A meta-analysis of chemokines in vitiligo: Recruiting immune cells towards melanocytes.

Chemokine research offers insightful information on the pathogenesis of cutaneous immune disorders, such as vitiligo. Compared to cytokines, the higher detectable levels of chemokines display promising potential as future disease biomarkers. Nonetheless, some published study results are contradictory, which can be attributed to patient characteristics and methodological differences. In this study, a meta-analysis was performed to compare chemokine expression in blood and skin samples from vitiligo patients versus healthy controls. Furthermore, the relationship between chemokine expression and disease activity was evaluated. Chemokine levels were investigated in 15 articles in the circulation and in 9 articles in vitiligo skin. Overall, some clear trends were observed. CXCR3 signaling by CXCL10 and CXCL9 has been confirmed by several reports, although CXCL10 showed more robust findings in blood samples. In this meta-analysis, CCL5, CXCL8, CXCL12, and CXCL16 levels were also significantly elevated. This indicates a complex immune pathway activation in vitiligo that overall supports a Th1-dominant response. Chemokines linked to the Th2 and Th17 pathways were less prevalent. Despite these findings, study protocols that examine a broader range of chemokines are encouraged, because current research is mostly focused on a small number of chemokines that were differentially expressed in previous studies.

From IL-17 to IFN-γ in inflammatory skin disorders: Is transdifferentiation a potential treatment target?

The targeted inhibition of effector cytokines such as interleukin 17 (IL-17) in psoriasis and IL-13 in atopic dermatitis offers impressive efficacy with a favorable side effect profile. In contrast, the downregulation of interferon gamma (IFN-γ) in T helper (Th) 1-dominant skin disorders may lead to more adverse events, given the crucial role of IFN-γ in antiviral and antitumoral immunity. Modulating Th17 and Th2 cell differentiation is performed by blocking IL-23 and IL-4, respectively, whereas anti-IL-12 antibodies are only moderately effective in downregulating Th1 lymphocyte differentiation. Therefore, a targeted approach of IFN-γ-driven disorders remains challenging. Recent literature suggests that certain pathogenic Th17 cell subsets with Th1 characteristics, such as CD4+CD161+CCR6+CXCR3+IL-17+IFN-y+ (Th17.1) and CD4+CD161+CCR6+CXCR3+IL-17-IFN-y+ (exTh17), are important contributors in Th1-mediated autoimmunity. Differentiation to a Th17.1 or exTh17 profile results in the upregulation of IFN-y. Remarkably, these pathogenic Th17 cell subsets are resistant to glucocorticoid therapy and the dampening effect of regulatory T cells (Treg). The identification of Th17.1/exTh17 cells in auto-immune disorders may explain the frequent treatment failure of conventional immunosuppressants. In this review, we summarize the current evidence regarding the cellular plasticity of Th17 cells in inflammatory skin disorders. A deeper understanding of this phenomenon may lead to better insights into the pathogenesis of various skin diseases and the discovery of a potential new treatment target.

Credibility and Generalization of the Minimally Important Difference Concept in Dermatology: A Scoping Review.

Importance: The minimally important difference (MID) represents the point at which a difference in an outcome measure (eg, Dermatology Life Quality Index) is important enough that it warrants a change in treatment, and, to the authors' knowledge, the robustness and limitations of MIDs have not been thoroughly evaluated in skin diseases. The MID is increasingly used in clinical trials to demonstrate that an intervention is worthwhile for patients; furthermore, MIDs also contribute to sample size calculations in clinical trials, influence treatment guidelines, and can guide clinicians to modify treatment. Objective: To evaluate the credibility and generalization of MIDs for patient-reported outcome measures (PROMs) in skin disorders. Evidence Review: A systematic search was conducted in PubMed and Embase for all original articles using the MID concept for skin disorders from inception to December 29, 2021. The credibility of MIDs obtained via an anchor-based approach (eg, global rating of change scale) was assessed with a previously developed credibility instrument. The validity of generalizing established MIDs to other patient groups was evaluated based on the diagnosis and the patient characteristics. Findings: A total of 126 articles were selected, and 84 different MIDs were identified for PROMs. A total of 13 of 84 MIDs (15.5%) for PROMs displayed acceptable credibility. The anchors used had varying capacity to assess minimal important changes from a patient's perspective and were deemed inappropriate for this purpose in 52 of 84 cases (61.9%). Correlations between the anchors and PROMs were frequently not determined (39 of 84; 46.4%). The time interval for anchor questions assessing a change in the experienced disease burden was not optimal for 10 of 32 transition anchors (>3 months), introducing potential recall bias. Previously reported MIDs were widely used to examine relevant changes in other study populations. However, the diagnosis and disease severity were different from the original MID population in 39 of 70 (55.7%) and 45 of 70 (64.3%) cases, respectively. Conclusions and Relevance: In this scoping review, only a minority of MIDs for PROMs demonstrated sufficient credibility in dermatology. Inappropriate generalization of previously reported MIDs to patient populations with different disease characteristics was found to be a major concern. Furthermore, the study supported the use of multiple anchors and encouraged consistent reporting of the correlation between changes in the anchor and changes in the outcome measures.

The Meaning and Reliability of Minimal Important Differences (MIDs) for Clinician-Reported Outcome Measures (ClinROMs) in Dermatology-A Scoping Review.

Background: Clinician-reported outcome measures (ClinROMs) are frequently used in clinical trials and daily practice to evaluate the disease status and evolution of skin disorders. The minimal important difference (MID) represents the smallest difference that decreases the disease impact enough to make a treatment change worthwhile for patients. As no clear guidance exists on the preferred method to calculate MIDs for ClinROMs, we evaluated how the published values for different skin disorders should be interpreted. Methods: A systematic search was performed for MIDs of ClinROMs that focus on skin disorders and/or symptoms. The results of the questions in the credibility instrument for MIDs of Devji et al., 2020 were analyzed to gain insights into the meaning of these MIDs. Results: 29 MIDs were identified. The most common skin diseases were atopic dermatitis/eczema, followed by bullous disorders and psoriasis. A minimal important difference from the patients' perspective was determined in 31% of the cases. However, in 41.4% of the cases, it concerned a substantial rather than a minimal difference in disease severity rated by physicians. Over half (55.1%) of the studies contained an inadequate number of patients (n < 150). MID values increased substantially in patients with severe compared to mild disease. Conclusions: MIDs of ClinROMs for skin disorders should be carefully interpreted due to the substantial differences in methodology between the studies. There is an urgent need for a consensus method to report reliable MIDs. Otherwise, this lack of uniformity could not only affect the design and conclusion of clinical trials but also skew treatment decisions.

The delicate relation between melanocytes and skin immunity: A game of hide and seek.

Melanocytes exhibit a complex and intriguing relationship with the skin immune response, leading to several clinical conditions. In some disorders, inappropriate melanocyte destruction (e.g., vitiligo, halo naevi) is problematic, while in others, immune tolerance should be broken (melanoma). Important parts of the dysregulated pathways have been unraveled in pigment disorders, ranging from upregulated interferon (IFN)-γ signaling to memory T cells, regulatory T cells, and immune checkpoints. Although a network of many factors is involved, targeting key players such as IFN-γ or checkpoint inhibitors (e.g., programmed death-ligand 1 (PD-L1)] can shift the balance and lead to impressive outcomes. In this review, we focus on the immunological mechanisms of the most common inflammatory disorders where the interaction of the immune system with melanocytes plays a crucial role. This can provide new insights into the current state of melanocyte research.

Autoimmunity in Segmental Vitiligo.

The autoimmune basis of segmental vitiligo (SV) has only recently been recognized. Systemic autoimmune diseases are less frequently associated compared to non-segmental vitiligo (NSV), but localized skin disorders - in particular linear morphea - have been repeatedly observed in patients with SV. The inflammatory response is documented on a clinical level with cases displaying erythematous borders or a hypochromic stage, on a histopathological level with predominantly CD8 lymphocytes migrating toward the basal layer and by flow cytometry demonstrating the antimelanocyte specificity of these cytotoxic T cells. The increased risk for halo naevi and NSV in these patients further underline the immune-mediated mechanisms of SV. Nonetheless, the localized and unique distribution pattern points to somatic mosaicism. This places SV in a category of similar diseases such as lichen striatus, blaschkitis, linear lupus erythematosus, and linear scleroderma where an immune reaction against genetically mutated skin cells is believed to be the underlying cause. All these disorders are characterized by a young age of onset, a temporary disease activity with spontaneous resolution, limited response to treatment, and often long-term sequelae. Although challenging, genetic research proving this genetic mosaicism could offer crucial insights into the pathogenesis of both segmental and non-segmental vitiligo.