Dendritic cells (DC) represent a heterogeneous population of antigen-presenting cells that are crucial in initiating and shaping immune responses. Although all DC are capable of antigen-uptake, ...processing, and presentation to T cells, DC subtypes differ in their origin, location, migration patterns, and specialized immunological roles. While in recent years, there have been rapid advances in understanding DC subset ontogeny, development, and function in mice, relatively little is known about the heterogeneity and functional specialization of human DC subsets, especially in tissues. In steady-state, DC progenitors deriving from the bone marrow give rise to lymphoid organ-resident DC and to migratory tissue DC that act as tissue sentinels. During inflammation additional DC and monocytes are recruited to the tissues where they are further activated and promote T helper cell subset polarization depending on the environment. In the current review, we will give an overview of the latest developments in human DC research both in steady-state and under inflammatory conditions. In this context, we review recent findings on DC subsets, DC-mediated cross-presentation, monocyte-DC relationships, inflammatory DC development, and DC-instructed T-cell polarization. Finally, we discuss the potential role of human DC in chronic inflammatory diseases.
Introduction
Dupilumab has recently been approved for the treatment of moderate to severe atopic dermatitis (AD) in adults. Daily practice data on dupilumab treatment are scarce.
Objective
To study ...the effect of 16‐week treatment with dupilumab on clinical response and serum biomarkers in adult patients with moderate‐severe AD in daily practice.
Methods
Data were extracted from the BioDay registry, a prospective multicenter registry. Sixteen‐week clinical effectiveness of dupilumab was expressed as number of patients achieving EASI‐50 (Eczema Area and Severity Index) or EASI‐75, as well as patient‐reported outcomes measures (Patient‐Oriented Eczema Measure, Dermatology Life Quality Index, Numeric Rating Scale pruritus). Twenty‐one biomarkers were measured in patients treated with dupilumab without concomitant use of oral immunosuppressive drugs at five different time points (baseline, 4, 8, 12, and 16 weeks).
Results
In total, 138 patients treated with dupilumab in daily practice were included. This cohort consisted of patients with very difficult‐to‐treat AD, including 84 (61%) patients who failed treatment on ≥2 immunosuppressive drugs. At week 16, the mean percent change in EASI score was 73%. The EASI‐50 and EASI‐75 were achieved by 114 (86%) and 82 (62%) patients after 16 weeks of treatment. The most reported side effect was conjunctivitis, occurring in 47 (34%) patients. During dupilumab treatment, disease severity‐related serum biomarkers (TARC, PARC, periostin, and IL‐22), eotaxin‐1, and eotaxin‐3 significantly decreased.
Conclusion
Treatment with dupilumab significantly improved disease severity and decreased severity‐related serum biomarkers in patients with very difficult‐to‐treat AD in a daily practice setting.
This study evaluated the clinical effectiveness and safety of 16‐weeks of dupilumab treatment in adults with AD. Dupilumab treatment significantly suppressed disease severity‐related serum biomarkers and eosinophil chemokines. By the end of the treatment, the EASI‐50 and EASI‐75 was achieved by 86% and 62% of patients, respectively.
Abbreviations: AD: Atopic dermatitis; DLQI: Dermatology life quality index; EASI: Eczema area and severity index; IGA: Investigators global assessment; NRS: Numeric rating scale; PARC: Pulmonary and activation‐regulated chemokine; POEM: Patient‐oriented eczema measure; TARC: Thymus‐ and activation‐regulated chemokine
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Treg cells are critical regulators of immune homeostasis, and environment-driven Treg cell differentiation into effector (e)Treg cells is crucial for optimal functioning. However, human Treg cell ...programming in inflammation is unclear. Here, we combine transcriptional and epigenetic profiling to identify a human eTreg cell signature. Inflammation-derived functional Treg cells have a transcriptional profile characterized by upregulation of both a core Treg cell (FOXP3, CTLA4, TIGIT) and effector program (GITR, BLIMP-1, BATF). We identify a specific human eTreg cell signature that includes the vitamin D receptor (VDR) as a predicted regulator in eTreg cell differentiation. H3K27ac/H3K4me1 occupancy indicates an altered (super-)enhancer landscape, including enrichment of the VDR and BATF binding motifs. The Treg cell profile has striking overlap with tumor-infiltrating Treg cells. Our data demonstrate that human inflammation-derived Treg cells acquire a conserved and specific eTreg cell profile guided by epigenetic changes, and fine-tuned by environment-specific adaptations.
Background
At present, no real‐world studies are available on different dupilumab dosing regimens in controlled atopic dermatitis (AD). The aim of this study was to clinically evaluate a ...patient‐centered dupilumab dosing regimen in patients with controlled AD and to relate this to serum drug levels and serum biomarkers.
Methods
Ninety adult AD patients from the prospective BioDay registry were included based on their dupilumab administration interval according to a predefined patient‐centered dosing regimen. Group A (n = 30) did not fulfill the criteria for interval prolongation and continued using the standard dupilumab dosage (300 mg/2 weeks), group B (n = 30) prolonged dupilumab interval with 50% (300 mg/4 weeks), and group C (n = 30) prolonged dupilumab interval with 66%–75% (300 mg/6–8 weeks). AD severity score, patient‐reported outcomes, serum dupilumab levels, and serum biomarkers were analyzed over time.
Results
Disease severity scores did not significantly change over time during the tapering period in any of the groups. In groups B and C, the Numeric Rating Scale (NRS)‐pruritus temporarily significantly increased after interval prolongation but remained low (median NRS‐pruritus≤4). Median dupilumab levels remained stable in group A (standard dosage), but significantly decreased in groups B and C (24.1 mg/L (IQR = 17.1–45.6); 12.5 mg/L (IQR = 1.7–22.3)) compared with the levels during the standard dosage (88.2 mg/L IQR = 67.1–123.0, p < .001). Disease severity biomarker levels (CCL17/CCL18) remained low in all study groups during the whole observation period.
Conclusions
This study showed that dose reduction was successful in a subgroup of patients with controlled AD by using a patient‐centered dosing regimen. These patients showed stable low disease activity and low severity biomarkers over time.
Dose reduction was successful in a subgroup of controlled AD patients by using a patient‐centered dupilumab dosing regimen. Despite significantly lower dupilumab levels, the EASI‐score and disease severity biomarkers (TARC/CCL17 and PARC/CCL18) in groups B (Q4W) and C (Q6W/Q8W) remained low and stable. These findings are the first step toward personalized dupilumab treatment for controlled AD patients in clinical practice.Abbreviations: AD, atopic dermatitis; EASI, eczema area and severity index; PARC (CCL18), pulmonary and activation‐regulated chemokine; PROMs, patient‐reported outcome measures; Q2W, every two weeks; Q4W, every four weeks; Q6W, every six weeks; Q8W, every eight weeks; TARC (CCL17), thymus and activation‐regulated chemokine
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background
Dupilumab‐associated ocular surface disease (DAOSD) is frequently reported as side effect in atopic dermatitis (AD) patients. Therefore, the aim of this study was to investigate the ...frequency and severity of DAOSD, ophthalmic treatment response and to learn more about the effect of dupilumab on conjunctival goblet cells (GC).
Methods
This prospective study included dupilumab‐treated AD patients between February 2020 and June 2022 from the University Medical Centre Utrecht. Patients were examined by an ophthalmologist and a dermatologist before start (baseline), and after 4 and 28 weeks of dupilumab treatment. Ophthalmological examination was assessed by the Utrecht Ophthalmic Inflammatory and Allergic disease (UTOPIA) score. DAOSD was defined as an increase in UTOPIA score of ≥3 points from baseline. To quantify conjunctival GCs and to investigate the percentage of Cytokeratin 19 (CK19)‐CD45‐Mucin 5 AC (MUC5AC)+ cells, conjunctival impression cytology samples were analysed.
Results
Ocular surface disease (OSD) was present in 91.3% (n = 63/69) patients at baseline. DAOSD was observed in 28.9% (n = 20/69) patients, in whom GC numbers remained stable and the percentage of CK19‐CD45‐MUC5AC+ cells decreased at onset of DAOSD compared with baseline. After 28 weeks of dupilumab treatment, DAOSD was seen in 14.5% (n = 10/69) patients. Of the 85.5% (n = 59/69) patients without DAOSD or with controlled DAOSD at Week 28, 40.7% (n = 24/59) patients received anti‐inflammatory ophthalmic drugs.
Conclusions
Ocular surface disease is common in moderate‐to‐severe AD patients before starting dupilumab. During treatment with dupilumab DAOSD severity improves with early ophthalmic treatment. The decrease in percentage of CK19‐CD45‐MUC5AC+ cells during dupilumab treatment suggests an impairment of the GC function due to dupilumab treatment.
We investigated the frequency and severity of DAOSD, ophthalmic treatment response, and the effect of dupilumab on conjunctival GCs in 69 moderate‐to‐severe AD patients. Many AD patients had OSD before starting dupilumab, and 59.4% started ophthalmic treatment, resulting in less severe (DA)OSD. 28.9% (n = 20/69) patients developed DAOSD, with stable but low GC numbers and reduced GC function compared to baseline. Abbreviations: AD, atopic dermatitis; DAOSD, dupilumab‐associated ocular surface disease; GC, goblet cell; MUC5AC, mucin 5AC; OSD, ocular surface disease; UTOPIA, Utrecht Ophthalmic Inflammatory and Allergic disease
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
T lymphocytes accumulate in inflamed tissues of patients with chronic inflammatory diseases (CIDs) and express pro‐inflammatory cytokines upon re‐stimulation in vitro. Further, a significant genetic ...linkage to MHC genes suggests that T lymphocytes play an important role in the pathogenesis of CIDs including juvenile idiopathic arthritis (JIA). However, the functions of T lymphocytes in established disease remain elusive. Here we dissect the transcriptional and the clonal heterogeneity of synovial T lymphocytes in JIA patients by single‐cell RNA sequencing combined with T cell receptor profiling on the same cells. We identify clonally expanded subpopulations of T lymphocytes expressing genes reflecting recent activation by antigen in situ. A PD‐1+TOX+EOMES+ population of CD4+ T lymphocytes expressed immune regulatory genes and chemoattractant genes for myeloid cells. A PD‐1+TOX+BHLHE40+ population of CD4+, and a mirror population of CD8+ T lymphocytes expressed genes driving inflammation, and genes supporting B lymphocyte activation in situ. This analysis points out that multiple types of T lymphocytes have to be targeted for therapeutic regeneration of tolerance in arthritis.
By combined analysis of single cell transcriptomes and T‐cell receptor profiling we identified functionally distinct populations of in situ antigen‐activated T‐cells in the inflamed joints of patients with juvenile idiopathic arthritis (JIA). The results could be the basis for the development of novel biomarkers and therapeutic approaches for JIA.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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