Pruritus is a common and distressing symptom among dialysis patients, yet its underlying mechanisms remain incompletely understood. Most previous research has focused on systemic inflammatory markers, while little is known about local skin alterations contributing to pruritus. This study aimed to characterize skin biomarker profiles in dialysis patients with pruritus, in comparison with dialysis patients without pruritus and healthy controls, and to explore differences between pruritic and non-pruritic skin sites. In this multi-center cross-sectional exploratory study, stratum corneum samples were obtained using the tape-stripping method from 91 participants (67 dialysis patients and 24 healthy controls). Biomarkers were quantified, and adjusted linear and logistic (mixed) models were used to assess group differences and skin site variations. Dialysis patients with pruritus exhibited a significantly elevated IL-1RA/IL-1α ratio and reduced IL-18 levels compared to non-pruritic patients. There was also a strong indication of concomitant increases in IL-1RA and IFN-β in pruritic skin. Across all dialysis patients, IL-8, CCL17, and CXCL10 levels were significantly lower than in healthy controls, independent of pruritus status. Dialysis patients with pruritus demonstrate distinct alterations in skin immune profiles suggestive of localized inflammation and potential involvement of the opioid pathway. These findings provide new insights into the inflammatory mechanisms underlying pruritus in this population and may inform the development of targeted, personalized therapies.

Vitiligo is an autoimmune disease characterized by depigmented skin lesions, caused by autoreactive-CD8-T-cells inducing melanocyte apoptosis. Effective treatment is challenging due to limited understanding of the processes underlying skin repigmentation. This study aimed to identify these processes using proteomics. Plasma and skin blister-fluid samples from 30 patients with vitiligo starting standard-of-care treatment were analyzed. A large proteomic screen of 5080 proteins was measured with Somascan on samples collected at baseline and at 3 months of treatment. Analyses of proteins that changed and did not change under treatment, revealed 5 proteins associated with repigmentation. Higher baseline levels of T-cell immunoglobulin and mucin domain 1, trefoil factor 3, and NACHT, LRR and PYD domains-containing protein 1 in blister-fluid and an increase of keratin type II cytoskeletal 5 in plasma under treatment, were associated with repigmentation. T-cell immunoglobulin and mucin domain 1 and trefoil factor 3 have immunosuppressive effects, while NACHT, LRR and PYD domains-containing protein 1 and keratin type II cytoskeletal 5 can stimulate melanogenesis. The NACHT, LRR and PYD domains-containing protein 1-inflammasome pathway was enriched in these proteins. These proteins and pathways were distinct from the previously identified differences between lesional and non-lesional skin, indicating differential expression of melanocyte-specific pathways. This suggests that treatment-induced repigmentation in vitiligo involves processes other than simply reversing lesional skin to a non-lesional state. These findings enhance the understanding of repigmentation in vitiligo and could guide future therapeutic strategies.

Response to immune checkpoint inhibitors (ICIs) in metastatic melanoma (MM) varies among patients, and current baseline biomarkers predicting treatment outcomes are limited. As mitochondrial (MT) metabolism has emerged as an important regulator of host immune function, we explored the association of host MT genetics (MT haplogroups) with ICI efficacy in 1,225 ICI-treated patients with MM from the clinical trial CheckMate-067 and the International Germline Immuno-Oncology Melanoma Consortium. We discovered and validated significant associations of MT haplogroup T (HG-T) with resistance to anti-programmed cell death protein-1-based ICI (both single-agent and combination) and have shown that HG-T is independent from established tumor predictors. We also found that patients belonging to HG-T exhibit a unique nivolumab-resistant baseline peripheral CD8+ T cell repertoire compared to other MT haplogroups, providing, to our knowledge, the first link between MT inheritance, host immunity and ICI resistance. The study proposes a host blood-based biomarker with stand-alone clinical value predicting ICI efficacy and points to an ICI-resistance mechanism associated with MT metabolism, with clinical relevance in immuno-oncology.

During the COVID-19 pandemic, the daily life of many patients with dermatological immune-mediated inflammatory diseases (DIMIDs), such as atopic dermatitis (AD), psoriasis, and vitiligo, was impacted by social restrictions caused by (fear of) morbidity, mortality associated with COVID-19, and vaccine hesitancy. This prospective observational, multicenter, multidisciplinary cohort study explored the impact of COVID-19 disease and vaccination on DIMIDs, specifically AD, psoriasis, and vitiligo. Data from patients with DIMIDs were collected as part of the Target2B! study (between February 2021 and October 2022). We analyzed the differences in baseline characteristics, risk of developing COVID-19, proportion of DIMIDs in patients reaching seroconversion upon vaccination per DIMID, and self-reported increase in DIMID activity by multivariable logistic regression and sensitivity analyses. A total of 424 patients with DIMID were included. COVID-19 disease commonly occurred in patients with vitiligo (51.1%), AD (42.0%), and psoriasis (34.3%) (p = 0.038). COVID-19 was not associated with the use of immunosuppressive therapy. Three patients (two with AD and one with vitiligo) were hospitalized due to COVID-19. Nearly all patients with DIMIDs exhibited effective seroconversion after regular vaccination regimens (vitiligo 100%, psoriasis 97.9%, AD 96.5%). Increased DIMID activity after COVID-19 (6.6%) or severe acute respiratory syndrome-related coronavirus (SARS-CoV-2) vaccination (12.26%) was reported in a minority of patients, with baseline progressive disease (disease activity 3 months preceding baseline survey) being the only associated risk factor (COVID-19: odds ratio [OR], 4.27 [p = 0.02]; vaccination OR, 3.45 [p = 0.002]). In conclusion, no alarming signs were shown in this study regarding (severe) COVID-19 in patients with AD, psoriasis, or vitiligo. Vaccination against COVID-19 is advised in patients with DIMIDs. Moreover, patients with DIMIDs can safely continue their immunosuppressant therapy, since this does not increase the risk of COVID-19, while vaccination-induced humoral responses are adequate. In only a minority of patients, increased DIMID activity after COVID-19 or SARS-CoV-2 vaccination occurred.

The treatment of nonsegmental vitiligo remains challenging and poorly understood. The aim of this study was to evaluate protein differences in lesional and nonlesional skin and changes of cellular and proteomic markers early in treatment in lesional skin and blood in relation to clinical response. This prospective exploratory study was conducted in 30 patients with nonsegmental vitiligo, 11 starting with standard-of-care topical therapy and 19 starting in combination with narrow-band UVB phototherapy. We identified 53 proteins that differed between blister fluids from lesional and nonlesional skin before treatment. After 3 months of therapy, CD3+, CD8+ T, and tissue-resident memory (CD69+CD103-) cell populations decreased in skin biopsies, together with changes in 47 blister fluid proteins. Percentages of circulating follicular T helper type 17, CD336+Nkbright, type 1 regulatory T (Tr1), and IL-10-secreting Tr1 cells decreased in blood. Decreases in tissue-resident memory, Tr1, and IL-10-secreting Tr1 cells and fatty acid-binding protein 4 were associated with repigmentation, measured by Vitiligo Extent Score at baseline and 6 months. Differences in lesional and nonlesional skin prior to treatment do not reflect changes in lesional skin early in therapy nor associations with clinical repigmentation response. We found an association between decreasing fatty acid-binding protein 4 and tissue-resident memory cells in the skin and IL-10-secreting Tr1 cells in the blood and repigmentation response to treatment of vitiligo.

Background: Tumor heterogeneity is a hurdle to effective therapy, as illustrated by the ‘mixed responses’ frequently seen in immunotherapy-treated patients. Previously, AXL+ tumor cells were identified to be highly resistant to targeted therapy, whereas more differentiated MITF+ tumor cells do respond to RAF and MEK inhibitors. Patients and methods: In this study, we analyzed tumor heterogeneity and explored the presence of the previously described AXL+ or MITF+ melanoma subpopulations in metastatic tissues by NanoString gene expression analysis, single-cell RNA sequencing and in situ multiplex immunofluorescence. Furthermore, we analyzed how these subpopulations correlate with immunological pressure and response to immunotherapy by immunomodulating antibodies or autologous tumor lysate-loaded dendritic cell vaccination. Results: Our data demonstrate large interpatient variability and variable therapy-induced changes independent of the type of therapy. We identify the presence of previously described AXL+ and MITF+ subpopulations in metastatic tissues both at the mRNA level and in situ at the protein level, and demonstrate that MITF+ melanoma cells are significantly decreased upon immunotherapy, while AXL+ melanoma cell numbers are stable. MITF+ tumor cells showed the most significant inverse correlation with CD8+ T cells. Our patient cohort also shows that immunotherapy-induced changes in the abundance of AXL+ or MITF+ tumor cells did not correlate with improved survival. Conclusions: Overall, this study suggests that more differentiated MITF+ tumors are efficiently targeted by immunotherapy, while AXL+ tumor cells may be more resistant, analogous to their response to targeted therapy.

Regulatory T cells (Tregs), a suppressive subpopulation of T cells, are potent mediators of peripheral tolerance, responsible for immune homeostasis. Many autoimmune diseases exhibit disruptions in Treg function or quantity, resulting in an imbalance between protective and pathogenic immune cells. Selective expansion or manipulation of Tregs is a promising therapeutic approach for autoimmune diseases. However, the extensive diversity of Treg subpopulations and the multiple approaches used for Treg identification leads to high complexity, making it difficult to develop a successful treatment capable of modulating Tregs. In this review, we describe the suppressive mechanisms, subpopulations, classification, and identification methodology for Tregs, and their role in the pathogenesis of autoimmune diseases.

International Journal of DermatologyVolume 63, Issue 1 p. e4-e6 Correspondence Addition of cell suspension transplantation to UVB and topical treatment in non-segmental vitiligo: a randomized controlled study Sanne E. Uitentuis MD, PhD, Corresponding Author Sanne E. Uitentuis MD, PhD [email protected] orcid.org/0000-0002-6031-2116 Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the NetherlandsSearch for more papers by this authorJanny E. Lommerts MD, PhD, Janny E. Lommerts MD, PhD Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the NetherlandsSearch for more papers by this authorMarcella Willemsen MSc, Marcella Willemsen MSc Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the NetherlandsSearch for more papers by this authorKarina Willemsen, Karina Willemsen Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the NetherlandsSearch for more papers by this authorMenno A. de Rie MD, PhD, Menno A. de Rie MD, PhD Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the NetherlandsSearch for more papers by this authorRosalie M. Luiten PhD, Rosalie M. Luiten PhD Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the NetherlandsSearch for more papers by this authorMarcel W. Bekkenk MD, PhD, Marcel W. Bekkenk MD, PhD Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the NetherlandsSearch for more papers by this authorAlbert Wolkerstorfer MD, PhD, Albert Wolkerstorfer MD, PhD Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the NetherlandsSearch for more papers by this author Sanne E. Uitentuis MD, PhD, Corresponding Author Sanne E. Uitentuis MD, PhD [email protected] orcid.org/0000-0002-6031-2116 Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the NetherlandsSearch for more papers by this authorJanny E. Lommerts MD, PhD, Janny E. Lommerts MD, PhD Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the NetherlandsSearch for more papers by this authorMarcella Willemsen MSc, Marcella Willemsen MSc Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the NetherlandsSearch for more papers by this authorKarina Willemsen, Karina Willemsen Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the NetherlandsSearch for more papers by this authorMenno A. de Rie MD, PhD, Menno A. de Rie MD, PhD Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the NetherlandsSearch for more papers by this authorRosalie M. Luiten PhD, Rosalie M. Luiten PhD Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the NetherlandsSearch for more papers by this authorMarcel W. Bekkenk MD, PhD, Marcel W. Bekkenk MD, PhD Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the NetherlandsSearch for more papers by this authorAlbert Wolkerstorfer MD, PhD, Albert Wolkerstorfer MD, PhD Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Institute for Infection and Immunity, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the NetherlandsSearch for more papers by this author First published: 15 November 2023 https://doi.org/10.1111/ijd.16900 Conflict of interest: None. Funding source: A.W. received a research grant from Avita Medical. S.U. was supported by this research grant. The harvesting devices were provided by Avita Medical. Outside the submitted work A.W. reports grants from Novartis, Incyte, and Lumenis. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat No abstract is available for this article. References 1Mulekar SV. Long-term follow-up study of segmental and focal vitiligo treated by autologous, noncultured melanocyte-keratinocyte cell transplantation. Arch Dermatol. 2004; 140: 1211–1215. 10.1001/archderm.140.10.1211 PubMedWeb of Science®Google Scholar 2Van Geel N, Wallaeys E, Goh BK, De Mil M, Lambert J. Long-term results of noncultured epidermal cellular grafting in vitiligo, halo naevi, piebaldism and naevus depigmentosus. Br J Dermatol. 2010; 163: 1186–1193. 10.1111/j.1365-2133.2010.10014.x CASPubMedWeb of Science®Google Scholar 3Verma R, Grewal RS, Chatterjee M, Pragasam V, Vasudevan B, Mitra D. A comparative study of efficacy of cultured versus non cultured melanocyte transfer in the management of stable vitiligo. Med J Armed Forces India. 2014; 70: 26–31. 10.1016/j.mjafi.2013.09.004 PubMedGoogle Scholar 4Kachhawa D, Rao P, Kalla G. Simplified non-cultured non-trypsinised epidermal cell graft technique followed by psoralen and ultraviolet a light therapy for stable vitiligo. J Cutan Aesthet Surg. 2017; 10: 81–85. 10.4103/JCAS.JCAS_119_16 PubMedGoogle Scholar 5El-Zawahry BM, Zaki NS, Bassiouny DA, Sobhi RM, Zaghloul A, Khorshied MM, et al. Autologous melanocyte-keratinocyte suspension in the treatment of vitiligo. J Eur Acad Dermatol Venereol. 2011; 25: 215–220. 10.1111/j.1468-3083.2010.03759.x CASPubMedWeb of Science®Google Scholar Volume63, Issue1January 2024Pages e4-e6 ReferencesRelatedInformation

Non-melanoma skin cancers (NMSCs) occur frequently in the Caucasian population and are considered a burden for health care. Risk factors include ultraviolet (UV) radiation, ethnicity and immunosuppression. The incidence of NMSC is significantly higher in solid organ transplant recipients (SOTRs) than in immunocompetent individuals, due to immunosuppressive medication use by SOTRs. While the immunosuppressive agents, calcineurin inhibitors and purine analogues increase the incidence of NMSC in transplant recipients, mTOR inhibitors do not. This is most likely due to the different immunological pathways that are inhibited by each class of drug. This review will focus on what is currently known about the immune response against cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma (BCC), two of the main types of NMSC. Furthermore, we will describe the different classes of immunosuppressants given to SOTRs, which part of the immune system they target and how they can contribute to NMSC development. The risk of developing NMSC in SOTRs is the result of a combination of inhibiting immunological pathways involved in immunosurveillance against NMSC and the direct (pro/anti) tumor effects of immunosuppressants.

Clinical Implications•Patients with vitiligo have less risk of skin cancer.•There is a lower mutational burden in vitiligo lesions, despite lack of pigmentation.•Increased DNA repair may decrease mutational burden and skin cancer risk. •Patients with vitiligo have less risk of skin cancer.•There is a lower mutational burden in vitiligo lesions, despite lack of pigmentation.•Increased DNA repair may decrease mutational burden and skin cancer risk. Vitiligo is an autoimmune disease that targets skin melanocytes, resulting in a localized loss of epidermal melanocytes visible as depigmented skin lesions. Individuals with low skin pigmentation levels generally have an increased risk of skin cancer. However, the incidence of both melanoma and nonmelanoma skin cancer (NMSC) turns out to be lower in patients with vitiligo than in healthy individuals, despite the lack of pigmentation in vitiligo lesions or treatment by UV phototherapy (Paradisi et al., 2014Paradisi A. Tabolli S. Didona B. Sobrino L. Russo N. Abeni D. Markedly reduced incidence of melanoma and nonmelanoma skin cancer in a nonconcurrent cohort of 10,040 patients with vitiligo.J Am Acad Dermatol. 2014; 71: 1110-1116Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar; Teulings et al., 2013Teulings H.E. Overkamp M. Ceylan E. Nieuweboer-Krobotova L. Bos J.D. Nijsten T. et al.Decreased risk of melanoma and nonmelanoma skin cancer in patients with vitiligo: a survey among 1307 patients and their partners.Br J Dermatol. 2013; 168: 162-171Crossref PubMed Scopus (130) Google Scholar). Gupta et al., 2022Gupta I. Shankrit S. Narta K. Ghazi M. Grover R. Pandey R. et al.Whole-exome sequencing of vitiligo lesions indicates lower burden of somatic variations: implications in risk for nonmelanoma skin cancers.J Invest Dermatol. 2023; 143 (e8): 1111-1114Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar investigated the mutational burden in vitiligo skin as a potential mechanism for the decreased NMSC risk. They performed whole-exome sequencing of vitiligo skin samples and found a lower burden of somatic variations in lesional skin than in nonlesional skin of patients with vitiligo. Transcriptome analysis indicated upregulation of nuclear division and cellular response genes to DNA damage gene pathways in lesional skin. This is an intriguing finding, as increased DNA repair could contribute to the lower risk of skin cancer in vitiligo skin. Moreover, the authors chose to compare sun-exposed lesional skin with sun-protected nonlesional skin (Gupta et al., 2022Gupta I. Shankrit S. Narta K. Ghazi M. Grover R. Pandey R. et al.Whole-exome sequencing of vitiligo lesions indicates lower burden of somatic variations: implications in risk for nonmelanoma skin cancers.J Invest Dermatol. 2023; 143 (e8): 1111-1114Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar). Although more mutations would be expected in sun-exposed skin, these were lower in sun-exposed lesional skin than in sun-protected nonlesional skin. Therefore, the actual difference in mutational burden in lesional and nonlesional skin, both without sun exposure, may thus be even larger. The higher DNA repair in lesional skin would also imply that skin cancer lesions occur less in vitiligo lesions than in nonlesional skin. Although a systematic analysis of the localization of basal cell carcinoma (BCC) or cutaneous squamous cell carcinoma (SCC) lesions in patients with vitiligo is lacking, the occurrence of a BCC or SCC lesion within vitiligo lesions seems rare (Nordlund, 2011Nordlund J.J. Vitiligo: a review of some facts lesser known about depigmentation.Indian J Dermatol. 2011; 56: 180-189Crossref PubMed Scopus (23) Google Scholar; Rustemeyer et al., 2011Rustemeyer J. Günther L. Deichert L. A rare association: basal cell carcinoma in a vitiliginous macula.Oral Maxillofac Surg. 2011; 15: 175-177Crossref PubMed Scopus (9) Google Scholar), suggesting a lower incidence of skin cancer lesions in depigmented vitiligo skin. The difference in mutational burden between lesional and nonlesional skin might also imply that keratinocytes (KCs) differ between lesional and nonlesional skin. Indeed, the lesional KCs displayed holoclone-forming cells, characterized by stem cell properties and a higher self-renewal and DNA repair capacity. The observed upregulation of nuclear division genes, indicative of higher cell turnover, might result in faster clearance of mutant cells and a lower mutational burden. This finding raises the question of why KCs phenotypically differ between lesional and nonlesional skin and also whether this phenotypic difference is induced in KCs during the development of new vitiligo lesions. In other words, does the presence or absence of melanocytes alter the phenotype of KCs or influence the level of skin DNA repair in KCs in particular? In melanocytes, the control of DNA repair and pigmentation has been linked by the cofactor Mediator complex MED23 through the melanocyte master regulator MITF, leading to opposing effects on pigmentation and DNA repair (Xia et al., 2017Xia M. Chen K. Yao X. Xu Y. Yao J. Yan J. et al.Mediator MED23 links pigmentation and DNA repair through the transcription factor MITF.Cell Rep. 2017; 20: 1794-1804Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). The UV response in skin is mediated by paracrine factors produced by KCs, acting on melanocytes, leading to melanin production and transfer to KCs (Abdel-Malek et al., 2010Abdel-Malek Z.A. Kadekaro A.L. Swope V.B. Stepping up melanocytes to the challenge of UV exposure.Pigment Cell Melanoma Res. 2010; 23: 171-186Crossref PubMed Scopus (107) Google Scholar). However, any paracrine impact of melanocytes on KC phenotype or DNA repair is not known. The epidemiologic data on the decreased skin cancer risk in patients with vitiligo were based on a comparison of patients with vitiligo and healthy controls (Paradisi et al., 2014Paradisi A. Tabolli S. Didona B. Sobrino L. Russo N. Abeni D. Markedly reduced incidence of melanoma and nonmelanoma skin cancer in a nonconcurrent cohort of 10,040 patients with vitiligo.J Am Acad Dermatol. 2014; 71: 1110-1116Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar; Teulings et al., 2013Teulings H.E. Overkamp M. Ceylan E. Nieuweboer-Krobotova L. Bos J.D. Nijsten T. et al.Decreased risk of melanoma and nonmelanoma skin cancer in patients with vitiligo: a survey among 1307 patients and their partners.Br J Dermatol. 2013; 168: 162-171Crossref PubMed Scopus (130) Google Scholar). Therefore, the question arises whether the mutational burden in the nonlesional skin of patients with vitiligo is lower than that in healthy individuals. This question concerns the difference in whole-body mutational burden in both groups, which has not yet been addressed by the reported intra-patient comparisons of lesional and nonlesional skin of patients with vitiligo (Gupta et al., 2022Gupta I. Shankrit S. Narta K. Ghazi M. Grover R. Pandey R. et al.Whole-exome sequencing of vitiligo lesions indicates lower burden of somatic variations: implications in risk for nonmelanoma skin cancers.J Invest Dermatol. 2023; 143 (e8): 1111-1114Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar). The authors included a preliminary comparison of the vitiligo data to an independent data set of healthy donors, which is suggestive of this conclusion. It is tempting to speculate that increased DNA repair and a lower mutational burden in patients with vitiligo lead to a lower skin cancer risk in patients with vitiligo than in healthy individuals. This question therefore deserves further investigation through a direct comparative study of matched cohorts of patients with vitiligo and healthy controls. Such a study might, however, be practically challenging because of the variations in mutational burden among individuals, requiring a large number of participants and skin types. To minimize the influence of variation in sun exposure levels because of geographical locations, such studies might be best performed in sun-protected skin areas. Interestingly, a lower incidence of other cancers has also been reported in patients with vitiligo than in healthy controls (Wen et al., 2020Wen Y. Wu X. Peng H. Li C. Jiang Y. Liang H. et al.Cancer risks in patients with vitiligo: a Mendelian randomization study.J Cancer Res Clin Oncol. 2020; 146: 1933-1940Crossref PubMed Scopus (12) Google Scholar). In this context, it would be fascinating to know whether other tissues than the skin in patients with vitiligo also display increased DNA repair activity and decreased mutational load. This phenomenon might thereby lower the risk of more cancer types than just skin cancer, for example, by eliminating the mutagenic effects of smoking in respiratory tract cells or other carcinogens. The germline genetic susceptibility to vitiligo has been well characterized, predominantly including immune-related genes and, to a lesser extent, pigmentation genes (Jin et al., 2016Jin Y. Andersen G. Yorgov D. Ferrara T.M. Ben S. Brownson K.M. et al.Genome-wide association studies of autoimmune vitiligo identify 23 new risk loci and highlight key pathways and regulatory variants.Nat Genet. 2016; 48: 1418-1424Crossref PubMed Scopus (182) Google Scholar). No DNA repair genes were found in the vitiligo genetic profile, arguing against DNA repair as an inherited feature of vitiligo. However, it does not exclude the possibility of aberrant regulation of DNA repair at the protein level. Including another tissue than skin, if feasible, in the comparative study of mutational burden in patients with vitiligo and healthy controls would shed light on this question. The lower skin cancer risk found in patients with vitiligo likely also involves autoimmune activity. In the context of the study by Gupta et al., 2022Gupta I. Shankrit S. Narta K. Ghazi M. Grover R. Pandey R. et al.Whole-exome sequencing of vitiligo lesions indicates lower burden of somatic variations: implications in risk for nonmelanoma skin cancers.J Invest Dermatol. 2023; 143 (e8): 1111-1114Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar, it is relevant to mention that a higher mutational burden may also give rise to mutated proteins that may be recognized as foreign by the immune system as neo-antigens (Schumacher and Schreiber, 2015Schumacher T.N. Schreiber R.D. Neoantigens in cancer immunotherapy.Science. 2015; 348: 69-74Crossref PubMed Scopus (3367) Google Scholar). A lower mutational burden may thus decrease the chance of malignant cells being eliminated by the immune system. However, the increased immune activation state in patients with vitiligo may still provide immune surveillance against malignant cells that arise despite the lower mutation frequency. In conclusion, the lower mutational burden found in vitiligo is likely an important aspect determining the risk of skin cancer, as a skin biological feature in combination with the autoimmune pathogenesis of vitiligo. The author states no conflict of interest. Whole-Exome Sequencing of Vitiligo Lesions Indicates Lower Burden of Somatic Variations: Implications in Risk for Nonmelanoma Skin CancersJournal of Investigative DermatologyVol. 143Issue 6PreviewGenetic depigmentary conditions such as albinism with complete loss of epidermal pigmentation pose a higher risk for cutaneous malignancies (Lekalakala et al., 2015; Kromberg et al., 1989). By analogy, clinical management for photoprotection of the acquired depigmented skin in vitiligo is of serious concern. It is believed that vitiligo would pose a similar, elevated risk. Systematic evaluation of a large cohort of subjects with vitiligo indicated a decreased risk for both melanoma and nonmelanoma skin cancers (Hexsel et al., 2009; Kim et al., 2020; Paradisi et al., 2014; Rodrigues, 2017; Schallreuter et al., 2002; Teulings et al., 2013; Weng et al., 2021). Full-Text PDF

INTRODUCTION:Lesional skin of atopic dermatitis (AD) is often colonised by Staphylococcus aureus and the bacterial abundance increases during a flare. However, the role of S. aureus and the skin microbiome in the pathogenesis of AD, including its influence on the dysfunctional skin barrier and immune response, remains to be elucidated. In this study, the temporal relationship between alterations in the skin barrier function, inflammation and microbiome is examined in adults with AD.METHODS AND ANALYSIS:This clinical study consists of 81 adult patients with AD, as defined by the Hanifin and Rajka criteria, and 41 age and sex-matched controls. The objectives are to examine alterations in the skin microbiome, skin barrier and immune response during (1) an untreated AD flare, (2) an AD flare treated with topical corticosteroids (TCS), (3) an AD flare treated with systemic dicloxacillin/placebo and TCS or (4) cutaneous exposure to either autologous S. aureus, staphylococcal enterotoxin B or a vehicle. Skin biopsies, tape strips, skin and nasal swabs are collected and analysed using RNA sequencing, multiplex immunoassays, liquid chromatography-mass spectrometry and 16S rDNA. Blood samples are analysed for filaggrin gene mutations and leucocyte gene expression.ETHICS AND DISSEMINATION:The scientific Ethical Committee of the Capital Region in Denmark (phases I and II: H-20011047, phases III and IV: H-21079287), the local data protection agency (phases I and II: P-2020-165, phases III and IV: P-2022-250) and the Danish Medicines Agency (phases III and IV: EudraCT 2021-006883-25, ClinicalTrials.gov: NCT05578482) have approved the studies. Participants will give written informed consent prior to study initiation. The study is conducted in accordance with the Helsinki Declaration. Outcomes will be presented at national and international conferences and in international peer-reviewed publications.TRIAL REGISTRATION NUMBER:NCT05578482, EudraCT 2021-006883-2.

Vitiligo is caused by an autoimmune reaction against melanocytes leading to melanocyte loss. The cause of vitiligo is an interaction between genetic susceptibility and environmental factors. Both the adaptive immune system-through cytotoxic CD8+ T cells and melanocyte specific antibodies-and the innate immune system are involved in these immune processes in vitiligo. While recent data stressed the importance of innate immunity in vitiligo, the question remains why vitiligo patients' immune response becomes overly activated. Could a long-term increase in innate memory function, described as trained immunity after vaccination and in other inflammatory diseases, play a role as an enhancer and continuous trigger in the pathogenesis of vitiligo? After exposure to certain stimuli, innate immune system is able to show an enhanced immunological response to a secondary trigger, indicating a memory function of the innate immune system, a concept termed trained immunity. Trained immunity is regulated by epigenetic reprogramming, including histone chemical modifications and changes in chromatin accessibility that cause sustained changes in the transcription of specific genes. In responses to an infection, trained immunity is beneficial. However, there are indications of a pathogenic role of trained immunity in inflammatory and autoimmune diseases, with monocytes presenting features of a trained phenotype, resulting in increased cytokine production, altered cell metabolism through mTOR signaling, and epigenetic modifications. This hypothesis paper focusses on vitiligo studies that have shown these indications, suggesting the involvement of trained immunity in vitiligo. Future studies focusing on metabolic and epigenetic changes in innate immune cell populations in vitiligo could help in elucidating the potential role of trained immunity in vitiligo pathogenesis.

Journal of the European Academy of Dermatology and VenereologyVolume 37, Issue 6 p. e782-e785 LETTER TO THE EDITOR NB-UVB phototherapy response of different body regions in non-segmental vitiligo This article relates to: Deciphering differential response to NB-UVB: The hair matters Rhea Ahuja, Somesh Gupta, Journal of the European Academy of Dermatology and Venereology First Published online: November 16, 2023 Vidhya S. Narayan, Corresponding Author Vidhya S. Narayan [email protected] orcid.org/0000-0003-4328-1132 Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, Location University of Amsterdam, Amsterdam, The Netherlands Correspondence Vidhya S. Narayan, Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Email: [email protected]Search for more papers by this authorElnaz Alagha, Elnaz Alagha Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, Location University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorWouter Ouwerkerk, Wouter Ouwerkerk Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, Location University of Amsterdam, Amsterdam, The Netherlands National Heart Centre Singapore, Hospital Drive, Singapore City, SingaporeSearch for more papers by this authorSanne E. Uitentuis, Sanne E. Uitentuis orcid.org/0000-0002-6031-2116 Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, Location University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorJanny E. Lommerts, Janny E. Lommerts Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, Location University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorSamia Esmat, Samia Esmat Department of Dermatology, Faculty of Medicine Cairo University, Cairo, EgyptSearch for more papers by this authorRania M. Mogawer, Rania M. Mogawer Department of Dermatology, Faculty of Medicine Cairo University, Cairo, EgyptSearch for more papers by this authorNanis Ragab, Nanis Ragab Department of Dermatology, Faculty of Medicine Cairo University, Cairo, EgyptSearch for more papers by this authorSai Yee Chuah, Sai Yee Chuah orcid.org/0000-0003-1321-4377 Department of Dermatology, National Skin Centre, Singapore City, SingaporeSearch for more papers by this authorSteven Thng, Steven Thng Department of Dermatology, National Skin Centre, Singapore City, SingaporeSearch for more papers by this authorAlbert Wolkerstorfer, Albert Wolkerstorfer Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, Location University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorRosalie M. Luiten, Rosalie M. Luiten Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, Location University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorMarcel W. Bekkenk, Marcel W. Bekkenk Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, Location University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this author Vidhya S. Narayan, Corresponding Author Vidhya S. Narayan [email protected] orcid.org/0000-0003-4328-1132 Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, Location University of Amsterdam, Amsterdam, The Netherlands Correspondence Vidhya S. Narayan, Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, Location University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Email: [email protected]Search for more papers by this authorElnaz Alagha, Elnaz Alagha Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, Location University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorWouter Ouwerkerk, Wouter Ouwerkerk Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, Location University of Amsterdam, Amsterdam, The Netherlands National Heart Centre Singapore, Hospital Drive, Singapore City, SingaporeSearch for more papers by this authorSanne E. Uitentuis, Sanne E. Uitentuis orcid.org/0000-0002-6031-2116 Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, Location University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorJanny E. Lommerts, Janny E. Lommerts Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, Location University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorSamia Esmat, Samia Esmat Department of Dermatology, Faculty of Medicine Cairo University, Cairo, EgyptSearch for more papers by this authorRania M. Mogawer, Rania M. Mogawer Department of Dermatology, Faculty of Medicine Cairo University, Cairo, EgyptSearch for more papers by this authorNanis Ragab, Nanis Ragab Department of Dermatology, Faculty of Medicine Cairo University, Cairo, EgyptSearch for more papers by this authorSai Yee Chuah, Sai Yee Chuah orcid.org/0000-0003-1321-4377 Department of Dermatology, National Skin Centre, Singapore City, SingaporeSearch for more papers by this authorSteven Thng, Steven Thng Department of Dermatology, National Skin Centre, Singapore City, SingaporeSearch for more papers by this authorAlbert Wolkerstorfer, Albert Wolkerstorfer Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, Location University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorRosalie M. Luiten, Rosalie M. Luiten Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, Location University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this authorMarcel W. Bekkenk, Marcel W. Bekkenk Department of Dermatology, Netherlands Institute for Pigment Disorders, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, Location University of Amsterdam, Amsterdam, The NetherlandsSearch for more papers by this author First published: 03 February 2023 https://doi.org/10.1111/jdv.18946Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat REFERENCES 1Nordal EJ, Guleng GE, Rönnevig JR. 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Although light skin types are associated with increased skin cancer risk, a lower incidence of both melanoma and nonmelanoma skin cancer (NMSC) has been reported in patients with vitiligo. We performed a systematic review and meta-analysis on the NMSC risk in patients with vitiligo, indicating a reduced relative risk ratio of NMSC in vitiligo. Furthermore, we propose a series of hypotheses on the underlying mechanisms, including both immune-mediated and nonimmunemediated pathways. This study reveals insights into the relationship between vitiligo and keratinocyte cancer and can also be used to better inform patients with vitiligo.

Non-melanoma skin cancer (NMSC) represents the most frequent type of cancers among Caucasians. Consisting of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), which both develop in the epidermis of the skin. The incidence of NMSC has increased by 33% over the past 10 years. The steadily increasing number of cases continue to cause burden to society and health care. Vitiligo is an autoimmune disease characterized by white depigmented skin lesions due to local loss of melanocytes. We showed the protective effect of vitiligo against melanoma and clinical and epidemiological data suggest that vitiligo may also suppress NMSC. Non-immunological pathways, such as the p53 pathway of which increased expression has been found in vitiligo skin, could be involved in the protection against NMSC. The aim of this study is to explore the potential role of p53 expression in vitiligo skin and its relation to NMSC. Validation of the increased P53 expression in vitiligo skin will be done using lesional and nonlesional biopsies versus healthy skin. Additionally, p53 deregulation in keratinocytes and infiltrating immune cells will be explored using two independent scRNAseq vitiligo datasets and confirmed using immunohistochemistry. Furthermore we will analyze p53 expression in BCCs from a vitiligo patient who developed halo-regions (depigmented regions) around superficial BCCs that partially went into regression, while nodular BCCs without a halo did not. Additionally, we will investigate if p53 expression correlates NMSC regression. Finally we will explore if imiquimod also induces p53 expression in normal skin.

ABSTRACT:The infiltration of tissue-resident memory (TRM) cells in melanoma correlates with improved survival, suggesting an important role for TRM cells in immunity against melanoma. However, little is known about the presence of TRM cells in nonmalignant and premalignant melanocytic lesions. This study aimed to evaluate the presence of TRM cells in human skin melanocytic lesions, representing the spectrum from healthy skin to metastatic melanoma. FFPE sections from healthy skin, sun-exposed skin, benign nevi, lentigo maligna (LM), primary LM melanoma, and primary cutaneous and metastatic melanoma were analyzed by immunohistochemistry. The number of infiltrating cells expressing TRM-associated markers, CD3, CD4, CD8, CD69, CD103, and CD49a, was quantified by digital analyses. Multiplex immunofluorescence was performed to analyze coexpression of TRM cell markers. More T cells and CD69+ cells were found in melanoma lesions, as compared with healthy skin and nevi. CD103+ and CD49a+ cell numbers did not significantly differ. More importantly, no differences were seen in expression of all markers between healthy skin and benign nevi. Similar results, except for CD69, were observed in LM melanoma, as compared with LM and sun-exposed skin. Interestingly, multiplex immunofluorescence showed that nevi tissues have comparable CD103+ T cell numbers with healthy skin but comprise more CD103+ CD8+ cells. Expression of TRM cell markers is significantly increased in melanoma, as compared with nonmalignant skin. Our data also show that TRM cells are not abundantly present already in premalignant tissues. Further studies on the specificity of TRM cells for melanocyte/melanoma antigens may reveal their significance in cancer immunosurveillance.

Narrow-Band Ultraviolet B (NB-UVB) in combination with topical therapy is a widely used treatment for non-segmental vitiligo (NSV). The location of the vitiligo lesions is of influence on the potential repigmentation response after therapy. To date however, these differences in therapeutic response between specific anatomical areas of the body have not been fully characterized. This study aimed to evaluate the clinical response NB-UVB therapy in 19 different body regions. A multicentre study of NSV patients starting with NB-UVB therapy was performed in hospitals in Egypt, Singapore and the Netherlands. Evaluation of the depigmented surface area of 19 different body regions was conducted with the VES at baseline and after 6 months of therapy. A total of 101 NSV patients completed the study. The highest repigmentation was found in lesions on the lower facial region, followed by the upper facial region and lower trunk (> 75% repigmentation in 58%, 48% and 46% of the patients, respectively). The lower face showed a significant better repigmentation than the upper face. The lowest repigmentation rates (<25% repigmentation) were observed at the feet (81%), followed by the hands (68%). Left-right and dorsal-ventral sides of the body demonstrated no significant differences in repigmentation. In addition, lesions on the torso and limbs showed similar repigmentation after treatment. This study is the first to evaluate and compare 19 different body regions after NB-UVB therapy. We found that the BSA can be classified into 4 composite body regions with similar prognosis of repigmentation after treatment, i.e. face; torso&limbs; axillae; hands&feet, from highest to lowest repigmentation, respectively. These results may be of direct use to clinicians as it provides more detailed information on treatment prognosis per body region.

To date the COVID-19 pandemic is still ongoing with over 5 million registered deaths and over 1 million confirmed new cases daily Still limited information about the possible risks and protective factors for the severity and mortality of COVID-19 The initiation of the immune response in vitiligo is triggered by IFN-I production. Likewise, IFN-I and plasmacytoid dendritic cells (pDCs) play also an important role against SARS-CoV-2 virus including COVID-19 Patients with vitiligo have a genetic susceptibility profile that encodes for immune and apoptotic regulators A retrospective online questionnaire study (4 categories) was conducted in a cohort of vitiligo patients and healthy controls between November 2021 and January 2022. Categories: 1. Participant characteristics 2. COVID-19 risk factors 3. COVID-19 4. Vitiligo 209 participants completed the questionnaire 1. Do vitiligo patients clear a SARS-CoV-2 infection more efficiently compared to healthy controls? There was no significant relationship between vitiligo and developing COVID-19 [P=.930]. 35 [22%] vitiligo patients and 11 [22%] controls developed COVID-19. Univariate logistic regression models showed no confounding factors for developing COVID-19. 2. Do vitiligo patients have a higher risk of developing severe COVID-19 compared to healthy controls? There was a significant difference between having fever in vitiligo patients compared to healthy controls [p=.036], all other symptoms did not show a significant difference. 1 patient with vitiligo was admitted to the hospital, he was known with obesity and ITP. 10 vitiligo patients [28.6%] and 25 controls [45.5%] suffered from post-COVID-19 symptoms [P=.297]. The lingering symptoms between the two groups were similar: loss of smell, tiredness and shortness of breath were mostly reported. 3. Does a SARS-CoV-2 infection or COVID-19 increase the activity of vitiligo? 10 vitiligo patients reported that their vitiligo increased after COVID-19, all these patients already had an active vitiligo before or during COVID-19. 25 vitiligo patients reported that their vitiligo remained stable after COVID-19.