediatric Dermatological Outpatient Clinic: A Clinical and Epidemiological Evaluation.

OBJECTIVES: The aim of this study was to evaluate the clinical and epidemiological profile of hair and scalp disorders in children referred to the Pediatric Dermatology Outpatient Clinic. MATERIALS AND METHODS: We performed a retrospective study of children with hair loss problems or scalp diseases who turned to the Pediatric Dermatology Service, Anna Meyer Pediatric Hospital, Florence, Italy, from January 1, 2009, to December 31, 2009. Demographics, personal and familial medical history, laboratory tests, clinical examination, final diagnosis and therapeutic interventions were obtained from the manual chart review. RESULTS: Of the 2,640 children who had access to the Pediatric Dermatology Service, 190 (7.19%) had a hair or scalp disorder. Among the 190 children, 60 (31.57%) presented with nonscarring alopecia, 56 (29.47%) had benign neoplasias, hamartomas or vascular malformations of the scalp, 51 (26.84%) had scalp inflammatory diseases, 14 (7.36%) had scarring alopecia, 5 (2.63%) had infections and 2 (1.05%) had infestation of the scalp. A case of constitutional hypertrichosis (0.52%) and also a case (0.52%) of lamellar ichthyosis were diagnosed. CONCLUSIONS: Our results underline that hair and scalp diseases represent an important percentage of admittances to a dermatological pediatric outpatient clinic. The variety and complexity of the diseases observed in this study included diseases commonly found also in adulthood.

Evaluation of an oral supplement containing Phyllanthus emblica fruit extracts, vitamin E, and carotenoids in vitiligo treatment.

Phyllanthus emblica, vitamin E, and caroteinods are compounds showing antioxidative, anti-inflammatory, and repigmenting effects, whose role in vitiligo treatment has not been evaluated so far. Sixty-five subjects (group A) were treated with one tablet of an oral supplement containing P. emblica (100 mg), vitamin E (10 mg), and carotenoids (4.7 mg) three times/day for 6 months and compared with a control group (group B, 65 patients), which instead was not treated with antioxidants. Both groups were simultaneously treated with a comparable topical therapy and/or phototherapy. After a 6 months follow-up, a significantly higher number of patients in group A had a mild repigmentation on the head/neck regions (p = 0.019) and on the trunk (trend, p = 0.051). The number of patients who presented no repigmentation in head/neck, trunk, upper, and lower limbs was significantly higher in group B (respectively, p = 0.009, p = 0.001, p = 0.001, p = 0.025). Moreover, group B patients showed higher signs of inflammation (p = 0.002), a more rapid growth of the lesions (p = 0.039), a higher percentage of worsening disease (p = 0.003), and more erythema (p = 0.059), whereas group A patients showed a higher percentage of steady disease (p = 0.065). Our results suggest that the supplement with antioxidants in patients with vitiligo might represent a valuable instrument to increase the effectiveness of other vitiligo treatments. [Correction added after online publication 06-Oct-2014: the dosages of vitamin E and carotenoids have been updated.].

Correlation of Serum Thyroid Hormones Autoantibodies with Self-Reported Exposure to Thyroid Disruptors in a Group of Nonsegmental Vitiligo Patients.

Vitiligo is a pigmentary disorder strongly associated with autoimmune thyroid disorders (ATD). Thyroid hormones antibodies (THAb) directed toward thyroxine (T3) and triiodothyronine (T4) (T3- and T4-Ab) are rare in the general population but are increased in individuals wit ATD and extrathyroid autoimmune disorders. Because it is known that alcohol, smoke, iodine, and some thyroid disruptors can elicit the appearance of ATD, the aim of our study was to evaluate possible correlation between T3- and T4-Ab expression and past toxic exposures in vitiligo patients. Seventy vitiligo patients were examined and self-reported exposure to thyroid disruptors (4,4'-isopropylidenediphenol, perchlorates, polychlorinated biphenyls (PCBs), hexachlorobenzene, resorcinol, dichlorodiphenyltrichloroethane, alachlor/amitriole, nitrate, thiocyanate, soy isoflavones), iodine intake, smoke, and alcohol consumption were investigated through standardized questionnaires. Immunoglobulin (Ig)M-T3-Ab, IgG-T3-Ab, IgM-T4-Ab,and IgG-T4-Ab were dosed by a radioimmunoprecipitation technique. Seventy-seven (95.7 %) patients had at least one type of THAb. Most of them had contemporarily both T3- and T4-Ab (50/70). We found a significant association between PCBs and T4-IgG-Ab (P = 0.039) and between food intake containing nitrate, thiocyanate, and soy isoflavones with (IgM + IgG)-T3-Ab (P = 0.041). Our study underlines a possible influence of diet and environment in vitiligo patients in eliciting THAb. Therefore, in the event of a positive exposure to thyroid disruptors, an evaluation of thyroid function might be useful to early detect possible associated thyroid autoantibodies such as THAb.

Efficacy and Safety of Pulse Intravenous Methylprednisolone in Pediatric Epileptic Encephalopathies: Timing and Networks Consideration.

Background: Epileptic encephalopathies (EE) are characterized by severe drug-resistant seizures, early onset, and unfavorable developmental outcomes. This article discusses the use of intravenous methylprednisolone (IVMP) pulse therapy in pediatric patients with EE to evaluate its efficacy and tolerability. Methods: This is a retrospective study from 2020 to 2023. Inclusion criteria were ≤18 years at the time of IVMP pulse therapy and at least 6 months of follow-up. Efficacy and outcome, defined as seizure reduction > 50% (responder rate), were evaluated at 6 and 9 months of therapy, and 6 months after therapy suspension; quality of life (QoL) was also assessed. Variables predicting positive post-IVMP outcomes were identified using statistical analysis. Results: The study included 21 patients, with a responder rate of 85.7% at 6 and 9 months of therapy, and 80.9% at 6 months after therapy suspension. Variables significantly predicting favorable outcome were etiology (p = 0.0475) and epilepsy type (p = 0.0475), with the best outcome achieved in patients with genetic epilepsy and those with encephalopathy related to electrical status epilepticus during slow-wave sleep (ESES). All patients evidenced improvements in QoL at the last follow-up, with no relevant adverse events reported. Conclusions: Our study confirmed the efficacy and high tolerability of IVMP pulse therapy in pediatric patients with EE. Genetic epilepsy and ESES were positive predictors of a favorable clinical outcome. QOL, EEG tracing, and postural-motor development showed an improving trend as well. IVMP pulse therapy should be considered earlier in patients with EE.

Commentary from the Editorial Board to Vitiligo: interplay between oxidative stress and immune system (Laddha et al.).

Vitiligo pathogenesis is very puzzling, and novel mechanisms possibly involved in the development of this disorder are frequently explored. Recently, some authors proposed an interplay between oxidative stress and immune system at the basis of melanocyte loss. According to the experimental evidence, they suggest that exposition to environmental agents might lead to an association between vitiligo and other autoimmune diseases. Accordingly, it is proposed that increased reactive oxygen species due to environmental agents could induce a modification of both melanocytic structures and other tissue proteins, or might disregulate the immune system, influencing the appearance of vitiligo and autoimmune comorbidities.

Contribution of CACNA1H Variants in Autism Spectrum Disorder Susceptibility.

Autism Spectrum Disorder (ASD) is a highly heterogeneous neuropsychiatric disorder with a strong genetic component. The genetic architecture is complex, consisting of a combination of common low-risk and more penetrant rare variants. Voltage-gated calcium channels (VGCCs or Cav) genes have been implicated as high-confidence susceptibility genes for ASD, in accordance with the relevant role of calcium signaling in neuronal function. In order to further investigate the involvement of VGCCs rare variants in ASD susceptibility, we performed whole genome sequencing analysis in a cohort of 105 families, composed of 124 ASD individuals, 210 parents and 58 unaffected siblings. We identified 53 rare inherited damaging variants in Cav genes, including genes coding for the principal subunit and genes coding for the auxiliary subunits, in 40 ASD families. Interestingly, biallelic rare damaging missense variants were detected in the CACNA1H gene, coding for the T-type Cav3.2 channel, in ASD probands from two different families. Thus, to clarify the role of these CACNA1H variants on calcium channel activity we performed electrophysiological analysis using whole-cell patch clamp technology. Three out of four tested variants were shown to mildly affect Cav3.2 channel current density and activation properties, possibly leading to a dysregulation of intracellular Ca2+ ions homeostasis, thus altering calcium-dependent neuronal processes and contributing to ASD etiology in these families. Our results provide further support for the role of CACNA1H in neurodevelopmental disorders and suggest that rare CACNA1H variants may be involved in ASD development, providing a high-risk genetic background.

Implication of Human Bacterial Gut Microbiota on Immune-Mediated and Autoimmune Dermatological Diseases and Their Comorbidities: A Narrative Review.

During the last decade, the advent of modern sequencing methods (next generation techniques, NGS) has helped describe the composition of the human gut microbiome, enabling us to understand the main characteristics of a healthy gut microbiome and, conversely, the magnitude of its disease-related changes. This new knowledge has revealed that healthy gut microbiota allow the maintenance of several crucial physiological functions, such as the ability to regulate the innate and adaptive immune systems. Increasing evidence has pointed out a condition of dysbiosis in several autoimmune/immune mediated dermatological conditions and specific gut microbial signatures have also been reported to correlate with clinical and prognostic parameters of such diseases. Based on a literature search of relevant published articles, this review debates the current knowledge and the possible pathogenic implications of bacterial gut microbiota composition assessed through NGS techniques in systemic lupus erythematosus, atopic dermatitis, psoriasis, and alopecia areata. Evidence of a potential role of specific gut microbiota signatures in modulating the clinical course of such diseases and their main comorbidities has been also reviewed.

The gut microbiota is defined as the collection of microbes (bacteria, fungi, archaea, and viruses) inhabiting the human gut. If healthy, it allows the maintenance of several crucial physiological functions, such as the ability to regulate the immune system. Accordingly, increasing evidence has pointed out a condition of imbalance in the gut microbial community (dysbiosis) in several autoimmune/immune mediated dermatological conditions. Specific gut dysbioses have also been reported to correlate with clinical and prognostic parameters of such diseases.In this review, the current knowledge and the possible pathogenic implications of bacterial gut microbiota composition assessed through advanced techniques in systemic lupus erythematosus, atopic dermatitis, psoriasis, and alopecia areata are discussed. Furthermore, evidence of a potential role of specific gut microbiota signatures affecting the clinical course and main associated diseases is also reviewed. In this scenario, an increased knowledge of gut microbiota composition and functions in autoimmune/immune mediated dermatological diseases might suggest additional treatments besides conventional therapies, and predict clinical evolution and comorbidities association.

Hydrochlorothiazide Use and Risk of Nonmelanoma Skin Cancers: A Biological Plausibility Study.

Recent studies reported the association between increased risk of nonmelanoma skin cancers (NMSCs) and the use of hydrochlorothiazide (HCTZ), one of the most commonly prescribed diuretic, antihypertensive drug, over the world. Although HCTZ is known to be photosensitizing, the mechanisms involved in its potential prophotocarcinogenic effects remain unclear. Under acute exposure, therapeutically relevant concentrations of HCTZ (70, 140, and 370 ng/mL) amplified UVA-induced double-strand breaks, oxidative DNA, and protein damage in HaCaT human keratinocytes, and this effect was associated to a defective activity of the DNA repair enzyme, OGG1. Oxidative damage to DNA, but not that to proteins, was reversible within few hours. After chronic, combined exposure to HCTZ (70 ng/mL) and UVA (10 J/cm2), for 9 weeks, keratinocytes acquired a dysplastic-like phenotype characterized by a multilayered morphology and alterations in cell size, shape, and contacts. At the ultrastructural level, several atypical and enlarged nuclei and evident nucleoli were also observed. These transformed keratinocytes were apoptosis resistant, exhibited enhanced clonogenicity capacity, increased DNA damage and inflammation, defective DNA repair ability, and increased expression of the oncogene ΔNp63α and intranuclear ß-catenin accumulation (a hallmark of Wnt pathway activation), compared to those treated with UVA alone. None of these molecular, morphological, or functional effects were observed in cells treated with HCTZ alone. All these features resemble in part those of preneoplastic lesions and NMSCs and provide evidence of a biological plausibility for the association among exposure to UVA, use of HCTZ, and increased risk of NMSCs. These results are of translational relevance since we used environmentally relevant UVA doses and tested HCTZ at concentrations that reflect the plasma levels of doses used in clinical practice. This study also highlights that drug safety data should be followed by experimental evaluations to clarify the mechanistic aspects of adverse events.

Drug consumption and melanocytic nevi: correlation between oral contraceptives or hormone replacement therapy and a high melanocytic nevi count.

The prolonged use of drugs such as beta-blockers, acetylsalicylic acid, omeprazole, statins, oral contraceptives and hormone replacement therapy might have some role in melanocytic nevi development and be ultimately linked to melanoma risk. Aims of the study were to evaluate a possible association between the above-mentioned drugs and features such as number and atypia of melanocytic nevi in long-term users. We retrospectively looked at pharmacological, clinical and dermoscopic records of 1321 patients that attended our unit for routine mole check between January 2013 and January 2018. Patients were divided into two groups (low or high melanocytic nevi count), and multivariate analysis was performed with regards to the presence and number of melanocytic nevi and drug assumption. A positive association between the use of oral contraceptives or hormone replacement therapy (P = 0.012) and a high melanocytic nevi count was found through multivariate analysis, after adjusting for sex, age and multiple confounding factors, such as freckles, phototype and a reported history of sun exposure and sunburns. Further prospective studies are necessary to establish whether women using oral contraceptives or on hormone replacement therapy should undergo periodic monitoring of pigmented lesions.

Vitiligo: new and emerging treatments.

Vitiligo is a cosmetically disfiguring condition, and, although there is no therapeutic full solution yet, some treatment may induce good results in most patients. The disease can be successfully treated with various medical options. Both nonfocused or focused narrowband ultraviolet B phototherapy represents the current treatment of choice, to minimize side effects and reach optimal clinical results. Topical novel approaches are also considered. Surgical methods, consisting of autologous transplantation methods, is generally recommended for focal/stable vitiligo, after medical therapy has failed. Finally, for patients with extensive vitiligo, depigmentation of the residual melanin should be taken into account.

The role of stress and beta-adrenergic system in melanoma: current knowledge and possible therapeutic options.

PURPOSE: The aim of the present review was to discuss recent findings on the role of beta-adrenergic system in melanoma, in order to provide information on the biological responses elicited by its activation and its potential application for melanoma treatment. METHODS: A literature search was performed, and evidences regarding the involvement of stress and beta-adrenergic system in cancer and melanoma were found and discussed. RESULTS: Our search pointed out that beta-adrenergic system is a key regulator of important biological processes involved in the onset and progression of some solid tumors. In the last decade, functional beta-adrenoceptors have been also identified on melanoma cells, as well as on their microenvironment cells. Similarly to other common cancers too, the activation of such adrenoceptors by catecholamines, usually released under stress conditions, has been found to trigger pro-tumorigenic pathways contributing to cell proliferation and motility, immune system regulation, apoptosis, epithelial-mesenchymal transition, invasion and neoangiogenesis. CONCLUSIONS: The biological evidences we found clarify and sustain the clinical evidences reporting the involvement of chronic stress in melanoma onset and progression. In such scenario, it is conceivable that a therapeutic approach targeting beta-adrenergic system could constitute a novel and promising strategy for melanoma treatment.

Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants.

Vitiligo is an autoimmune disease in which depigmented skin results from the destruction of melanocytes, with epidemiological association with other autoimmune diseases. In previous linkage and genome-wide association studies (GWAS1 and GWAS2), we identified 27 vitiligo susceptibility loci in patients of European ancestry. We carried out a third GWAS (GWAS3) in European-ancestry subjects, with augmented GWAS1 and GWAS2 controls, genome-wide imputation, and meta-analysis of all three GWAS, followed by an independent replication. The combined analyses, with 4,680 cases and 39,586 controls, identified 23 new significantly associated loci and 7 suggestive loci. Most encode immune and apoptotic regulators, with some also associated with other autoimmune diseases, as well as several melanocyte regulators. Bioinformatic analyses indicate a predominance of causal regulatory variation, some of which corresponds to expression quantitative trait loci (eQTLs) at these loci. Together, the identified genes provide a framework for the genetic architecture and pathobiology of vitiligo, highlight relationships with other autoimmune diseases and melanoma, and offer potential targets for treatment.

Oxidative stress and immune system in vitiligo and thyroid diseases.

Vitiligo is an acquired dermatological disease frequently associated with autoimmune thyroid disorders. Several theories have been proposed so far to unravel the complex vitiligo pathogenesis. Currently, the autocytotoxic and the autoimmune theories are the most accredited hypothesis, since they are sustained by several important clinical and experimental evidences. A growing body of evidences shows that autoimmunity and oxidative stress strictly interact to finally determine melanocyte loss. In this scenario, associated thyroid autoimmunity might play an active and important role in triggering and maintaining the depigmentation process of vitiligo.