Atopic dermatitis (AD) is a chronic inflammatory skin disease for which new targeted therapies are currently available. Due to the increased rates of ocular surface disease (OSD) reported during ...treatment with these new targeted treatments, more insight into the occurrence and pathomechanism of OSD in moderate‐to‐severe AD patients is needed. Therefore, this review's first part highlights that most patients with moderate‐to‐severe AD already have characteristics of OSD before starting targeted treatment. Remarkably, not all AD patients with OSD report ocular symptoms. OSD in AD is associated with less conjunctival goblet cells (GC) compared to healthy controls. In addition, OSD severity in AD patients is associated with high AD activity, the presence of eyelid and/or facial eczema, and high levels of AD‐related severity biomarkers in tear fluid. The second part of this review highlights that pre‐existing ocular pathology (e.g. in combination with the use of ophthalmic medication or eyelid eczema) may be associated with the development of dupilumab‐associated ocular surface disease (DAOSD). During dupilumab treatment, DAOSD (which can be new‐onset OSD or worsening of pre‐existing OSD) is observed in approximately one‐third of the dupilumab‐treated AD patients. Anti‐inflammatory ophthalmic treatment improves DAOSD, and dose reduction of dupilumab may also be an effective treatment option. The pathomechanism of DAOSD is still not fully elucidated. In a prospective study low, but stable conjunctival GC numbers were observed in moderate‐to‐severe AD patients, before and during dupilumab treatment. However, the Mucin 5 AC (MUC5AC) expression of GCs decreased during dupilumab treatment, suggesting an impairment of the GC function by dupilumab treatment. In addition, higher dupilumab tear fluid levels were found in dupilumab‐treated AD patients with moderate‐to‐severe OSD compared to patients with no or mild OSD, whereas the dupilumab serum levels are similar. Clinicians should be aware of the frequent occurrence of OSD in moderate‐to‐severe AD patients, and a low‐threshold referral to an ophthalmologist is recommended.
Ocular surface disease is very common in AD patients, and not all patients reported ocular symptoms. Less conjunctival goblet cells were found in AD patients compared to healthy controls. During dupilumab treatment, approximately 30% of the dupilumab‐treated AD patients developed dupilumab‐associated ocular surface disease. Stable but low conjunctival goblet cell numbers were found, with a decrease in the Mucin 5AC production. Clinicians should be aware of (DA)OSD in AD patients.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Objective
Juvenile dermatomyositis (DM) is a heterogeneous systemic immune‐mediated vasculopathy. This study was undertaken to 1) identify inflammation/endothelial dysfunction–related biomarker ...profiles reflecting disease severity at diagnosis, and 2) establish whether such biomarker profiles could be used for predicting the response to treatment in patients with juvenile DM.
Methods
In total, 39 biomarkers related to activation of endothelial cells, endothelial dysfunction, and inflammation were measured using multiplex technology in serum samples from treatment‐naive patients with juvenile DM from 2 independent cohorts (n = 30 and n = 29). Data were analyzed by unsupervised hierarchical clustering, nonparametric tests with correction for multiple comparisons, and Kaplan‐Meier tests with Cox proportional hazards models for analysis of treatment duration. Myositis‐specific antibodies (MSAs) were measured in the patients’ serum using line blot assays.
Results
Severe vasculopathy in patients with juvenile DM was associated with low serum levels of intercellular adhesion molecule 1 (Spearman's rho rs = 0.465, P = 0.0111) and high serum levels of endoglin (rs = −0.67, P < 0.0001). In the discovery cohort, unsupervised hierarchical clustering analysis of the biomarker profiles yielded 2 distinct patient clusters, of which the smaller cluster (cluster 1; n = 8) exhibited high serum levels of CXCL13, CCL19, galectin‐9, CXCL10, tumor necrosis factor receptor type II (TNFRII), and galectin‐1 (false discovery rate <0.0001), and this cluster had greater severity of muscle disease and global disease activity (each P < 0.05 versus cluster 2). In the validation cohort, correlations between the serum levels of galectin‐9, CXCL10, TNFRII, and galectin‐1 and the severity of global disease activity were confirmed (rs = 0.40–0.52, P < 0.05). Stratification of patients according to the 4 confirmed biomarkers identified a cluster of patients with severe symptoms (comprising 64.7% of patients) who were considered at high risk of requiring more intensive treatment in the first 3 months after diagnosis (P = 0.0437 versus other cluster). Moreover, high serum levels of galectin‐9, CXCL10, and TNFRII were predictive of a longer total treatment duration (P < 0.05). The biomarker‐based clusters were not evidently correlated with patients’ MSA serotypes.
Conclusion
Results of this study confirm the heterogeneity of new‐onset juvenile DM based on serum biomarker profiles. Patients with high serum levels of galectin‐9, CXCL10, TNFRII, and galectin‐1 may respond suboptimally to conventional treatment, and may therefore benefit from more intensive monitoring and/or treatment.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
RasGRP1 is a Ras guanine nucleotide exchange factor, and an essential regulator of lymphocyte receptor signaling. In mice, Rasgrp1 deletion results in defective T lymphocyte development. ...RASGRP1‐deficient patients suffer from immune deficiency, and the RASGRP1 gene has been linked to autoimmunity. However, how RasGRP1 levels are regulated, and if RasGRP1 dosage alterations contribute to autoimmunity remains unknown. We demonstrate that diminished Rasgrp1 expression caused defective T lymphocyte selection in C57BL/6 mice, and that the severity of inflammatory disease inversely correlates with Rasgrp1 expression levels. In patients with autoimmunity, active inflammation correlated with decreased RASGRP1 levels in CD4+ T cells. By analyzing H3K27 acetylation profiles in human T cells, we identified a RASGRP1 enhancer that harbors autoimmunity‐associated SNPs. CRISPR‐Cas9 disruption of this enhancer caused lower RasGRP1 expression, and decreased binding of RUNX1 and CBFB transcription factors. Analyzing patients with autoimmunity, we detected reduced RUNX1 expression in CD4+ T cells. Lastly, we mechanistically link RUNX1 to transcriptional regulation of RASGRP1 to reveal a key circuit regulating RasGRP1 expression, which is vital to prevent inflammatory disease.
Reduced RASGRP1 expression prompts aberrant positive thymocyte selection and antinuclear antibodies in mice. Moreover, patients CD4+ T cells express low RASGRP1 in active autoimmune inflammatory conditions. We show that RUNX1 regulates RASGRP1 transcription via an auto‐immunity associated enhancer, implicating that aberrant regulation of RASGRP1 expression promotes mechanisms of autoimmune pathology.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Background
Dupilumab has proven to be an effective and safe treatment for atopic dermatitis (AD) in pediatric patients in clinical trials. However, few daily practice studies are available. The aim ...of this study is to evaluate the effect of 28 weeks dupilumab treatment on effectiveness, safety, and serum biomarkers in pediatric patients with moderate‐to‐severe AD in daily practice.
Methods
Patients visited the outpatient clinic at baseline, 4, 16, and 28 weeks of treatment. Disease severity was assessed by the Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), Numeric Rating Scale (NRS)‐pruritus and ‐pain, and the Patient‐Oriented Eczema Measure (POEM). Side effects were evaluated. Nineteen severity‐associated serum biomarkers were measured. Predicted‐EASI (p‐EASI) was calculated.
Results
Sixty‐one patients were included. Respectively 75.4%, 49.2%, and 24.6% reached EASI‐50, EASI‐75, and EASI‐90 and 36.1% achieved an IGA‐score (almost) clear. Improvement of ≥4 points on POEM, NRS‐pruritus, and NRS‐pain was reached by 84.7%, 45.3%, and 77.4%, respectively. Most reported side effects were conjunctivitis (n = 10) and headache (n = 4). Biomarkers TARC, PARC, periostin, sIL‐2Ra, and eotaxin‐3 significantly decreased during treatment. The p‐EASI showed a significant correlation with disease severity.
Conclusion
Dupilumab treatment significantly improved disease severity and disease‐associated symptoms and decreased severity‐associated serum biomarkers in pediatric AD patients in daily practice.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Chronic inflammatory diseases are characterized by a disturbed immune balance leading to recurring episodes of inflammation in specific target tissues, such as the joints in juvenile idiopathic ...arthritis. The tissue becomes infiltrated by multiple types of immune cell, including high numbers of CD4 and CD8 T-cells, which are mostly effector memory cells. Locally, these T-cells display an environment-adapted phenotype, induced by inflammation- and tissue-specific instructions. Some of the infiltrated T-cells may become tissue resident and play a role in relapses of inflammation. Adaptation to the environment may lead to functional (re)programming of cells and altered cellular interactions and responses. For example, specifically at the site of inflammation both CD4 and CD8 T-cells can become resistant to regulatory T-cell-mediated regulation. In addition, CD8 and CD4 T-cells show a unique profile with pro- and anti-inflammatory features coexisting in the same compartment. Also regulatory T-cells are neither homogeneous nor static in nature and show features of functional differentiation, and plasticity in inflammatory environments. Here we will discuss the recent insights in T-cell functional specialization, regulation, and clonal expansion in local (tissue) inflammation.
T lymphocytes (T cells) are major players of the adaptive immune response. Naive T cells are primed in the presence of cytokines, leading to polarization into distinct T‐cell subsets with specific ...functions. These subsets are classified based on their T‐cell receptor profile, expression of transcription factors, surface cytokine and chemokine receptors, and their cytokine production, which together determine their specific function. This review provides an overview of the various T‐cell subsets and their function in several inflammatory skin disorders ranging from allergic inflammation to skin tumors. Moreover, we highlight similarities of T‐cell responses across different skin disorders, demonstrating the presence of similar and opposing functions for the different T‐cell subsets. Finally, we discuss the effects of currently available and promising therapeutic approaches to harness T cells in inflammatory skin diseases for which efficacy next to unwanted side effects provide new insights into the pathophysiology of skin disorders.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The underlying molecular mechanisms for many autoimmune diseases are poorly understood. Juvenile idiopathic arthritis (JIA) is an exceptionally well-suited model for studying autoimmune diseases due ...to its early onset and the possibility to analyze cells derived from the site of inflammation. Epigenetic profiling, utilizing primary JIA patient-derived cells, can contribute to the understanding of autoimmune diseases. With H3K27ac chromatin immunoprecipitation, we identified a disease-specific, inflammation-associated, typical enhancer and super-enhancer signature in JIA patient synovial-fluid-derived CD4+ memory/effector T cells. RNA sequencing of autoinflammatory site-derived patient T cells revealed that BET inhibition, utilizing JQ1, inhibited immune-related super-enhancers and preferentially reduced disease-associated gene expression, including cytokine-related processes. Altogether, these results demonstrate the potential use of enhancer profiling to identify disease mediators and provide evidence for BET inhibition as a possible therapeutic approach for the treatment of autoimmune diseases.
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•Identification of a disease-specific, inflammation-associated, enhancer signature•Inflammatory-site-derived cells are epigenetically different from peripheral cells•Enrichment of disease-related SNPs in disease-associated super-enhancers•BET inhibition of JIA patient T cells preferentially reduced JIA gene expression
By defining the active super-enhancer profile of autoimmune disease patients, Peeters et al. identify a disease-specific, inflammation-associated super-enhancer signature. In addition, inhibition of super-enhancer activity, using a BET inhibitor, in autoimmune disease patient-derived cells preferentially reduced disease-associated gene expression. These findings suggest a role for enhancers and super-enhancers in autoimmune diseases and demonstrates the potential use of BET inhibitors for the treatment of such diseases.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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