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 disordersin particular linear morpheahave 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 immunemediated 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.

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.

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.

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.

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.