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Annals of Dermatology Oct 2022
PubMed: 36198636
DOI: 10.5021/ad.20.094 -
The Journal of Dermatology Jan 2023Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a typical type-2 inflammation involving T-helper type-2 cells and impairing quality of life due to nasal...
Chronic rhinosinusitis with nasal polyposis (CRSwNP) is a typical type-2 inflammation involving T-helper type-2 cells and impairing quality of life due to nasal obstruction, discharge and reduced sense of smell. Recently, the anti-IL4Rα antibody dupilumab was approved for CRSwNP. While dermatologic side effects in patients treated with dupilumab for atopic dermatitis are frequently observed, there is limited knowledge about these effects in patients with CRSwNP. We aimed to investigate frequency and characteristics of dermatologic side effects following initiation of dupilumab treatment in a cohort of Austrian CRSwNP patients. Therefore, CRSwNP patients presenting at the Department of Otorhinolaryngology, Head and Neck Surgery at the Vienna General Hospital were retrospectively evaluated for newly developed skin eruptions while under dupilumab treatment. Incidence was calculated and details on clinical symptoms were collected. One hundred and ninety-two CRSwNP patients receiving dupilumab treatment were included, comprising a cumulative follow-up of 89.65 years (median: 5.5, IQR: 5.9). We observed dermatologic side effects in four patients starting at a median time of 15.5 (range 4-23) weeks after dupilumab initiation corresponding to an incidence-rate of 4.46 (95%-confidence interval 1.39-11.23) events per 100 patient-years follow-up. The majority (75%, 3/4) of affected patients developed psoriasis-like dermatitis, whereas one individual experienced rosacea-like folliculitis and alopecia areata. While dupilumab dosing was reduced in 3/4 CRSwNP patients, one patient completely stopped dupilumab therapy. Our study provides the first comprehensive evaluation of both frequency and characteristics of dermatologic side effects caused by dupilumab in CRSwNP patients. All affected patients developed Th1-inflammatory associated skin disorders - previously observed only in individuals with prior affections of the skin (i.e. atopic dermatitis). Thus, individuals receiving dupilumab for CRSwNP may develop novel symptoms that require interdisciplinary management. Future studies on dupilumab in a real-world setting will be required to further explore its spectrum of side effects.
Topics: Humans; Dermatitis, Atopic; Quality of Life; Retrospective Studies; Antibodies, Monoclonal, Humanized; Sinusitis; Drug-Related Side Effects and Adverse Reactions; Nasal Polyps; Chronic Disease
PubMed: 36177732
DOI: 10.1111/1346-8138.16595 -
Cureus Aug 2022Immune checkpoint inhibitors (ICIs), a class of anticancer agents that upregulate T-cell response to tumor cells, are associated with immune-related adverse events...
Immune checkpoint inhibitors (ICIs), a class of anticancer agents that upregulate T-cell response to tumor cells, are associated with immune-related adverse events (irAEs), and the skin is one of the most commonly affected organs. We report the first two cases of a unique ICI-induced clinicopathological entity. A psoriasiform-appearing eruption with psoriasiform, spongiotic, and lichenoid dermatitis pattern on histopathology. A 73-year-old male with stage IV melanoma treated with nivolumab and a 63-year-old female with stage IV colorectal cancer treated with pembrolizumab and TAK-981 separately presented to our clinic with a psoriasiform rash. In both patients, punch biopsy revealed an unusual combination of psoriasiform, spongiotic, and lichenoid dermatitis. Treatment with apremilast in the first patient yielded some improvement, while treatment with ixekizumab in the second patient yielded a complete resolution of the eruption. Our cases add to the growing body of reported immune toxicities related to ICI use and illustrate the utility of targeted immune suppression of pathways in disease phenotype to allow for ICI continuation and optimization of cancer treatment.
PubMed: 36134105
DOI: 10.7759/cureus.28010 -
British Journal of Clinical Pharmacology Feb 2023Secukinumab, the first interleukin 17A inhibitor, is widely used to treat immune diseases, including plaque psoriasis, psoriatic arthritis and ankylosing spondylitis....
AIMS
Secukinumab, the first interleukin 17A inhibitor, is widely used to treat immune diseases, including plaque psoriasis, psoriatic arthritis and ankylosing spondylitis. Recently, many studies have reported adverse events associated with secukinumab, including gastrointestinal disorders, infections and infestations, and hypersensitive and nervous system disorders.
OBJECTIVE
Here, we aimed to explore the clinical characteristics, outcomes and time to onset of the four main toxicities of secukinumab using post-marketing data.
METHODS
Our study utilized data from the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database from 2015 to 2021, using disproportionality analysis. Toxicities were defined based on the standardized Medical Dictionary for Regulatory Activities queries. Two disproportionality methods were used to detect potential signals: information component (IC) and reporting odds ratio (ROR). The signals were defined as ROR > 1 and IC > 0.
RESULTS
A total of 73 945 398 records were included in this study, of which 300 665 records were related to secukinumab. Diarrhoea (N = 3538), nasopharyngitis (N = 3458), pruritus (N = 4277) and rash (N = 3270) were the most common adverse events. Inflammatory bowel disease (IC /ROR = 3.25/9.69), genital candidiasis (IC /ROR = 3.46/11.54), dermatitis psoriasiform (IC /RO = 1.94/4.04) and anosmia (IC /ROR = 1.62/3.17) had the highest IC values of all toxicities. The time to onset of the four toxicities was mainly concentrated in the first month. Some patients simultaneously presented with two or more toxicities.
CONCLUSION
This pharmacovigilance study systematically explored the four main toxicities of secukinumab and provided new safety signals based on past safety information. Some high-risk signals need to be given attention.
Topics: United States; Humans; Pharmacovigilance; United States Food and Drug Administration; Antibodies, Monoclonal, Humanized; Psoriasis; Adverse Drug Reaction Reporting Systems
PubMed: 36106653
DOI: 10.1111/bcp.15535 -
The Journal of Investigative Dermatology Mar 2023Psoriasis is driven by the interplay between hyperproliferative keratinocytes and infiltrating inflammatory cells. GDF15, a member of the TGF-β superfamily, has been...
Psoriasis is driven by the interplay between hyperproliferative keratinocytes and infiltrating inflammatory cells. GDF15, a member of the TGF-β superfamily, has been implicated in cachexia, metabolic control, and cancer invasion. However, the expression and immunomodulatory role of GDF15 in inflammatory diseases has not been clarified. In this study, we report that GDF15 is decreased in the epidermis of patients with psoriasis and in an imiquimod-induced psoriasis-like mouse model. TNF-α suppresses GDF15 expression in keratinocytes by inhibiting the protein level of the transcription factor GATA2. GDF15 deficiency aggravates the development of psoriatic lesions, as evidenced by more severe skin inflammation in imiquimod-treated Gdf15-knockout (Gdf15) mice compared with that in wild-type mice. Importantly, GDF15 limited the synthesis of a panel of keratinocyte cytokines and chemokines by inhibiting TAK1/NF-κB activation and directly inhibited neutrophil adhesion and migration by inhibiting the activation of the small GTPase Rap1. Epidermal hyperplasia, infiltration of neutrophils, and transcripts of psoriasis-related markers in imiquimod-induced psoriasiform dermatitis were significantly alleviated by a topical supplement of recombinant murine GDF15. In summary, our study revealed an unexpected role of GDF15 in keratinocyte and neutrophil function in the skin of psoriasis, implying its therapeutic potential in treating psoriasis.
Topics: Mice; Animals; Imiquimod; Neutrophil Infiltration; Psoriasis; Skin; Dermatitis; Keratinocytes; Disease Models, Animal; Mice, Inbred BALB C
PubMed: 36049542
DOI: 10.1016/j.jid.2022.07.026 -
Zhongguo Ying Yong Sheng Li Xue Za Zhi... Mar 2022To investigate the effects and mechanisms of Astragalus polysaccharide on improving imiquimod-induced psoriasiform dermatitis in mice. Forty healthy female C57BL/6...
To investigate the effects and mechanisms of Astragalus polysaccharide on improving imiquimod-induced psoriasiform dermatitis in mice. Forty healthy female C57BL/6 mice were randomly divided into 5 groups, including blank control group, model group, astragalus polysaccharide high-dose group (200 mg/kg), medium-dose group (100 mg/kg) and low-dose group (50 mg/kg), with 8 mice in each group. The mice in model group and astragalus polysaccharide treatment group were treated with 5% imiquimod cream on the back to induce psoriasiform dermatitis. PASI score was monitored, and the secretion of inflammatory factors was determined by ELISA. The secretion of inflammatory factors was closely related to the infiltration of macrophages. The infiltration of macrophages in skin was detected by flow cytometry to further explore the effect of different concentrations of APS on psoriasis. Compared with control group, the PASI score and the serum levels of TNF-α, IL-1β and IL-6 were increased significantly (<0.05), and the infiltration of macrophages in skin tissue was increased significantly in model group (<0.05). Compared with model group, the PASI score was decreased significantly (<0.05), and the serum levels of TNF-α, IL-1β and IL-6 were down-regulated significantly in astragalus polysaccharide high-dose and medium-dose groups (<0.05). The infiltrating macrophages in skin tissue were decreased significantly in Astragalus polysaccharide high-dose group (<0.05). Astragalus polysaccharide improve psoriasiform dermatitis in mice by inhibiting the infiltration of macrophages in skin tissue and decreasing the secretion of TNF-α, IL-1β and IL-6 in serum.
Topics: Animals; Astragalus Plant; Dermatitis; Disease Models, Animal; Female; Imiquimod; Interleukin-6; Mice; Mice, Inbred C57BL; Polysaccharides; Skin; Tumor Necrosis Factor-alpha
PubMed: 36031574
DOI: 10.12047/j.cjap.6214.2022.022 -
Frontiers in Medicine 2022Atopic dermatitis (AD) is a chronic recurrent inflammatory disease, and dupilumab, a human monoclonal antibody, is the firstly approved biological drug for AD....
Case report: Clinical and histopathological characteristics of psoriasiform erythema and IL-17A cytokines expression on lesioned skin in atopic dermatitis children treated with dupilumab.
BACKGROUND
Atopic dermatitis (AD) is a chronic recurrent inflammatory disease, and dupilumab, a human monoclonal antibody, is the firstly approved biological drug for AD. Psoriasiform erythema (PE) during dupilumab treatment in adults has been reported. This study describes the risk of PE in children after initiation of dupilumab treatment.
OBJECTIVES
To evaluate the cytokines gene expression in the transition of atopic dermatitis symptoms to psoriasiform erythema during dupilumab treatment in children.
METHODS
Two 17-year-old teenage twin patients with AD were included in this study who developed psoriasiform erythema after initiation of dupilumab. The lesional skin biopsy specimens were obtained for the histopathological investigation and RNA Fluorescence Hybridization (RNA-FISH). Dermoscopy, cytometry (cytokine detection in the blood), and blood investigations were completed for the pedigree and the lesioned descriptions.
RESULTS
Two twin patients with AD presented with erythematic scaly plaques on the back, scalp, abdomen, and extensor extremities after 20 weeks of dupilumab treatment. The transitional change of AD to psoriasiform erythema treated with dupilumab was observed. Our subjects' dermoscopy showed pinpoint bleeding and white scales on pink background. Histopathology features showed psoriasiform hyperplasia, epidermal hyperplasia (acanthosis), ectatic capillaries, perivascular lymphocytes infiltration, and parakeratosis, with the absence of the granular cell layer. mRNA (RNA-FISH) cytokines gene expression showed a significantly high concentration of IL-17A. Blood investigation results showed a high concentration of (Immunoglobulin E) IgE and Eosinophils, and cytokines detection in blood showed IL-5,6 and IL-17 in one patient; however, only IL-5 in another patient. The dupilumab was discontinued and initiated with Baricitinib. Baricitinib showed a significant reduction in skin lesions.
CONCLUSION
Psoriasiform erythema can appear during dupilumab treatment in atopic dermatitis children. Potently, by suppressing skewed Th2 activation in patients with AD, the balance might shift toward Th1/Th17 predominance, and psoriasis develops. Baricitinib is a potential drug for psoriasiform erythema with significant therapeutic effects.
PubMed: 35966849
DOI: 10.3389/fmed.2022.932766 -
The Journal of Investigative Dermatology Jan 2023The extensive involvement of lysine methyltransferase 2C (KMT2C) in the inflammatory response is well-documented. However, little is known about the role of KMT2C in...
The extensive involvement of lysine methyltransferase 2C (KMT2C) in the inflammatory response is well-documented. However, little is known about the role of KMT2C in psoriasis. We identified that KMT2C was significantly upregulated in the epidermis of psoriatic skin lesions and the psoriasiform cell model. KMT2C knockdown diminished keratinocyte proliferation and the secretion of IL-6, IL-8, CCL20, and S100A9 in vitro and in vivo. In psoriasiform keratinocytes, KMT2C promoted the transcription of PIK3R3 by regulating the enrichment of histone H3 lysine 4 trimethylation at the PIK3R3 promoter and histone 3 lysine 4 monomethylation at the enhancer. The PIK3R3/protein kinase B/NF-κB pathway is a vital step in KMT2C-mediated alleviation of cytokine-primed inflammation. The long noncoding RNA FABP5P3 sustained KMT2C mRNA stability by recruiting human antigen R. Furthermore, inhibition of KMT2C attenuated epidermal hyperplasia and skin inflammation in mice with psoriasis. Taken together, our findings indicated a link between KMT2C and psoriasis and opened the possibility of using KMT2C as a potential therapeutic target for psoriasis treatment.
Topics: Animals; Humans; Mice; Eczema; Inflammation; Keratinocytes; Lysine; Phosphatidylinositol 3-Kinases; Psoriasis; RNA, Long Noncoding; DNA-Binding Proteins
PubMed: 35870559
DOI: 10.1016/j.jid.2022.06.025 -
Frontiers in Pharmacology 2022: Psoriasis is characterized by keratinocyte proliferation and massive inflammatory leukocytes infiltration, affecting 0.14%-1.99% of the world's population. Our aim was...
: Psoriasis is characterized by keratinocyte proliferation and massive inflammatory leukocytes infiltration, affecting 0.14%-1.99% of the world's population. Our aim was to identify novel potential therapeutic strategies for psoriasis. : Weighted gene co-expression network analysis (WGCNA) was performed to identify gene modules that were closely related to psoriasis based on the GSE30999 dataset, which contained expression data from 85 patients with moderate-to-severe psoriasis. Then, angiopoietin-like 4 (ANGPTL4), one of the most related hub genes, was selected for and functional assays. In our experiments, imiquimod (IMQ)-induced psoriasiform dermatitis in mice and human keratinocytes (HaCaT) cells were used to study the potential roles and mechanisms of ANGPTL4 in psoriasis. : WGCNA analysis revealed the turquoise module was most correlated with psoriasis, and ANGPTL4 is one of the most related hub genes that significantly upregulated in psoriasis lesions compared with non-lesional skin. Consistent with the bioinformatic analysis, the expression of ANGPTL4 was significantly upregulated in IMQ-induced psoriasiform skin of mice. Exogenous recombinant ANGPLT4 protein treatment could promote the proliferation and induce the expression of inflammatory cytokines in HaCaTs, whereas silencing of ANGPTL4 effectively inhibited these effects. Then we demonstrated that recombinant ANGPTL4 protein exacerbated psoriasiform inflammation and epidermal hyperproliferation . Mechanismly, extracellular signal-regulated kinase 1/2 (ERK1/2) and signal transducer and activator of transcription 3 (STAT3) pathways were involved in ANGPTL4-mediated regulation of proliferation and inflammation. : We found ANGPTL4 was significantly increased in IMQ-induced psoriasiform skin of mice. ANGPTL4 could promote keratinocyte proliferation and inflammatory response ERK1/2 and STAT3 dependent signaling pathways in psoriasis.
PubMed: 35860030
DOI: 10.3389/fphar.2022.850967 -
The Journal of Investigative Dermatology Dec 2022Complex interactions between keratinocytes and various cell types, such as inflammatory cells and stromal cells, contribute to the pathogenesis of chronic inflammatory...
Complex interactions between keratinocytes and various cell types, such as inflammatory cells and stromal cells, contribute to the pathogenesis of chronic inflammatory skin lesions. In proinflammatory cytokine‒mediated disease settings, IL-9 plays a pathological role in inflammatory dermatitis. However, IL-9‒related mechanisms remain incompletely understood. In this study, we established tamoxifen-induced keratinocyte-specific IL-9RA-deficient mice (K14Il9ra mice) to examine the role of IL-9 in multicellular interactions under chronic skin inflammatory conditions. Studies using an imiquimod-induced psoriasis-like model showed that K14Il9ra mice exhibited a significantly reduced severity of dermatitis and mast cell infiltration compared with control K14Il9ra mice. Transcriptome analyses of psoriasis-like lesions showed that the level of peptide Y-Y (Pyy), a member of the neuropeptide Y family, was markedly downregulated in K14Il9ra epidermis. Pyy blockade suppressed epidermal thickening and mast cell numbers in imiquimod-treated wild-type mice. Together with in vitro studies indicating that Pyy induced IL-9 production and chemotactic activity in bone marrow‒derived mast cells, these findings suggest that Pyy-mediated interplay between keratinocytes and mast cells contributes to psoriasiform inflammation. Further investigation focusing on the IL-9‒Pyy axis may provide valuable information for the development of new treatment modalities for inflammatory dermatitis.
Topics: Animals; Mice; Dermatitis; Disease Models, Animal; Imiquimod; Inflammation; Interleukin-9; Keratinocytes; Peptide YY; Psoriasis; Skin
PubMed: 35850207
DOI: 10.1016/j.jid.2022.06.021