Real-life management of atopic dermatitis patients with an inadequate response to on-label use of dupilumab.

In patients with moderate to severe atopic dermatitis (AD) showing an inadequate response to dupilumab 300mg/2weeks, few real-life studies reported the response to alternative regimen maintaining dupilumab. To assess and analyze the response to an increased dose of dupilumab or its combination with cyclosporin A (CsA), methotrexate (MTX), or itraconazole (ITRA), all adult AD patients from 7 French University Hospitals were retrospectively included if they achieved an inadequate response to dupilumab 300mg/2weeks and were subsequently treated with an increased dose of dupilumab (300mg every 7 or 10 days), or a combination of dupilumab 300mg/2weeks with CsA, MTX or ITRA. The response after 3 months, along with epidemiological, clinical, and therapeutic baseline characteristics, were collected. Overall, 68.75% of the 48 included patients achieved an improved response, including 45.8% of complete response (CR). No strategy proved significantly better. Patients showing an initial no response never achieved a further CR versus 52.4% of patients with an initial partial response (p = 0.025). Digestive intolerance and tachycardia led to MTX and ITRA discontinuation in 3 patients. Increasing the dose of dupilumab or combining it with CsA, MTX, or ITRA could be alternative and safe options, to be evaluated in further medico-economic studies.

Type I interferon signaling induces melanoma cell-intrinsic PD-1 and its inhibition antagonizes immune checkpoint blockade.

Programmed cell death 1 (PD-1) is a premier cancer drug target for immune checkpoint blockade (ICB). Because PD-1 receptor inhibition activates tumor-specific T-cell immunity, research has predominantly focused on T-cell-PD-1 expression and its immunobiology. In contrast, cancer cell-intrinsic PD-1 functional regulation is not well understood. Here, we demonstrate induction of PD-1 in melanoma cells via type I interferon receptor (IFNAR) signaling and reversal of ICB efficacy through IFNAR pathway inhibition. Treatment of melanoma cells with IFN-α or IFN-ß triggers IFNAR-mediated Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling, increases chromatin accessibility and resultant STAT1/2 and IFN regulatory factor 9 (IRF9) binding within a PD-1 gene enhancer, and leads to PD-1 induction. IFNAR1 or JAK/STAT inhibition suppresses melanoma-PD-1 expression and disrupts ICB efficacy in preclinical models. Our results uncover type I IFN-dependent regulation of cancer cell-PD-1 and provide mechanistic insight into the potential unintended ICB-neutralizing effects of widely used IFNAR1 and JAK inhibitors.

Type-2 immunity associated with type-1 related skin inflammatory diseases: friend or foe?

Chronic inflammatory skin diseases are multifactorial diseases that combine genetic predisposition, environmental triggers, and metabolic disturbances associated with abnormal immune responses. From an immunological perspective, the better understanding of their physiopathology has demonstrated a large complex network of immune cell subsets and related cytokines that interact with both epidermal and dermal cells. For example, in type-1-associated diseases such as alopecia areata, vitiligo, and localized scleroderma, recent evidence suggests the presence of a type-2 inflammation that is well known in atopic dermatitis. Whether this type-2 immune response has a protective or detrimental impact on the development and chronicity of these diseases remains to be fully elucidated, highlighting the need to better understand its involvement for the management of patients. This mini-review explores recent insights regarding the potential role of type-2-related immunity in alopecia areata, vitiligo, and localized scleroderma.

Consensus statement on the diagnosis and treatment of sclerosing diseases of the skin, Part 2: Scleromyxoedema and scleroedema.

The term 'sclerosing diseases of the skin' comprises specific dermatological entities, which have fibrotic changes of the skin in common. These diseases mostly manifest in different clinical subtypes according to cutaneous and extracutaneous involvement and can sometimes be difficult to distinguish from each other. The present consensus provides an update to the 2017 European Dermatology Forum Guidelines, focusing on characteristic clinical and histopathological features, diagnostic scores and the serum autoantibodies most useful for differential diagnosis. In addition, updated strategies for the first- and advanced-line therapy of sclerosing skin diseases are addressed in detail. Part 2 of this consensus provides clinicians with an overview of the diagnosis and treatment of scleromyxoedema and scleroedema (of Buschke).

Stigma in vitiligo: associated factors and severity strata of the Patient Unique Stigmatization Holistic tool in Dermatology (PUSH-D) score.

BACKGROUND: Vitiligo is the most common cause of skin depigmentation worldwide. Patients with vitiligo may experience stigma and this needs to be addressed. OBJECTIVES: To evaluate stigma in patients with vitiligo, search for associated factors and establish severity strata for the Patient Unique Stigmatization Holistic tool in Dermatology (PUSH-D) for patients with vitiligo. METHODS: We conducted a cross-sectional study in ComPaRe Vitiligo, an e-cohort of adult patients with vitiligo. Stigmatization was assessed using the PUSH-D, a recently validated dermatology-specific stigmatization assessment tool. We conducted univariate and multivariable linear regression to identify patient and disease factors associated with the stigmatization. We used an anchor-based approach to define severity strata for the PUSH-D. RESULTS: In total, 318 patients participated (mean age 49.7 years; 73.9% women). Fitzpatrick skin phototype IV-VI, severe facial involvement (high Self-Assessment Vitiligo Extent Score of the face) and depression (high Patient Health Questionnaire-9 score) were positively -associated with a higher stigmatization score, although this association was weak [r = 0.24 (P < 0.001) and r = 0.30 (P < 0.001), respectively]. PUSH-D cutoff values that best discriminated patients with high and low stigma, as defined by the anchor question, were 13 and 23 (κ = 0.622, 95% confidence interval 0.53-0.71). CONCLUSIONS: Our study is the first to use a skin-specific stigmatization tool to assess stigma in patients with vitiligo. Creating strata helps to better interpret the PUSH-D in daily practice and may facilitate its use in clinical trials.

Vitiligo is an acquired autoimmune condition characterized by well-defined depigmented patches of skin on the body. The condition affects approximately 1% of the world's population and those living with vitiligo have long experienced stigmatization. Despite the fact that previous research has investigated the correlation between stigma and vitiligo using non-specific stigma tools, to our knowledge, no study has specifically assessed stigma in people with vitiligo. This study was carried out among French patients with vitiligo to evaluate both felt and actual stigma using the Patient Unique Stigmatization Holistic tool in Dermatology (PUSH-D), a new skin-specific stigma score. We also looked for correlations between PUSH-D scores and other questionnaires measuring levels of anxiety (GAD-7) and depression (PHQ-9). We found that PHQ-9 scores for depression were significantly positively correlated with PUSH-D scores, although these correlations were weak. When examining which factors were associated with higher stigma, we found that darker skin phototypes and severe facial involvement predicted higher stigma. However, we found that hand involvement did not. Overall, vitiligo is associated with a lot of stigma and it has been shown to be a barrier to employment. Therefore, an objective evaluation of vitiligo is required in order to facilitate access and reimbursement of treatment (including those existing and under development). The findings from this study highlight how further research is needed with more diverse groups of people, to better objectify stigma associated with vitiligo.

Evaluation of Facial Vitiligo Severity with a Mixed Clinical and Artificial Intelligence Approach.

Vitiligo is the most common depigmenting skin disorder. Given the ongoing development of new targeted therapies, it has become important to evaluate adequately the surface area involved. Assessment of vitiligo scores can be time consuming, with variations between investigators. Therefore, the aim of this study was to build an artificial intelligence system capable of assessing facial vitiligo severity. One hundred pictures of faces of patients with vitiligo were used to train and validate the artificial intelligence model. Sixty-nine additional pictures of facial vitiligo were then used as a final dataset. Three expert physicians scored the facial vitiligo on the same 69 pictures. Inter and intrarater performances were evaluated by comparing the scores between raters and artificial intelligence. Algorithm assessment achieved an accuracy of 93%. Overall, the scores reached a good agreement between vitiligo raters and the artificial intelligence model. Results demonstrate the potential of the model. It provides an objective evaluation of facial vitiligo and could become a complementary/alternative tool to human assessment in clinical practice and/or clinical research.

Resident memory T cells in nonlesional skin and healed lesions of patients with chronic inflammatory diseases: Appearances can be deceptive.

Tissue-resident memory T (TRM) cells serve as a first line of defense in peripheral tissues to protect the organism against foreign pathogens. However, autoreactive TRM cells are increasingly implicated in autoimmunity, as evidenced in chronic autoimmune and inflammatory skin conditions. This highlights the need to characterize their phenotype and understand their role for the purpose of targeting them specifically without affecting local immunity. To date, the investigation of TRM cells in human skin diseases has focused mainly on lesional tissues of patients. Accumulating evidence suggests that self-reactive TRM cells are still present in clinically healed lesions of patients and play a role in disease flares, but TRM cells also populate skin that is apparently normal. This review discusses the ontogeny of TRM cells in the skin as well as recent insights regarding the presence of self-reactive TRM cells in both clinically healed skin and nonlesional skin of patients with autoimmune and inflammatory skin conditions, with a particular focus on psoriasis, atopic dermatitis, and vitiligo.

Effect of abrocitinib on skin biomarkers in patients with moderate-to-severe atopic dermatitis.

BACKGROUND: This is the first report on the effects of abrocitinib, a Janus kinase 1-selective inhibitor, on the expression of skin biomarkers in patients with moderate-to-severe atopic dermatitis (AD). METHODS: JADE MOA (NCT03915496) was a double-blind Phase 2a trial. Adults were randomly assigned 1:1:1 to receive monotherapy with once-daily abrocitinib 200 mg, abrocitinib 100 mg, or placebo for 12 weeks. The primary endpoint was change from baseline in markers of inflammation (matrix metalloproteinase [MMP]-12), epidermal hyperplasia (keratin-16 [KRT16]), T-helper 2 (Th2) immune response (C-C motif chemokine ligand [CCL]17, CCL18, and CCL26), and Th22 immune response (S100 calcium binding protein A8, A9, and A12 [S100A8, S100A9, and S100A12]) in skin through 12 weeks. RESULTS: A total of 46 patients received abrocitinib 200 mg (n = 14), abrocitinib 100 mg (n = 16), or placebo (n = 16). Abrocitinib improved AD clinical signs and reduced itch. Gene expression of MMP-12, KRT16, S100A8, S100A9, and S100A12 was significantly decreased from baseline with abrocitinib 200 mg (at Weeks 2, 4, and 12) and abrocitinib 100 mg (at Weeks 4 and 12) in a dose-dependent manner. Abrocitinib 200 mg resulted in significant decreases from baseline in CCL17 expression at Week 12 and CCL18 expression at Weeks 2, 4, and 12; no significant decreases were observed for CCL26. CONCLUSIONS: Alongside improvements in clinical signs and symptoms of AD, 12 weeks of abrocitinib treatment resulted in downregulation of genes associated with inflammation, epidermal hyperplasia, and Th2 and Th22 immune responses in the skin of patients with moderate-to-severe AD.

Inhibition of T-cell activity in alopecia areata: recent developments and new directions.

Alopecia areata (AA) is an autoimmune disease that has a complex underlying immunopathogenesis characterized by nonscarring hair loss ranging from small bald patches to complete loss of scalp, face, and/or body hair. Although the etiopathogenesis of AA has not yet been fully characterized, immune privilege collapse at the hair follicle (HF) followed by T-cell receptor recognition of exposed HF autoantigens by autoreactive cytotoxic CD8+ T cells is now understood to play a central role. Few treatment options are available, with the Janus kinase (JAK) 1/2 inhibitor baricitinib (2022) and the selective JAK3/tyrosine kinase expressed in hepatocellular carcinoma (TEC) inhibitor ritlecitinib (2023) being the only US Food and Drug Administration-approved systemic medications thus far for severe AA. Several other treatments are used off-label with limited efficacy and/or suboptimal safety and tolerability. With an increased understanding of the T-cell-mediated autoimmune and inflammatory pathogenesis of AA, additional therapeutic pathways beyond JAK inhibition are currently under investigation for the development of AA therapies. This narrative review presents a detailed overview about the role of T cells and T-cell-signaling pathways in the pathogenesis of AA, with a focus on those pathways targeted by drugs in clinical development for the treatment of AA. A detailed summary of new drugs targeting these pathways with expert commentary on future directions for AA drug development and the importance of targeting multiple T-cell-signaling pathways is also provided in this review.

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

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

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

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

Vitiligo patient population and disease burden in France: VIOLIN study results from the CONSTANCES cohort.

BACKGROUND: Vitiligo is a chronic autoimmune disease resulting in skin depigmentation. OBJECTIVES: This study assessed the prevalence, disease burden and treatment of vitiligo in France. METHODS: VIOLIN was a cross-sectional study nested in the national CONSTANCES cohort, which consists of randomly selected adults aged 18-69 years in France. In VIOLIN, longitudinal data were collected prospectively from 158,898 participants during 2012-2018 and linked to the National Health Data System (SNDS), a healthcare utilization database. Patients with physician-diagnosed vitiligo were matched (1:3) with control participants based on age, sex, geographic region, year of inclusion and skin phototype. Patients completed a questionnaire in 2022 to collect disease characteristics, disease burden and quality-of-life (QoL) data. RESULTS: Vitiligo prevalence was 0.71% (681/95,597) in 2018. The mean age in the vitiligo population was 51.2 years; 51.4% were women. Most patients (63%) were diagnosed before age 30 years, mainly by dermatologists (83.5%). Most patients (81.1%) had visible lesions (i.e. on face, hands). Vitiligo was limited to <10% of the body surface area (BSA) in 85.8% of patients. Comorbidities including thyroid disease (18.0% vs. 9.0%), psoriasis (13.7% vs. 9.7%), atopic dermatitis (12.4% vs. 10.3%), depression (18.2% vs. 14.6%) and alopecia areata (4.3% vs. 2.4%) were significantly more common in patients with vitiligo versus matched controls (n = 2043). QoL was significantly impaired in patients with >5% BSA involvement or visible lesions, particularly with ≥10% facial involvement. Vitiligo-specific instruments (i.e. Vitiligo Impact Patient scale and Vitiligo-specific QoL instrument) were more sensitive to QoL differences among subgroups versus general skin instruments, and generic instruments were least sensitive. Most patients (83.8%) did not receive any prescribed treatment. CONCLUSIONS: Patients with vitiligo in France have a high disease burden, particularly those with visible lesions or higher BSA involvement. Most patients are not receiving treatment, highlighting the need for new effective treatments and patient/physician education.