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Dupilumab, an IL4R-blocking antibody, has shown clinical efficacy for atopic dermatitis (AD) treatment. In addition to conjunctivitis/blepharitis, the de novo appearance of head/neck dermatitis is now recognized as a distinct side effect, occurring in up to 10% of patients. Histopathological features distinct from AD suggest a drug effect, but exact underlying mechanisms remain unknown. We profiled punch biopsies from dupilumab-associated head and neck dermatitis (DAHND) by using single-cell RNA sequencing and compared data with untreated AD and healthy control skin. We show that dupilumab treatment was accompanied by normalization of IL-4/IL-13 downstream activity markers such as CCL13, CCL17 , CCL18 and CCL26 . By contrast, we found strong increases in type 22-associated markers ( IL22, AHR ) especially in oligoclonally expanded T cells, accompanied by enhanced keratinocyte activation and IL-22 receptor upregulation. Taken together, we demonstrate that dupilumab effectively dampens conventional type 2 inflammation in DAHND lesions, with concomitant hyperactivation of IL22 -associated responses. Dupilumab-associated head and neck dermatitis has been described in a subset of patients treated with the IL4R-blocker dupilumab. Here the authors characterise the immune cell composition and single-cell transcriptome in comparison with untreated forms of atopic dermatitis in a small cohort showing increases in IL-22-associated genes.

A 52‐year‐old Caucasian woman was referred for an allergy workup of suspected type I allergy to the interleukin (IL)‐17A inhibitor ixekizumab. Five months after ixekizumab initiation, she suddenly developed intense pruritus and three small wheals at the injection site approximately 30 min after injection, lasting up to 3 days. With each additional application, she experienced a crescendo‐like amplification of skin symptoms. Allergy skin tests with ixekizumab, adalimumab (anti‐TNF‐α), brodalumab (anti‐IL17RA), risankizumab (anti‐IL‐23p19) and tildrakizumab (anti‐IL‐23p19) were performed. Skin prick testing showed positive results for ixekizumab with negative results for all other tested biologics. Intradermal testing, confirmed positive reactivity for ixekizumab already at a lower concentration. Intradermal testing was also positive for undiluted brodalumab, risankizumab and tildrakizumab. Allergy skin tests confirmed type I allergy to ixekizumab and suggested cross‐sensitization to brodalumab, risankizumab and tildrakizumab, for which the patient was treatment‐naïve. Capsule summary A 52‐year‐old woman developed pruritus and wheals at the injection site five months after starting ixekizumab. With each additional application, she experienced a crescendo‐like amplification of symptoms. Allergy skin tests with different biologics were performed. Skin prick testing was positive for ixekizumab. Intradermal testing confirmed positive reactivity for ixekizumab and was also positive for brodalumab, risankizumab, and tildrakizumab. Allergy tests confirmed type I allergy to ixekizumab and suggest cross‐sensitization to brodalumab, risankizumab, and tildrakizumab, for which the patient was treatment‐naïve.

Chronic rhinosinusitis with nasal polyps is affecting up to 3% of Western populations. About 10% of patients with nasal polyps also suffer from asthma and intolerance to aspirin, a syndrome called aspirin-exacerbated respiratory disease. Although eosinophilic inflammation is predominant in polyps of both diseases, phenotypic differences in the tissue-derived microenvironment, elucidating disease-specific characteristics, have not yet been identified. We sought to obtain detailed information about phenotypic and transcriptional differences in epithelial and immune cells in polyps of aspirin-tolerant and intolerant patients. Cytokine profiles in nasal secretions and serum of patients suffering from aspirin-exacerbated respiratory disease (n = 10) or chronic rhinosinusitis with nasal polyps (n = 9) were assessed using a multiplex mesoscale discovery assay. After enrichment for immune cell subsets by flow cytometry, we performed transcriptomic profiling by employing single-cell RNA sequencing. Aspirin-intolerant patients displayed significantly elevated IL-5 and CCL17 levels in nasal secretions corresponding to a more pronounced eosinophilic type 2 inflammation. Transcriptomic profiling revealed that epithelial and mast cells not only complement one another in terms of gene expression associated with the 15-lipoxygenase pathway but also show a clear type 2-associated inflammatory phenotype as identified by the upregulation of POSTN , CCL26 , and IL13 in patients with aspirin-exacerbated respiratory disease. Interestingly, we also observed cellular stress responses indicated by an increase of MTRNR2L12 , MTRNR2L8 , and NEAT1 across all immune cell subsets in this disease entity. In conclusion, our findings support the hypothesis that epithelial and mast cells act in concert as potential drivers of the pathogenesis of the aspirin-exacerbated respiratory disease.

Atopic dermatitis (AD) typically starts in infancy or early childhood, showing spontaneous remission in a subset of patients, while others develop lifelong disease. Despite an increased understanding of AD, factors guiding its natural course are only insufficiently elucidated. We thus performed suction blistering in skin of adult patients with stable, spontaneous remission from previous moderate-to-severe AD during childhood. Samples were compared to healthy controls without personal or familial history of atopy, and to chronic, active AD lesions. Skin cells and tissue fluid obtained were used for single-cell RNA sequencing and proteomic multiplex assays, respectively. We found overall cell composition and proteomic profiles of spontaneously healed AD to be comparable to healthy control skin, without upregulation of typical AD activity markers (e.g., IL13, S100As, and KRT16). Among all cell types in spontaneously healed AD, melanocytes harbored the largest numbers of differentially expressed genes in comparison to healthy controls, with upregulation of potentially anti-inflammatory markers such as PLA2G7. Conventional T-cells also showed increases in regulatory markers, and a general skewing toward a more Th1-like phenotype. By contrast, gene expression of regulatory T-cells and keratinocytes was essentially indistinguishable from healthy skin. Melanocytes and conventional T-cells might thus contribute a specific regulatory milieu in spontaneously healed AD skin.

Non-steroidal anti-inflammatory drugs-exacerbated respiratory disease (N-ERD) affects up to 10% of patients suffering from nasal polyps and has a severe impact on quality of life. Dupilumab, a monoclonal antibody targeting the IL-4 receptor α chain, leads to symptom relief and reduction in nasal type 2 mediator levels. Here, we investigated the impact of dupilumab treatment on the composition and diversity of the nasal microbiome. Nasal microbiome was analyzed by 16s rRNA gene amplicon sequencing in 28 patients before, 4, 12, and 24 weeks after dupilumab therapy. After stringent decontamination and removal of patients whose samples contained less than 500 reads at ≥ one of the four visits, full datasets from 8 out of 28 patients remained for downstream analysis of microbiome data. All 8 patients showed significant reduction in TPS (total polyp score; p=0.0078) and an improvement in SNOT-22 (Sino-nasal outcome test-22, a quality of life questionnaire; p=0.0781) after dupilumab therapy. During 24 weeks of dupilumab therapy, there were no major changes in microbiome diversity or composition observed (Shannon index: V1-V4:p-adj=0.25, Chao 1 Index V1-V4:p-adj=0.31), and only 2 out of 8 patients showed a decrease in staphylococci abundance. More than 70% of the samples did not pass quality control, this warrants further refinement of nasal microbiome sampling techniques and mandatory guidelines on stringent quality control for analysis of this low biomass data in future. Furthermore, dupilumab did not have an impact on microbiome diversity or composition.

Background In dermatomyostis (DM) patients, inflammation, reduced activity, and medication have a negative impact on the musculoskeletal system. Several endocrine factors are involved in muscle growth and bone turnover. Objective: We aimed to investigate factors regulating myogenesis and bone metabolism and to evaluate possible associations between these endocrine factors, muscle strength, and functional tests in DM patients. Methods We conducted a cross-sectional study in 20 dermatomyositis patients. Serum levels of myostatin (MSTN), follistatin (FSTN), dickkopf 1 (Dkk1), sclerostin (SOST), periostin (PSTN), the receptor activator nuclear factor kB ligand (RANKL):osteoprotegerin (OPG) ratio and fibroblast growth factor 23 (FGF23) were determined. Physical function was evaluated by hand-held strength measurement, chair rising test, timed up and go test and the 3-min walking test. Results Serum MSTN and FGF23 levels (2.5 [1.9; 3.2] vs. 1.9 [1.6; 2.3] and 2.17 [1.45; 3.26] vs. 1.28 [0.79; 1.96], respectively; p  <  0.05) were significantly higher in DM patients than in controls. Dkk1 was significantly lower (11.4 [6.9; 20.0] vs. 31.8 [14.3; 50.6], p  <  0.01). Muscle strength and physical function tests correlated with each other (e.g. hip flexion – timed up and go test: r  = − 0.748, p  < 0.01). Conclusion In DM patients, biochemical musculo-skeletal markers are altered and physical function shows deficits. All these tests reflect independent of each other different deficits in long-term DM patients which is important for the assessment of DM patients as well as planning of therapeutic interventions in clinical routine.

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by type 2 cytokine-driven skin inflammation and epithelial barrier dysfunction. The latter is believed to allow the increased penetration of chemicals, toxins, and allergens into the skin. House dust mite allergens, particularly Der p 2, are important triggers in sensitized individuals with AD; the precise actions of these allergens in epithelial biology remain, however, incompletely understood. In this study, we compared the effects of the protein allergen Der p 2 and a mix of non-IgE-reactive Der p 2 peptides on skin cells using patch tests in AD patients and healthy participants. We then analyzed mRNA expression profiles of keratinocytes by single-cell RNA-sequencing. We report that existing barrier deficiencies in the non-lesional skin of AD patients allow deep penetration of Der p 2 and its peptides, leading to local microinflammation. Der p 2 protein specifically upregulated genes involved in the innate immune system, stress, and danger signals in suprabasal KC. Der p 2 peptides further downregulated skin barrier genes, in particular the expression of genes involved in cell–matrix and cell–cell adhesion. Peptides also induced genes involved in hyperproliferation and caused disturbances in keratinocyte differentiation. Furthermore, inflammasome-relevant genes and IL18 were overexpressed, while KRT1 was downregulated. Our data suggest that Der p 2 peptides contribute to AD initiation and exacerbation by augmenting hallmark features of AD, such as skin inflammation, barrier disruption, and hyperplasia of keratinocytes.

Psoriasis is a chronic skin disorder driven by IL-23 and the downstream T-helper cell 17 (Th17) pathway. Tildrakizumab is a humanized monoclonal antibody selectively targeting the p19 subunit of IL-23, a key cytokine for Th17 cells. Here, we provide an overview of IL-23 in the context of psoriasis pathogenesis and review the results of the Phase I, II and III clinical trials for tildrakizumab in patients with moderate-to-severe chronic plaque psoriasis in order to assess its efficacy, safety and clinical usefulness. In all clinical trials, tildrakizumab demonstrated significant clinical improvement and a favorable safety profile. In Phase III trials, 75% of tildrakizumab-treated patients reached a Psoriasis Area and Severity Index 75 at week 28 demonstrating superior efficacy as compared with etanercept treatment. The tildrakizumab-induced reduction in skin inflammation proves the important pathogenic role of IL-23 in psoriasis and further supports the utility of drugs targeting the IL-23/Th17 pathway. Targeting IL-23p19 with tildrakizumab augments the therapeutic repertoire for patients with moderate-to-severe chronic plaque psoriasis.

Background: Topical pimecrolimus may maintain remissions of atopic dermatitis (AD) by inhibiting subclinical inflammation. Objective: To evaluate clinical and cytological effects of pimecrolimus in topical corticosteroid-treated and resolved AD lesions. Methods: Patients (n = 67) with resolved AD lesions were randomized to 3-week double-blind treatment with either pimecrolimus cream 1% or vehicle cream. Outcome measures were reduction in Eczema Area and Severity Index (EASI) and number of leukocytes in skin biopsies in all randomized patients who were evaluable at the end of study. Results: The proportion of patients with a localized EASI <2 at the end of study was higher with pimecrolimus cream 1% than with vehicle cream (73.5 vs. 39.4%, respectively). There was a significant decrease in the number of infiltrating CD45+ cells in pimecrolimus cream 1% compared with placebo cream (–88.2 vs. 43.2 cells/mm 2 , respectively, p = 0.047) and a slight but nonsignificant reduction in the number of dermal dendritic cells, Langerhans cells, T cells and macrophages with pimecrolimus versus vehicle cream. Limitations: This was an exploratory study. Conclusion: Topical pimecrolimus was effective at maintaining betamethasone-17α-valerate-induced AD remission by inhibiting recurrences of the inflammatory infiltrate in the skin.

A proof-of-concept phase I clinical trial demonstrates that targeting interleukin (IL)-23 with an antibody that binds to the p19 subunit leads to clinical improvement of disease in patients with moderate to severe psoriasis. Antibody treatment of psoriasis Sauzanne Khalilieh and colleagues report a proof-of-concept phase I clinical trial which demonstrates that targeting the pro-inflammatory cytokine interleukin-23 (IL-23) with tildrakizumab, an antibody that binds to the p19 subunit of IL-23, leads to symptomatic improvement of disease in patients with moderate to severe psoriasis. The antibody is well tolerated, suggesting that selective targeting of IL-23 merits further study. Psoriasis is a chronic inflammatory skin disorder that affects approximately 2–3% of the population worldwide and has severe effects on patients’ physical and psychological well-being 1 , 2 , 3 . The discovery that psoriasis is an immune-mediated disease has led to more targeted, effective therapies; recent advances have focused on the interleukin (IL)-12/23p40 subunit shared by IL-12 and IL-23. Evidence suggests that specific inhibition of IL-23 would result in improvement in psoriasis. Here we evaluate tildrakizumab, a monoclonal antibody that targets the IL-23p19 subunit, in a three-part, randomized, placebo-controlled, sequential, rising multiple-dose phase I study in patients with moderate-to-severe psoriasis to provide clinical proof that specific targeting of IL-23p19 results in symptomatic improvement of disease severity in human subjects. A 75% reduction in the psoriasis area and severity index (PASI) score (PASI75) was achieved by all subjects in parts 1 and 3 (pooled) in the 3 and 10 mg kg −1 groups by day 196. In part 2, 10 out of 15 subjects in the 3 mg kg −1 group and 13 out of 14 subjects in the 10 mg kg −1 group achieved a PASI75 by day 112. Tildrakizumab demonstrated important clinical improvement in moderate-to-severe psoriasis patients as demonstrated by improvements in PASI scores and histological samples.