175 results on '"Krueger, James G."'
Search Results
2. Tape strips detect molecular alterations and cutaneous biomarkers in skin of patients with hidradenitis suppurativa.
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Navrazhina, Kristina, Renert-Yuval, Yael, Khattri, Saakshi, Hamade, Hassan, Meariman, Marguerite, Andrews, Elizabeth, Kim, Madeline, NandyMazumdar, Monali, Gour, Digpal S., Bose, Swaroop, Williams, Samuel C., Garcet, Sandra, Correa da Rosa, Joel, Gottlieb, Alice B., Krueger, James G., and Guttman-Yassky, Emma
- Abstract
Hidradenitis suppurativa (HS) has a high unmet need for better treatments. Biopsies are considered the gold standard for studying molecular alterations in skin. A reproducible, minimally invasive approach is needed for longitudinal monitoring in trials and in pediatric populations. To determine whether skin tape strips can detect molecular alterations in HS and identify biomarkers of disease activity. We performed RNA sequencing on tape strips collected from lesional and healthy-appearing (nonlesional) HS skin (n = 22) and healthy controls (n = 21). We correlated the expression of skin biomarkers between tape strips and a previously published gene-signature of HS biopsies. Tape strips detected upregulation of known HS biomarkers (eg, Interleukin[IL]-17A) in nonlesional and/or lesional skin and also identified novel clinically actionable targets, including OX40 and JAK3. The expression of Th17 and tumor necrosis factor-α pathways were highly correlated between tape strips and biopsies. HS clinical severity was significantly associated with expression of biomarkers (eg tumor necrosis factor-α , IL-17 A/F, OX40, JAK1-3, IL-4R) in HS lesional and/or nonlesional skin. Sample size. Tape stripping is limited in depth. This study validates tape strips as a minimally-invasive approach to identify cutaneous biomarkers in HS. This provides a novel avenue for monitoring treatment efficacy and a potential step toward individualized therapy in HS. [ABSTRACT FROM AUTHOR]
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- 2024
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3. Single-cell transcriptomics suggest distinct upstream drivers of IL-17A/F in hidradenitis versus psoriasis.
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Kim, Jaehwan, Lee, Jongmi, Li, Xuan, Lee, Hyun Soo, Kim, Katherine, Chaparala, Vasuma, Murphy, William, Zhou, Wei, Cao, Junyue, Lowes, Michelle A., and Krueger, James G.
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- 2023
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4. Proteomic characterization of atopic dermatitis blood from infancy to adulthood.
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Del Duca, Ester, Renert-Yuval, Yael, Pavel, Ana B., Mikhaylov, Daniela, Wu, Jianni, Lefferdink, Rachel, Fang, Milie, Sheth, Anjani, Blumstein, Alli, Facheris, Paola, Estrada, Yeriel D., Rangel, Stephanie M., Krueger, James G., Paller, Amy S., and Guttman-Yassky, Emma
- Abstract
Patients with atopic dermatitis (AD) have systemic biomarker dysregulation that differs by age group; however, the proteomic characteristics of these age-based changes are unknown. To profile blood proteins of patients with AD across different age groups versus age-appropriate controls. Using the Olink high-throughput proteomic platform, we profiled 375 serum proteins of 20 infants (age, 0-5 years), 39 children (age, 6-11 years), 21 adolescents (age, 12-17 years), and 20 adults (age, ≥18 years) with moderate-to-severe AD and 83 age-appropriate controls. Each group presented a distinct systemic proteomic signature. Th2-related proteins were increased in infant AD and further intensified with age through adolescence and adulthood (interleukin 4/CCL13/CCL17). In contrast, Th1 axis down-regulation was detected in infants with AD and gradually reversed to increased Th1 products (interferon γ/CXCL9/CXCL10/CCL2) in patients with AD from childhood to adulthood. Despite their short disease duration, infants already had evidence of systemic inflammation, with significant upregulation of innate immunity (interleukin 17C/ interleukin-1RN), T-cell activation/migration (CCL19), Th2 (CCL13/CCL17), and Th17 (PI3) proteins. Adults with AD present unique upregulation of cardiovascular proteins related to coagulation and diabetes. Cross-sectional observational study with a single time point. Systemic immune signatures of AD are age-specific beyond the shared Th2 immune activation. These data advocate for precision medicine approaches based on age-specific AD profiles. [ABSTRACT FROM AUTHOR]
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- 2023
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5. A systematic review and critical appraisal of pharmacological treatments for pediatric hidradenitis suppurativa.
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Moreno, Ariana, Williams, Samuel C., Goto, Rie, Krueger, James G., and Renert-Yuval, Yael
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- 2023
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6. 50378 Clinical efficacy of TAK-279, a highly selective oral tyrosine kinase 2 (TYK2) inhibitor, is associated with modulation of disease and TYK2 pathway biomarkers in patients with moderate-to-severe psoriasis.
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Krueger, James G., Garcet, Sandra, Cheng, Jie, Kumar, Sachin, Blau, Jessamyn, Zhao, Yiwei, Zhang, Wenwen, Arunachalam, Vinayagam, Heap, Graham A., Thakker, Paresh, and Choudhury, Amit
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- 2024
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7. 52675 Bimekizumab efficacy across subgroups of patients with moderate to severe plaque psoriasis: Pooled analysis from up to 3 years of treatment in 5 phase 3/3b clinical trials.
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Strober, Bruce, Krueger, James G., Magnolo, Nina, Vender, Ronald, Boehncke, Wolf-Henning, Hong, H. Chih-ho, Tilt, Nicola, Staelens, Fabienne, Wiegratz, Susanne, and Paul, Carle
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- 2024
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8. 52676 Safety and efficacy over one year of spesolimab treatment in patients with hidradenitis suppurativa (HS): Interim analysis of an open-label extension (OLE) study.
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Kimball, Alexa B., Alavi, Asfaneh, Prens, Errol, Krueger, James G., Frew, John W., Garg, Amit, Mukhopadhyay, Sutirtha, Wang, Hui, Ivanoff, Natalie B., Hernandez Daly, Ana Cristina, and Zouboulis, Christos C.
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- 2024
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9. Pustular psoriasis: Molecular pathways and effects of spesolimab in generalized pustular psoriasis.
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Baum, Patrick, Visvanathan, Sudha, Garcet, Sandra, Roy, Janine, Schmid, Ramona, Bossert, Sebastian, Lang, Benjamin, Bachelez, Hervé, Bissonnette, Robert, Thoma, Christian, and Krueger, James G.
- Abstract
The IL-36 pathway plays a key role in the pathogenesis of generalized pustular psoriasis (GPP). In a proof-of-concept clinical trial, treatment with spesolimab, an anti–IL-36 receptor antibody, resulted in rapid skin and pustular clearance in patients presenting with GPP flares. We sought to compare the molecular profiles of lesional and nonlesional skin from patients with GPP or palmoplantar pustulosis (PPP) with skin from healthy volunteers, and to investigate the molecular changes after spesolimab treatment in the skin and blood of patients with GPP flares. Pre- and post-treatment skin and blood samples were collected from patients with GPP who participated in a single-arm, phase I study (n = 7). Skin biopsies from patients with PPP (n = 8) and healthy volunteers (n = 16) were obtained for comparison at baseline. Biomarkers were assessed by RNA-sequencing, histopathology, and immunohistochemistry. In GPP and PPP lesions, 1287 transcripts were commonly upregulated or downregulated. Selected transcripts from the IL-36 signaling pathway were upregulated in untreated GPP and PPP lesions. In patients with GPP, IL-36 pathway–related signatures, T H 1/T H 17 and innate inflammation signaling, neutrophilic mediators, and keratinocyte-driven inflammation pathways were downregulated by spesolimab as early as week 1. Spesolimab also decreased related serum biomarkers and cell populations in the skin lesions from patients with GPP, including CD3
+ T, CD11c+ , and IL-36γ+ cells and lipocalin-2–expressing cells. In patients with GPP, spesolimab showed rapid modulation of commonly dysregulated molecular pathways in GPP and PPP, which may be associated with improved clinical outcomes. [Display omitted] [ABSTRACT FROM AUTHOR]- Published
- 2022
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10. Secukinumab improves mild-to-moderate psoriasis: A randomized, placebo-controlled exploratory clinical trial.
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Kim, Jaehwan, Lee, Jongmi, Hawkes, Jason E., Li, Xuan, Kunjravia, Norma, Rambhia, Darshna, Cueto, Inna, Moreno, Ariana, Hur, Hong, Garcet, Sandra, Zhou, Wei, Cao, Junyue, and Krueger, James G.
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- 2023
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11. Su1743 GUSELKUMAB BINDING TO CD64+ IL-23–PRODUCING MYELOID CELLS ENHANCES POTENCY FOR NEUTRALIZING IL-23 SIGNALING.
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Abreu, Maria T., Atreya, Raja, Krueger, James G., Eyerich, Kilian, Greving, Carrie, Hammaker, Deepa, Stoveken, Brian, Hartman, John, Leppard, Kristin L., Sarabia, Indra, Wertheimer, Joshua, Deming, Janise, Kohler, Kristen, Li, He (., Freeman, Tom C., Hart, Amy, Keyes, Brice, Ritchlin, Christopher, McInnes, Iain B., and Allez, Matthieu
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- 2024
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12. Scalp and serum profiling of frontal fibrosing alopecia reveals scalp immune and fibrosis dysregulation with no systemic involvement.
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Dubin, Celina, Glickman, Jacob W., Del Duca, Ester, Chennareddy, Sumanth, Han, Joseph, Dahabreh, Dante, Estrada, Yeriel D., Zhang, Ning, Kimmel, Grace W., Singer, Giselle, Chowdhury, Mashkura, Zheng, Andrew Y., Angelov, Michael, Gay-Mimbrera, Jesús, Ruano Ruiz, Juan, Krueger, James G., Pavel, Ana B., and Guttman-Yassky, Emma
- Abstract
Background: Frontal fibrosing alopecia (FFA) is a progressive, scarring alopecia of the frontotemporal scalp that poses a substantial burden on quality of life. Large-scale global profiling of FFA is lacking, preventing the development of effective therapeutics.Objective: To characterize FFA compared to normal and alopecia areata using broad molecular profiling and to identify biomarkers linked to disease severity.Methods: This cross-sectional study assessed 33,118 genes in scalp using RNA sequencing and 350 proteins in serum using OLINK high-throughput proteomics. Disease biomarkers were also correlated with clinical severity and a fibrosis gene set.Results: Genes differentially expressed in lesional FFA included markers related to Th1 (IFNγ/CXCL9/CXCL10), T-cell activation (CD2/CD3/CCL19/ICOS), fibrosis (CXCR3/FGF14/FGF22/VIM/FN1), T-regulatory (FOXP3/TGFB1/TGFB3), and Janus kinase/JAK (JAK3/STAT1/STAT4) (Fold changes [FCH]>1.5, FDR<.05 for all). Only one protein, ADM, was differentially expressed in FFA serum compared to normal (FCH>1.3, FDR<.05). Significant correlations were found between scalp biomarkers (IL-36RN/IL-25) and FFA severity, as well as between JAK/STAT and fibrosis gene-sets (r>.6; P <.05).Limitations: This study was limited by a small sample size and predominantly female FFA patients.Conclusion: Our data characterize FFA as an inflammatory condition limited to scalp, involving Th1/JAK skewing, with associated fibrosis and elevated T-regulatory markers, suggesting the potential for disease reversibility with JAK/STAT inhibition. [ABSTRACT FROM AUTHOR]- Published
- 2022
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13. The inflammatory proteome of hidradenitis suppurativa skin is more expansive than that of psoriasis vulgaris.
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Navrazhina, Kristina, Garcet, Sandra, Frew, John W., Zheng, Xiuzhong, Coats, Israel, Guttman-Yassky, Emma, and Krueger, James G.
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Background: Although hidradenitis suppurativa (HS) shares some transcriptomic and cellular infiltrate features with psoriasis, their skin proteome remains unknown.Objective: To define and compare inflammatory protein biomarkers of HS and psoriasis skin.Methods: We assessed 92 inflammatory biomarkers in HS (n = 13), psoriasis (n = 11), and control skin (n = 11) using Olink high-throughput proteomics. We also correlated HS skin and blood biomarkers using proteomics and RNA sequencing.Results: We identified 57 differentially expressed proteins (DEPs) in lesional psoriasis and 64 DEPs in lesional HS skin, compared to healthy controls. Both HS and psoriasis lesional skin demonstrated a significant upregulation of T helper 1 and T helper 17 proteins. Healthy-appearing perilesional HS skin had 63 DEPs compared to healthy controls. Nonlesional HS and psoriasis skin had 24 and 7 DEPs, respectively, compared to healthy controls. Tumor necrosis factor and 8 other proteins were significantly correlated with clinical severity in perilesional HS skin (2 cm from a nodule).Limitations: Inclusion of only moderate-to-severe patients and the cohort size.Conclusion: HS has a greater inflammatory profile and is more diffusely distributed compared with psoriasis. Proteins correlated with disease severity are potential disease mediators. Perilesional skin is comparably inflamed to lesional skin, suggesting the need to treat beyond skin nodules. [ABSTRACT FROM AUTHOR]- Published
- 2022
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14. Tyrosine kinase 2 and Janus kinase‒signal transducer and activator of transcription signaling and inhibition in plaque psoriasis.
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Krueger, James G., McInnes, Iain B., and Blauvelt, Andrew
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Plaque psoriasis is a common, chronic, systemic, immune-mediated inflammatory disease. The Janus kinase-signal transducer and activator of transcription pathway plays a major role in intracellular cytokine signaling in inflammatory processes involved in psoriasis. Although Janus kinase (JAK) 1-3 inhibitors have demonstrated efficacy in patients with moderate-to-severe psoriasis, safety concerns persist and no JAK inhibitor has received regulatory approval to treat psoriasis. Thus, an opportunity exists for novel oral therapies that are safe and efficacious in psoriasis. Tyrosine kinase 2 (TYK2) is a member of the JAK family of kinases and regulates signaling and functional responses downstream of the interleukin 12, interleukin 23, and type I interferon receptors. Deucravacitinib, which is an oral, selective inhibitor that binds to the regulatory domain of TYK2, and brepocitinib (PF-06700841) and PF-06826647, which are topical and oral TYK2 inhibitors, respectively, that bind to the active (adenosine triphosphate-binding) site in the catalytic domain, are in development for psoriasis. Selective, allosteric inhibition of TYK2 signaling may reduce the potential for toxicities associated with pan-JAK inhibitors. This article reviews Janus kinase-signal transducer and activator of transcription and TYK2 signaling and the efficacy and safety of JAK inhibitors in psoriasis to date, focusing specifically on TYK2 inhibitors. [ABSTRACT FROM AUTHOR]
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- 2022
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15. Single-cell transcriptomics applied to emigrating cells from psoriasis elucidate pathogenic versus regulatory immune cell subsets.
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Kim, Jaehwan, Lee, Jongmi, Kim, Hyun Je, Kameyama, Naoya, Nazarian, Roya, Der, Evan, Cohen, Steven, Guttman-Yassky, Emma, Putterman, Chaim, and Krueger, James G.
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In previous human skin single-cell data, inflammatory cells constituted only a small fraction of the overall cell population, such that functional subsets were difficult to ascertain. Our aims were to overcome the aforesaid limitation by applying single-cell transcriptomics to emigrating cells from skin and elucidate ex vivo gene expression profiles of pathogenic versus regulatory immune cell subsets in the skin of individuals with psoriasis. We harvested emigrating cells from human psoriasis skin after incubation in culture medium without enzyme digestion or cell sorting and analyzed cells with single-cell RNA sequencing and flow cytometry simultaneously. Unsupervised clustering of harvested cells from psoriasis skin and control skin identified natural killer cells, T-cell subsets, dendritic cell subsets, melanocytes, and keratinocytes in different layers. Comparison between psoriasis cells and control cells within each cluster revealed that (1) cutaneous type 17 T cells display highly differing transcriptome profiles depending on IL-17A versus IL-17F expression and IFN-γ versus IL-10 expression; (2) semimature dendritic cells are regulatory dendritic cells with high IL-10 expression, but a subset of semimature dendritic cells expresses IL-23A and IL-36G in psoriasis; and (3) CCL27-CCR10 interaction is potentially impaired in psoriasis because of decreased CCL27 expression in basal keratinocytes. We propose that single-cell transcriptomics applied to emigrating cells from human skin provides an innovative study platform to compare gene expression profiles of heterogenous immune cells in various inflammatory skin diseases. [ABSTRACT FROM AUTHOR]
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- 2021
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16. Immune and barrier characterization of atopic dermatitis skin phenotype in Tanzanian patients.
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Lang, Claudia C.V., Renert-Yuval, Yael, Del Duca, Ester, Pavel, Ana B., Wu, Jianni, Zhang, Ning, Dubin, Celina, Obi, Ashley, Chowdhoury, Mashkura, Kim, Madeline, Estrada, Yeriel D., Krueger, James G., Kaderbhai, Hashim, Semango, George, Schmid-Grendelmeier, Peter, Brüggen, Marie-Charlotte, Masenga, John E., Guttman-Yassky, Emma, and Duca, Ester Del
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- 2021
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17. The molecular features of normal and atopic dermatitis skin in infants, children, adolescents, and adults.
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Renert-Yuval, Yael, Del Duca, Ester, Pavel, Ana B., Fang, Milie, Lefferdink, Rachel, Wu, Jianni, Diaz, Aisleen, Estrada, Yeriel D., Canter, Talia, Zhang, Ning, Wagner, Annette, Chamlin, Sarah, Krueger, James G., Guttman-Yassky, Emma, and Paller, Amy S.
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Although atopic dermatitis (AD) often presents in infancy and persists into adulthood, comparative characterization of AD skin among different pediatric age groups is lacking. We sought to define skin biopsy profiles of lesional and nonlesional AD across different age groups (0-5-year-old infants with disease duration <6 months, 6-11-year-old children, 12-17-year-old adolescents, ≥18-year-old adults) versus age-appropriate controls. We performed gene expression analyses by RNA-sequencing and real-time PCR (RT-PCR) and protein expression analysis using immunohistochemistry. T H 2/T H 22 skewing, including IL-13, CCL17/thymus and activation-regulated chemokine, IL-22, and S100As, characterized the common AD signature, with a global pathway-level enrichment across all ages. Nevertheless, specific cytokines varied widely. For example, IL-33, IL-1RL1/IL-33R, and IL-9, often associated with early atopic sensitization, showed greatest upregulations in infants. T H 17 inflammation presented a 2-peak curve, with highest increases in infants (including IL-17A and IL-17F), followed by adults. T H 1 polarization was uniquely detected in adults, even when compared with adolescents, with significant upregulation in adults of IFN-γ and CXCL9/CXCL10/CXCL11. Although all AD age groups had barrier abnormalities, only adults had significant decreases in filaggrin expression. Despite the short duration of the disease, infant AD presented robust downregulations of multiple barrier-related genes in both lesional and nonlesional skin. Clinical severity scores significantly correlated with T H 2/T H 22-related markers in all pediatric age groups. The shared signature of AD across ages is T H 2/T H 22-skewed, yet differential expression of specific T H 2/T H 22-related genes, other T H pathways, and barrier-related genes portray heterogenetic, age-specific molecular fingerprints. [ABSTRACT FROM AUTHOR]
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- 2021
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18. Epithelialized tunnels are a source of inflammation in hidradenitis suppurativa.
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Navrazhina, Kristina, Frew, John W., Gilleaudeau, Patricia, Sullivan-Whalen, Mary, Garcet, Sandra, and Krueger, James G.
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Hidradenitis suppurativa (HS), also known as acne inversa, is a chronic, painful, and burdensome inflammatory disease manifesting in nodules and abscesses, with progression to chronically draining tunnels in later-stage disease. We sought to determine whether HS tunnels are immunologically active participants in disease activity. Skin biopsy specimens were obtained by using ultrasound guidance in untreated patients with HS and those enrolled in an open-label study of brodalumab (ClinicalTrials.gov identifier NCT03960268) for patients with moderate-to-severe HS. Immunohistochemistry of HS biopsy specimens demonstrated that the epithelialized HS tunnels recapitulate the psoriasiform epidermal hyperplasia morphology of the overlying epidermis, displaying molecular inflammation, including S100A7 (psoriasin) positivity, as well as features of epidermal skin, including loricrin, filaggrin, lipocalin-2, and Melan-A positive cells. Tunnels were associated with increased infiltration of T cells, dendritic cells, and neutrophils; formation of neutrophil extracellular traps, and increased expression of psoriasiform proinflammatory cytokines. Unsupervised hierarchical clustering demonstrated a separation of HS samples based on the presence or absence of tunnels. Tunnels isolated by microdissection had higher levels of epithelium-derived inflammatory cytokines compared with the overlying epidermis and healthy controls. Clinically, the size and draining of the tunnels were decreased with treatment with the IL-17RA antagonist brodalumab. These data suggest that tunnels are a source of inflammation in HS. [Display omitted] [ABSTRACT FROM AUTHOR]
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- 2021
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19. Mild atopic dermatitis lacks systemic inflammation and shows reduced nonlesional skin abnormalities.
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He, Helen, Del Duca, Ester, Diaz, Aisleen, Kim, Hyun Je, Gay-Mimbrera, Jesús, Zhang, Ning, Wu, Jianni, Beaziz, Jessica, Estrada, Yeriel, Krueger, James G., Pavel, Ana B., Ruano, Juan, and Guttman-Yassky, Emma
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Molecular studies in atopic dermatitis (AD) are largely restricted to patients with moderate-to-severe disease. Our aim was to evaluate skin and blood abnormalities in mild, moderate, and severe AD. Skin and blood samples were obtained from 61 patients with AD (20 with mild or limited disease, 17 with moderate disease, and 24 with severe disease) and 20 healthy subjects. Immune and barrier markers were measured in lesional, nonlesional, and healthy skin by quantitative real-time PCR and immunohistochemistry, and in blood by using the OLINK proteomic assay. Cellular markers of epidermal hyperplasia and T-cell/dendritic cell infiltration were increased in AD tissues of all patients in all severity groups versus in those of controls, whereas downstream T H 2 cell–, T H 22 cell–, T H 1 cell–, and T H 17 cell–related mediators demonstrated incremental elevations with increasing disease severity, in both lesional and nonlesional skin. Whereas the levels of the T H 2 (IL13, CCL17, and CCL26) and T H 22 (IL-22) cytokines were significantly elevated in both AD lesional and nonlesional skin of all patients regardless of the severity of their disease, patients with mild or limited AD showed increases in their levels of T H 1 cell (IFNG, CXCL9, and CXCL10) and T H 17 cell (IL-17A, CCL20, and CXCL1) markers in lesional but not nonlesional skin. Regulatory T-cell–related mediators (IL-10 and FOXP3) were comparably upregulated in all groups, without displaying the severity-based gradient in other immune axes. Unsupervised clustering aligned samples along a severity spectrum, where nonlesional mild or limited AD skin clustered with the samples from healthy controls. Furthermore, whereas the blood profiles of patients with moderate and severe AD showed gradual increases in the levels of T H 1 cell–, T H 2 cell–, and T H 17 cell–related and atherosclerosis and/or cardiovascular risk (CCL7, FGF21, and IGFBP1) proteins, the blood profiles of patients with mild or limited AD lacked significant differences from those of the controls. Mild and limited AD show high levels of T H 2/T H 22 cell activation that is primarily localized to skin lesions and lacks the systemic inflammation of moderate and severe disease. [Display omitted] [ABSTRACT FROM AUTHOR]
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- 2021
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20. Cross-sectional study of blood biomarkers of patients with moderate to severe alopecia areata reveals systemic immune and cardiovascular biomarker dysregulation.
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Glickman, Jacob W., Dubin, Celina, Renert-Yuval, Yael, Dahabreh, Dante, Kimmel, Grace W., Auyeung, Kelsey, Estrada, Yeriel D., Singer, Giselle, Krueger, James G., Pavel, Ana B., and Guttman-Yassky, Emma
- Abstract
Background: Although there is increased understanding of the alopecia areata (AA) pathogenesis based on studies in scalp tissues, little is known about its systemic profile.Objective: To evaluate the blood proteomic signature of AA and determine biomarkers associated with increased disease severity.Methods: In a cross-sectional study, we assessed 350 inflammatory and cardiovascular proteins using OLINK high-throughput proteomics in patients with moderate to severe AA (n = 35), as compared with healthy individuals (n = 36), patients with moderate to severe psoriasis (n = 19), and those with atopic dermatitis (n = 49).Results: Seventy-four proteins were significantly differentially expressed between AA and control individuals (false discovery rate, <.05) including innate immunity (interleukin [IL] 6/IL-8), T helper (Th) type 1 (interferon [IFN] γ/CXCL9/CXCL10/CXCL11), Th2 (CCL13/CCL17/CCL7), Th17 (CCL20/PI3/S100A12), and cardiovascular-risk proteins (OLR1/OSM/MPO/PRTN3). Eighty-six biomarkers correlated with AA clinical severity (P < .05), including Th1/Th2, and cardiovascular/atherosclerosis-related proteins, including SELP/PGLYRP1/MPO/IL-18/OSM (P < .05). Patients with AA totalis/universalis showed the highest systemic inflammatory tone, including cardiovascular risk biomarkers, compared to control individuals and even to patients with atopic dermatitis and those with psoriasis. The AA profile showed some Th1/Th2 differences in the setting of concomitant atopy.Limitations: Our analysis was limited to 350 proteins.Conclusion: This study defined the abnormalities of moderate to severe AA and associated circulatory biomarkers. It shows that AA has systemic immune, cardiovascular, and atherosclerosis biomarker dysregulation, suggesting the need for systemic treatment approaches. [ABSTRACT FROM AUTHOR]- Published
- 2021
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21. Tape strips detect distinct immune and barrier profiles in atopic dermatitis and psoriasis.
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He, Helen, Bissonnette, Robert, Wu, Jianni, Diaz, Aisleen, Saint-Cyr Proulx, Etienne, Maari, Catherine, Jack, Carolyn, Louis, Maudeline, Estrada, Yeriel, Krueger, James G., Zhang, Ning, Pavel, Ana B., and Guttman-Yassky, Emma
- Abstract
Our current understanding of atopic dermatitis (AD) and psoriasis pathophysiology is largely derived from skin biopsy studies that cause scarring and may be impractical in large-scale clinical trials. Although tape strips show promise as a minimally invasive technique in these common diseases, a comprehensive molecular profiling characterizing and differentiating the 2 diseases in tape strips is unavailable. Our aim was to construct a global transcriptome of tape strips from lesional and nonlesional skin of adults with moderate-to-severe AD and psoriasis. A total of 20 tape strips were obtained from lesional and nonlesional skin of patients with AD and psoriasis and skin from controls (n = 20 each); the strips were subjected to RNA sequencing (RNA-seq), with quantitative RT-PCR validation of immune and barrier biomarkers. We detected RNA-seq profiles in 96 of 100 of samples (96%), with 4123 and 5390 genes differentially expressed in AD and psoriasis lesions versus in controls, respectively (fold change ≥ 2; false discovery rate [FDR] < 0.05). Nonlesional tape-stripped skin from patients with AD was more similar to lesional skin than to nonlesional skin of patients with psoriasis, which showed larger differentiation from lesions. AD and psoriasis tissues shared increases in levels of dendritic cell and T-cell markers (CD3, ITGAX/CD11c, and CD83), but AD tissues showed preferential T H 2 skewing (IL-13, CCL17/TARC, and CCL18), whereas psoriasis was characterized by higher levels of expression of T H 17-related (IL-17A/F and IL-36A/IL-36G), T H 1-related (IFN-γ and CXCL9/CXCL10), and innate immunity–related (nitric oxide synthase 2/inducible nitric oxide synthase and IL-17C) products (FDR < 0.05). Terminal differentiation (FLG2 and LCE5A), tight junction (CLDN8), and lipid biosynthesis and metabolism (FA2H and ALOXE3) products were significantly downregulated in both AD and psoriasis (FDR < 0.05). Nitric oxide synthase 2/inducible nitric oxide synthase expression (determined by quantitative PCR) differentiated AD and psoriasis with 100% accuracy. RNA-seq tape strip profiling detected distinct immune and barrier signatures in lesional and nonlesional AD and psoriasis skin, suggesting their utility as a minimally invasive alternative to biopsies for detecting disease biomarkers. [ABSTRACT FROM AUTHOR]
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- 2021
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22. The effect of subcutaneous brodalumab on clinical disease activity in hidradenitis suppurativa: An open-label cohort study.
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Frew, John W., Navrazhina, Kristina, Grand, David, Sullivan-Whalen, Mary, Gilleaudeau, Patricia, Garcet, Sandra, Ungar, Jonathan, and Krueger, James G.
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Background: Hidradenitis suppurativa is an autoinflammatory disorder of keratinization, with dysregulation of T helper type 17 cytokines. Brodalumab is a monoclonal antibody that targets the interleukin (IL) 17 receptor A receptor.Objectives: To assess the safety and tolerability and clinical response at weeks 12 and 24 of brodalumab in moderate to severe HS. Ten participants with no history of inflammatory bowel disease were administered brodalumab 210 mg/1.5 mL subcutaneously at weeks 0, 1, and 2 and every 2 weeks thereafter until week 24. Participants were assessed for adverse events (grade 2/3 adverse events) and clinical response (Hidradenitis Suppurativa Clinical Response [HiSCR], Sartorius, International Hidradenitis Suppurativa Severity Scoring System [IHS4]), including ultrasonography and skin biopsies.Results: All 10 participants completed the study. No grade 2/3 adverse events associated with the use of brodalumab were reported. All patients (100%) achieved HiSCR, and 80% achieved IHS4 category change at week 12. HiSCR achievement occurred as early as week 2, likely due to the unique blockade of IL-17A, IL-17C, and IL-17F by brodalumab. Significant improvements were seen in pain, itch, quality of life, and depression.Conclusions: Brodalumab was well tolerated in this HS cohort, with no serious adverse events and improvement in clinical outcomes. Alterations in dose frequency may be required in those with advanced disease, which requires further exploration. [ABSTRACT FROM AUTHOR]- Published
- 2020
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23. Single-cell transcriptome analysis of human skin identifies novel fibroblast subpopulation and enrichment of immune subsets in atopic dermatitis.
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He, Helen, Suryawanshi, Hemant, Morozov, Pavel, Gay-Mimbrera, Jesús, Del Duca, Ester, Kim, Hyun Je, Kameyama, Naoya, Estrada, Yeriel, Der, Evan, Krueger, James G., Ruano, Juan, Tuschl, Thomas, and Guttman-Yassky, Emma
- Abstract
Atopic dermatitis (AD) is a prevalent inflammatory skin disease with a complex pathogenesis involving immune cell and epidermal abnormalities. Despite whole tissue biopsy studies that have advanced the mechanistic understanding of AD, single cell–based molecular alterations are largely unknown. Our aims were to construct a detailed, high-resolution atlas of cell populations and assess variability in cell composition and cell-specific gene expression in the skin of patients with AD versus in controls. We performed single-cell RNA sequencing on skin biopsy specimens from 5 patients with AD (4 lesional samples and 5 nonlesional samples) and 7 healthy control subjects, using 10× Genomics. We created transcriptomic profiles for 39,042 AD (lesional and nonlesional) and healthy skin cells. Fibroblasts demonstrated a novel COL6A5
+ COL18A1+ subpopulation that was unique to lesional AD and expressed CCL2 and CCL19 cytokines. A corresponding LAMP3+ dendritic cell (DC) population that expressed the CCL19 receptor CCR7 was also unique to AD lesions, illustrating a potential role for fibroblast signaling to immune cells. The lesional AD samples were characterized by expansion of inflammatory DCs (CD1A+ FCER1A+ ) and tissue-resident memory T cells (CD69+ CD103+ ). The frequencies of type 2 (IL13+ )/type 22 (IL22+ ) T cells were higher than those of type 1 (IFNG+ ) in lesional AD, whereas this ratio was slightly diminished in nonlesional AD and further diminished in controls. AD lesions were characterized by expanded type 2/type 22 T cells and inflammatory DCs, and by a unique inflammatory fibroblast that may interact with immune cells to regulate lymphoid cell organization and type 2 inflammation. [ABSTRACT FROM AUTHOR]- Published
- 2020
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24. Clinical response rates, placebo response rates, and significantly associated covariates are dependent on choice of outcome measure in hidradenitis suppurativa: A post hoc analysis of PIONEER 1 and 2 individual patient data.
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Frew, John W., Jiang, Caroline S., Singh, Neha, Grand, David, Navrazhina, Kristina, Vaughan, Roger, and Krueger, James G.
- Abstract
Background: The hidradenitis suppurativa clinical response (HiSCR) is the gold standard primary outcome measure for hidradenitis suppurativa clinical trials; however, it does not assess the presence of draining tunnels, a common finding in advanced disease. It is unclear what the effect of the presence or absence of draining tunnels has on the efficacy of adalimumab therapy in moderate and advanced disease.Objectives: We evaluated the efficacy of adalimumab versus placebo using the International Hidradenitis Suppurativa Severity Scoring System (IHS4). Additionally, we assessed the effect of draining tunnels on therapeutic response as measured by both the HiSCR and change in nodule counts.Methods: Reanalysis was conducted with the IHS4 and PIONEER 1 and 2 individual patient data. Both binary outcomes (achieving HiSCR and achieving change in IHS4 severity category) and continuous outcomes (nodule counts and IHS4 score) were calculated with R. Regression modeling was undertaken to assess the effect of draining tunnels and other variables. P < .05 was considered statistically significant.Results: The significance of adalimumab therapy depended on the outcome measure used. Placebo response rates were highest when binary outcome measures were used. Draining tunnels, smoking, antibiotics, and body mass index influenced HiSCR response in PIONEER 2. Significant differences in disease severity were observed between PIONEER 1 and 2 data sets.Conclusions: Elevated placebo response rates in PIONEER 1 and 2 are partially attributable to the use of binary outcome measures. Draining tunnels influence clinical response as measured by HiSCR and nodule counts in PIONEER 2. Further investigation into the effect of body mass index on clinical response is required. [ABSTRACT FROM AUTHOR]- Published
- 2020
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25. Comparing cutaneous molecular improvement with different treatments in atopic dermatitis patients.
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Glickman, Jacob W., Dubin, Celina, Han, Joseph, Dahabreh, Dante, Garcet, Sandra, Krueger, James G., Pavel, Ana B., and Guttman-Yassky, Emma
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- 2020
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26. The proteomic skin profile of moderate-to-severe atopic dermatitis patients shows an inflammatory signature.
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Pavel, Ana B., Zhou, Lisa, Diaz, Aisleen, Ungar, Benjamin, Dan, Joshua, He, Helen, Estrada, Yeriel D., Xu, Hui, Fernandes, Marie, Renert-Yuval, Yael, Krueger, James G., and Guttman-Yassky, Emma
- Abstract
Background: Moderate-to-severe atopic dermatitis (AD) is increasingly recognized as a systemic disease, largely due to proteomic blood studies. There are growing efforts to develop AD biomarkers using minimal tissues.Objective: To characterize the AD skin proteomic signature and its relationship with the blood proteome and genomic skin profile in the same individuals.Methods: We evaluated lesional and nonlesional biopsy samples and blood from 20 individuals with moderate-to-severe AD and 28 healthy individuals using Olink Proteomics (Uppsala, Sweden), using 10 μg/10 μL for skin and blood and RNA sequencing of the skin.Results: The AD skin proteome demonstrated significant upregulation in lesional and even in nonlesional skin compared with controls in inflammatory markers (matrix metalloproteinase 12; T-helper cell [Th]2/interleukin [IL]-1 receptor-like 1[IL1RL1]/IL-33R, IL-13, chemokine [C-C motif] ligand [CCL] 17; Th1/C-X-C motif chemokine 10; Th17/Th22/PI3, CCL20, S100A12), and in cardiovascular-associated proteins (E-selectin, matrix metalloproteinases, platelet growth factor, myeloperoxidase, fatty acid binding protein 4, and vascular endothelial growth factor A; false discovery rate, <0.05). Skin proteins demonstrated much higher and significant upregulations (vs controls) compared with blood, suggesting a skin source for the inflammatory/cardiovascular profile. Gene and protein expressions were correlated (r = 0.410, P < .001), with commonly upregulated inflammatory and cardiovascular risk-associated products, suggesting protein translation in skin.Limitations: Our analysis was limited to 354 proteins.Conclusions: The AD skin proteome shows an inflammatory and cardiovascular signature even in nonlesional skin, emphasizing the need for proactive treatment. Skin proteomics presents a sensitive option for biomarker monitoring. [ABSTRACT FROM AUTHOR]- Published
- 2020
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27. Short-term transcriptional response to IL-17 receptor-A antagonism in the treatment of psoriasis.
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Tomalin, Lewis E., Russell, Chris B., Garcet, Sandra, Ewald, David Adrian, Klekotka, Paul, Nirula, Ajay, Norsgaard, Hanne, Suàrez-Fariñas, Mayte, and Krueger, James G.
- Abstract
IL-17 antagonists induce impressive clinical benefits in psoriasis, but it is unknown to what extent cellular and molecular psoriasis characteristics are suppressed by a clinically relevant dose/schedule of any IL-17-receptor antagonist. We sought to examine the effects of the IL-17 receptor-A antagonist brodalumab, on clinical and molecular psoriasis features over a 12-week period. A subset of patients (n = 116) enrolled in 3 phase-3 randomized clinical trials (AMAGINE -1 [Efficacy, Safety, and Withdrawal and Retreatment With Brodalumab in Moderate to Severe Plaque Psoriasis Subjects], -2 [P3 Study Brodalumab in Treatment of Moderate to Severe Plaque Psoriasis], and -3 [Efficacy and Safety of Brodalumab Compared With Placebo and Ustekinumab in Moderate to Severe Plaque Psoriasis in Subjects]) participated in a mechanistic substudy where punch biopsies were collected (lesional and nonlesional skin) between baseline and 12 weeks. This cohort included moderate-to-severe psoriasis patients treated with 140 mg (n = 46), 210 mg (n = 41) brodalumab, or placebo (n = 29). Key epidermal psoriatic features, including T-cell and dendritic cell subsets, were examined using immunohistochemistry. Treatment-induced changes in lesional skin gene expression profiles were evaluated using Affymetrix arrays. IL-17 receptor-A antagonism caused extensive improvements in clinical, histologic, and transcriptomic features of psoriasis. Cellular infiltrates (CD3+, CD8+, CD11c+, CD163+), markers of keratinocyte proliferation (Ki67+, KRT16), and inflammatory cytokines (IL-17A/C/F, IL-23A, IL-12B) decreased progressively, reaching close to nonlesional levels, paralleled by decreases in epidermal thickness. Psoriasis transcriptome gene expression improved ∼85% to 95% in responders whose psoriasis area severity index improved by 75% from baseline by week 12 (n = 63), compared with ∼30% to 65% in nonresponders (n = 12), while the residual disease genomic profile was 10% of the psoriasis transcriptome, which is less than for earlier generation drugs. IL-17–dependent gene expression, including keratinocyte genes, improved earlier and more extensively following brodalumab treatment compared with ustekinumab treatment (anti-IL-23/-IL-12). The clinically approved dose and schedule for brodalumab leads to nearly complete resolution of clinical, histologic, and transcriptomic features of psoriasis. Evidently, IL-17–induced release of keratinocyte-derived inflammatory mediators is a key driver of psoriasis pathogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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28. Increased cardiovascular and atherosclerosis markers in blood of older patients with atopic dermatitis.
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He, Helen, Li, Randall, Choi, Seulah, Zhou, Lisa, Pavel, Ana, Estrada, Yeriel D., Krueger, James G., and Guttman-Yassky, Emma
- Published
- 2020
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29. Evolution of pathologic T-cell subsets in patients with atopic dermatitis from infancy to adulthood.
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Czarnowicki, Tali, He, Helen, Canter, Talia, Han, Joseph, Lefferdink, Rachel, Erickson, Taylor, Rangel, Stephanie, Kameyama, Naoya, Kim, Hyun Je, Pavel, Ana B., Estrada, Yeriel, Krueger, James G., Paller, Amy S., and Guttman-Yassky, Emma
- Abstract
The circulating immune phenotype was defined in adults and young children with early atopic dermatitis (AD), but chronologic changes in the blood of infants and children with AD through adolescence have not been explored. We sought to compare immune activation and cytokine polarization in the blood of 0- to 5-year-old (n = 39), 6- to 11-year-old (n = 26), 12- to 17-year-old (n = 21) and 18-year-old or older (n = 43) patients with AD versus age-matched control subjects. Flow cytometry was used to measure IFN-γ, IL-9, IL-13, IL-17, and IL-22 cytokine levels in CD4
+ /CD8+ T cells, with inducible costimulator molecule and HLA-DR defining midterm and long-term T-cell activation, respectively, within skin-homing/cutaneous lymphocyte antigen (CLA)+ versus systemic/CLA− T cells. Unsupervised clustering differentiated patients based on their blood biomarker frequencies. Although CLA+ T H 1 frequencies were significantly lower in infants with AD versus all older patients (P <.01), frequencies of CLA+ T H 2 T cells were similarly expanded across all AD age groups compared with control subjects (P <.05). After infancy, CLA− T H 2 frequencies were increased in patients with AD in all age groups, suggesting systemic immune activation with disease chronicity. IL-22 frequencies serially increased from normal levels in infants to highly significant levels in adolescents and adults compared with levels in respective control subjects (P <.01). Unsupervised clustering aligned the AD profiles along an age-related spectrum from infancy to adulthood (eg, inducible costimulator molecule and IL-22). The adult AD phenotype is achieved only in adulthood. Unique cytokine signatures characterizing individual pediatric endotypes might require age-specific therapies. Future longitudinal studies, comparing the profile of patients with cleared versus persistent pediatric AD, might define age-specific changes that predict AD clearance. [ABSTRACT FROM AUTHOR]- Published
- 2020
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30. Oral Janus kinase/SYK inhibition (ASN002) suppresses inflammation and improves epidermal barrier markers in patients with atopic dermatitis.
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Pavel, Ana B., Song, Teresa, Kim, Hyun-Je, Del Duca, Ester, Krueger, James G., Dubin, Celina, Peng, Xiangyu, Xu, Hui, Zhang, Ning, Estrada, Yeriel D., Denis, Louis, Rao, Niranjan, Gupta, Sandeep, Zammit, David J., Bissonnette, Robert, and Guttman-Yassky, Emma
- Abstract
Moderate-to-severe atopic dermatitis (AD) has been associated with significant disease burden and systemic abnormalities and often requires systemic treatments. Currently, safe and effective oral systemic treatments for moderate-to-severe AD are not yet available. ASN002 is an oral inhibitor of the Janus kinase/spleen tyrosine kinase signaling pathways, targeting several cytokine axes (T H 2/T H 22/T H 17/T H 1) and epidermal differentiation. We sought to evaluate the effect of ASN002 on the cellular and molecular biomarker profile of patients with moderate-to-severe AD and to correlate changes in biomarkers to improvements in clinical severity measures and pruritus. Thirty-six patients with moderate-to-severe AD were randomized to groups with dose escalation of ASN002 (20, 40, and 80 mg) and a placebo group. Skin biopsy specimens were performed at baseline, day 15, and day 29. Gene expression studies were conducted by using microarray and quantitative RT-PCR, and cellular infiltrates and protein expression were studied by using immunohistochemistry. ASN002 reversed the lesional skin transcriptome toward a nonlesional phenotype. It also rapidly and significantly suppressed key inflammatory pathways implicated in AD pathogenesis, including T H 2 (IL4 receptor [IL4R] , IL13 , CCL13 /monocyte chemoattractant protein 4, CCL17 /thymus and activation-regulated chemokine, CCL18 /pulmonary and activation-regulated chemokine, CCL22 /macrophage-derived chemokine, and CCL26 /eotaxin-3), T H 17/T H 22 (lipocalins, PI3 /elafin, CCL20 , S100A7 / S100A8 / S100A9 , and IL36G / IL36RN), and T H 1 (IFNG , CXCL9 / CXCL11 , and MX1) axes and barrier-related measures (filaggrin [FLG] and CLDN23). Significant improvements in AD gene signatures were observed predominantly in the 40- and 80-mg groups. Smaller and largely nonsignificant molecular changes were seen in the 20-mg and placebo groups. The Janus kinase/spleen tyrosine kinase inhibitor ASN002 significantly suppressed key AD inflammatory pathways, corresponding to clinical response. ASN002 might be an effective novel therapeutic agent for moderate-to-severe AD. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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31. Cutaneous p38 mitogen-activated protein kinase activation triggers psoriatic dermatitis.
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Sakurai, Kenji, Dainichi, Teruki, Garcet, Sandra, Tsuchiya, Soken, Yamamoto, Yosuke, Kitoh, Akihiko, Honda, Tetsuya, Nomura, Takashi, Egawa, Gyohei, Otsuka, Atsushi, Nakajima, Saeko, Matsumoto, Reiko, Nakano, Yuri, Otsuka, Masayuki, Iwakura, Yoichiro, Grinberg-Bleyer, Yenkel, Ghosh, Sankar, Sugimoto, Yukihiko, Guttman-Yassky, Emma, and Krueger, James G.
- Abstract
Psoriasis is a chronic inflammatory skin disease characterized by IL-17-mediated immune responses. p38 is known to be highly activated in the psoriatic epidermis; however, whether p38 is involved in the development of psoriasis is unclear. We sought to demonstrate that activation of p38 mitogen-activated protein kinase is sufficient to induce psoriatic inflammation in mice and that cutaneous p38 activities are the topical therapeutic targets for psoriasis. A p38 activator, anisomycin, was applied daily to murine skin. Transcriptomic analyses were performed to evaluate the similarities of the skin responses to those in human psoriasis and the existing animal model. BIRB796, a small-molecule inhibitor targeting p38 activities, was applied to the murine psoriatic models topically or to human psoriatic skin specimens ex vivo. Topical treatment with anisomycin induced key signatures in psoriasis, such as epidermal thickening, neutrophil infiltration, and gene expression of Il1a , Il1b , Il6 , Il24 , Cxcl1 , Il23a , and Il17a , in treated murine skin. These responses were fully abrogated by topical treatment with BIRB796, and were reduced in IL-17A–deficient mice. Transcriptomic analyses demonstrated the similarities of anisomycin-induced dermatitis to human psoriasis and imiquimod-induced murine psoriatic dermatitis. Furthermore, BIRB796 targeting of p38 activities reduced expression of psoriasis-related genes in both human keratinocytes stimulated with recombinant IL-17A in vitro and psoriatic skin specimens ex vivo. Therefore our findings suggest that cutaneous p38 activation can be a key event in patients with psoriasis and a potential topical therapeutic target of a small molecule. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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32. IL-17A inhibition by secukinumab induces early clinical, histopathologic, and molecular resolution of psoriasis.
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Krueger, James G., Wharton, Keith A., Schlitt, Thomas, Suprun, Maria, Torene, Rebecca I., Jiang, Xiaoyu, Wang, Claire Q., Fuentes-Duculan, Judilyn, Hartmann, Nicole, Peters, Thomas, Koroleva, Irina, Hillenbrand, Rainer, Letzkus, Martin, Yu, Xiaojing, Li, Yue, Glueck, Anton, Hasselberg, Anke, Flannery, Brian, Suárez-Fariñas, Mayte, and Hueber, Wolfgang
- Abstract
Hyperactivity of the IL-23/IL-17 axis is central to plaque psoriasis pathogenesis. Secukinumab, a fully human mAb that selectively inhibits IL-17A, is approved for treatment of psoriasis, psoriatic arthritis, and ankylosing spondylitis. Secukinumab improves the complete spectrum of psoriasis manifestations, with durable clinical responses beyond 5 years of treatment. In the feed-forward model of plaque chronicity, IL-17A has been hypothesized as the key driver of pathogenic gene expression by lesional keratinocytes, but in vivo evidence in human subjects is lacking. We performed a randomized, double-blind, placebo-controlled study (NCT01537432) of patients receiving secukinumab at the clinically approved dose up to 12 weeks. We then correlated plaque and nonlesional skin transcriptomic profiles with histopathologic and clinical measures of efficacy. After 12 weeks of treatment, secukinumab reversed plaque histopathology in the majority of patients and modulated thousands of transcripts. Suppression of the IL-23/IL-17 axis by secukinumab was evident at week 1 and continued through week 12, including reductions in levels of the upstream cytokine IL-23, the drug target IL-17A, and downstream targets, including β-defensin 2. Suppression of the IL-23/IL-17 axis by secukinumab at week 4 was associated with clinical and histologic responses at week 12. Secukinumab did not affect ex vivo T-cell activation, which is consistent with its favorable long-term safety profile. Our data suggest that IL-17A is the critical node within the multidimensional pathogenic immune circuits that maintain psoriasis plaques and that early reduction of IL-17A–dependent feed-forward transcripts synthesized by hyperplastic keratinocytes favors plaque resolution. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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33. The blood proteomic signature of early-onset pediatric atopic dermatitis shows systemic inflammation and is distinct from adult long-standing disease.
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Brunner, Patrick M., He, Helen, Pavel, Ana B., Czarnowicki, Tali, Lefferdink, Rachel, Erickson, Taylor, Canter, Talia, Puar, Neha, Rangel, Stephanie M., Malik, Kunal, Estrada, Yeriel, Krueger, James G., Guttman-Yassky, Emma, and Paller, Amy S.
- Abstract
Background: Despite increasing evidence that adults with long-standing atopic dermatitis (AD) have systemic inflammation, little is known about systemic inflammation in recent-onset early pediatric AD.Objective: To analyze blood inflammatory proteins of early pediatric AD.Methods: Using high-throughput proteomics (proximity extension assay), we assessed 257 inflammatory and cardiovascular risk proteins in the blood of 30 children with moderate to severe AD younger than 5 years of age (within 6 months of onset) compared with age-matched pediatric control individuals and adult patients with AD.Results: In pediatric AD blood, T helper (Th) type 2 (CCL13, CCL22) and Th17 (peptidase inhibitor-3/elafin) markers were increased, together with markers of tissue remodeling (matrix metalloproteinases 3/9/10, urokinase receptor), endothelial activation (E-selectin), T-cell activation (IL2RA), neutrophil activation (myeloperoxidase), lipid metabolism (FABP4), and growth factors (FGF21, transforming growth factor-α). Total numbers of dysregulated proteins were smaller in pediatric AD (n = 22) than in adult AD (n = 61). Clinical severity scores were positively correlated with receptors for interleukins 33 and 36 and inversely correlated with some Th1 markers (interferon gamma, CXCL11).Limitations: Different baseline expression levels in healthy pediatric vs adult samples.Conclusions: Within months of pediatric AD onset, systemic immune activation is present, with Th2/Th17 skewing but otherwise different proteomic patterns from adult AD. Future correlation of proteomic patterns with disease course, comorbidity development, and drug response may yield predictive biomarkers. [ABSTRACT FROM AUTHOR]- Published
- 2019
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34. The skin as an immune organ: Tolerance versus effector responses and applications to food allergy and hypersensitivity reactions.
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Guttman-Yassky, Emma, Zhou, Lisa, and Krueger, James G.
- Abstract
Skin is replete with immunocompetent cells that modulate signaling pathways to maintain a salubrious immunogenic/tolerogenic balance. This fertile immune environment plays a significant role in the development of allergic responses and sensitivities, but the mechanisms underlying these pathways have been underappreciated and underused with respect to developing therapeutics. Among the complex repertoire of cells that promote tolerogenic pathways in the periphery, 2 key classes include dendritic cells and regulatory T (Treg) cells. Immature dendritic cells are the first line of defense, patrolling the periphery, sampling antigens, and secreting cytokines that suppress immune cells and promote the survival of Treg cells. Skin-homing Treg cells also play a critical role in mitigating the reactivity of immune cells, secreting high levels of cytokines that promote tolerance. Therapeutic approaches that capitalize on our knowledge of the rich cellular and molecular environment are emerging and show great promise. We will discuss the advantages and challenges of 5 such strategies and how these therapies might mitigate the atopic march by facilitating tolerance. We conclude that skin is a multifaceted structure that provides a fertile ground for therapeutic discovery. Accordingly, ongoing work in this domain will no doubt continue to deliver exciting progress for improved health outcomes. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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35. A randomized, double-blind, placebo-controlled phase 1 study of multiple ascending doses of subcutaneous M1095, an anti-interleukin 17A/F nanobody, in moderate-to-severe psoriasis.
- Author
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Svecova, Danka, Lubell, Martin W., Casset-Semanaz, Florence, Mackenzie, Harald, Grenningloh, Roland, and Krueger, James G.
- Abstract
Background: Interleukin 17 is involved in the pathogenesis of psoriasis, a chronic debilitating disease.Objectives: To evaluate the safety/tolerability, immunogenicity, pharmacokinetics/pharmacodynamics, and efficacy of M1095, an anti-interleukin 17A/F nanobody, in moderate-to-severe plaque psoriasis.Methods: This multicenter, double-blind, placebo-controlled dose escalation phase 1 study randomized 44 patients 4:1 to treatment with subcutaneous M1095 (30, 60, 120, or 240 mg) or placebo biweekly for 6 weeks, in 4 ascending dose cohorts.Results: The most frequent treatment-emergent adverse events with M1095 were pruritus (n = 4) and headache (n = 3); 2 patients withdrew owing to adverse events (injection site reaction and elevated liver enzyme levels). The terminal half-life of M1095 was 11 to 12 days. The area under the curve/maximum concentration was dose proportional. Of 10 M1095-treated patients positive for antidrug antibodies, 5 showed treatment-emergent antidrug antibody responses. There was no effect on M1095 exposure. Marked decreases in psoriasis inflammatory markers were observed with M1095. By day 85, 100% and 56% of patients receiving M1095, 240 mg, achieved psoriasis area and severity index 90 and 100, respectively. Improvements in static Physician's Global Assessment and affected body surface area were also seen.Limitations: Interpretation of efficacy data is limited by the small sample size.Conclusion: Multiple subcutaneous doses of M1095 showed a favorable safety profile with dose-dependent improvements in psoriasis. [ABSTRACT FROM AUTHOR]- Published
- 2019
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36. Age-specific changes in the molecular phenotype of patients with moderate-to-severe atopic dermatitis.
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Zhou, Lisa, Leonard, Alexandra, Pavel, Ana B., Malik, Kunal, Raja, Aishwarya, Glickman, Jacob, Estrada, Yeriel D., Peng, Xiangyu, del Duca, Ester, Sanz-Cabanillas, Juan, Ruano, Juan, Xu, Hui, Zhang, Ning, Wen, Huei-Chi, Gonzalez, Juana, Garcet, Sandra, Krueger, James G., and Guttman-Yassky, Emma
- Abstract
Atopic dermatitis (AD) shows differential clinical presentation in older compared with younger patients. Nevertheless, changes in the AD molecular profile with age are unknown. We sought to characterize age-related changes in the AD profile. We evaluated age-specific changes in lesional and nonlesional tissues and blood from patients with moderate-to-severe AD (n = 246) and age-matched control subjects (n = 71) using immunohistochemistry, quantitative real-time PCR, and Singulex in a cross-sectional study. Patients were analyzed by age group (18-40, 41-60, and ≥61 years). Although disease severity/SCORAD scores were similar across AD age groups (mean, approximately 60 years; P =.873), dendritic cell infiltrates (CD1b
+ and FcεRI+ , P <.05) decreased with age. T H 2 measures (IL5 , IL13 , CCL13 , CCL18 , and CCL26) significantly decreased with age in patients with AD, despite increasing with age in control subjects. Consistent with T H 2 axis decreases, serum IgE levels and eosinophil counts negatively correlated with age in patients with AD (r = −0.24 and r = −0.23, respectively; P <.05). T H 22-secreted IL 22 expression levels also decreased with age uniquely in patients with AD (P <.05). Expression of T H 1-related (IFNG , IL12/23p40 , STAT1 , and CXCL9 ; P <.05 for CXCL9) and T H 17-related (IL 17A and IL 20 ; P <.05 for IL 20) markers increased with age in both patients with AD and control subjects. Expression of terminal differentiation measures significantly increased in older patients with AD (loricrin [LOR] and filaggrin [FLG] , P <.05), whereas expression of S100As (S100A8 , P <.01) and hyperplasia markers (epidermal thickness, keratin 16, and Ki67; P <.05 for keratin 16) decreased. Serum trends in AD mimicked skin findings, with T H 2 downregulation (CCL26; r = −0.32, P <.1) and T H 1 upregulation (IFN-γ; r = 0.48, P <.01) with age. The adult AD profile varies with age. Although T H 1/T H 17 skewing increases in both patients with AD and control subjects, patients with AD show unique decreases in T H 2/T H 22 polarization and normalization of epithelial abnormalities. Thus age-specific treatment approaches might be beneficial for AD. [ABSTRACT FROM AUTHOR]- Published
- 2019
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37. Psoriatic skin molecular and histopathologic profiles after treatment with risankizumab versus ustekinumab.
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Visvanathan, Sudha, Baum, Patrick, Vinisko, Richard, Schmid, Ramona, Flack, Mary, Lalovic, Bojan, Kleiner, Oliver, Fuentes-Duculan, Judilyn, Garcet, Sandra, Davis, Justin W., Grebe, Kristie M., Fine, Jay S., Padula, Steven J., and Krueger, James G.
- Abstract
IL-23 contributes to the activation, maintenance, and proliferation of T H 17 cells and plays a major role in psoriasis pathophysiology. IL-23p19 inhibition with risankizumab resulted in superior clinical responses in patients with psoriasis compared with ustekinumab (dual IL-12/IL-23 inhibitor), but comparative molecular effects have not been established. We investigated the similarities and differences in molecular and histopathologic profiles in skin lesions from patients with psoriasis receiving risankizumab versus ustekinumab at an early time point. Lesional skin biopsy samples from 81 patients with moderate-to-severe plaque psoriasis participating in 2 different studies (a phase I risankizumab study and a phase II study of risankizumab vs ustekinumab) were analyzed by using histopathology, immunohistochemistry, and RNA sequencing. Risankizumab induced a rapid decrease in levels of proteins and transcriptomic biomarkers associated with the IL-23 pathway, which were maintained through 8 weeks. At week 4, risankizumab decreased histopathologic expression of biomarkers, including K16, Ki67, CD3, lipocalin-2, CD11c, dendritic cell lysosome-associated membrane glycoprotein, β-defensin 2, and S100A7; global histopathologic scoring revealed that 54% and 69% of patients treated with 90 or 180 mg of risankizumab, respectively, were graded as experiencing "excellent improvement" versus 29% of patients treated with ustekinumab. At week 4, there was a common decrease in expression of 2645 genes expressed in lesional skin between patients receiving risankizumab and ustekinumab and a significant decrease in 2682 genes unique to risankizumab treatment. Risankizumab more strongly downregulated expression of genes associated with keratinocytes, epidermal cells, and monocytes, versus ustekinumab. Risankizumab demonstrated more pronounced changes in the molecular and histopathologic profile of psoriatic skin lesions compared with ustekinumab at week 4. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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38. Blood endotyping distinguishes the profile of vitiligo from that of other inflammatory and autoimmune skin diseases.
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Czarnowicki, Tali, He, Helen, Leonard, Alexandra, Kim, Hyun Je, Kameyama, Naoya, Pavel, Ana B., Li, Randall, Estrada, Yeriel, Wen, Huei-Chi, Kimmel, Grace W., Kim, Hee J., Chima, Margot, Lebwohl, Mark, Krueger, James G., and Guttman-Yassky, Emma
- Abstract
Peripheral blood skin-homing/cutaneous lymphocyte antigen (CLA)
+ T cells emerge as biomarkers of cutaneous immune activation in patients with inflammatory skin diseases (atopic dermatitis [AD] and alopecia areata [AA]). However, blood phenotyping across these subsets is not yet available in patients with vitiligo. We sought to measure cytokine production by circulating skin-homing (CLA+ ) versus systemic (CLA− ) "polar" CD4+ /CD8+ ratio and activated T-cell subsets in patients with vitiligo compared with patients with AA, AD, or psoriasis and control subjects. Flow cytometry was used to measure levels of the cytokines IFN-γ, IL-13, IL-9, IL-17, and IL-22 in CD4+ /CD8+ T cells in the blood of 19 patients with moderate-to-severe nonsegmental/generalized vitiligo, moderate-to-severe AA (n = 32), psoriasis (n = 24), or AD (n = 43) and control subjects (n = 30). Unsupervised clustering differentiated subjects into groups based on cellular frequencies. Patients with Vitiligo showed the highest CLA+ /CLA− T H 1/type 1 cytotoxic T-cell polarization, with parallel T H 2/T H 9/T H 17/T H 22 level increases to levels often greater than those seen in patients with AA, AD, or psoriasis (P <.05). Total regulatory T-cell counts were lower in patients with vitiligo than in control subjects and patients with AD or psoriasis (P <.001). Vitiligo severity correlated with levels of multiple cytokines (P <.1), whereas duration was linked with IFN-γ and IL-17 levels (P <.04). Patients and control subjects grouped into separate clusters based on blood biomarkers. Vitiligo is characterized by a multicytokine polarization among circulating skin-homing and systemic subsets, which differentiates it from other inflammatory/autoimmune skin diseases. Future targeted therapies should delineate the relative contribution of each cytokine axis to disease perpetuation. [ABSTRACT FROM AUTHOR]- Published
- 2019
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39. Modulation of inflammatory gene transcripts in psoriasis vulgaris: Differences between ustekinumab and etanercept.
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Brodmerkel, Carrie, Li, Katherine, Garcet, Sandra, Hayden, Karen, Chiricozzi, Andrea, Novitskaya, Inna, Fuentes-Duculan, Judilyn, Suarez-Farinas, Mayte, Campbell, Kim, and Krueger, James G.
- Published
- 2019
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40. Ichthyosis molecular fingerprinting shows profound TH17 skewing and a unique barrier genomic signature.
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Malik, Kunal, He, Helen, Huynh, Thy Nhat, Tran, Gary, Mueller, Kelly, Doytcheva, Kristina, Renert-Yuval, Yael, Czarnowicki, Tali, Magidi, Shai, Chou, Margaret, Estrada, Yeriel D., Wen, Huei-Chi, Peng, Xiangyu, Xu, Hui, Zheng, Xiuzhong, Krueger, James G., Paller, Amy S., and Guttman-Yassky, Emma
- Abstract
Background Ichthyoses are a group of rare skin disorders lacking effective treatments. Although genetic mutations are progressively delineated, comprehensive molecular phenotyping of ichthyotic skin could suggest much-needed pathogenesis-based therapy. Objective We sought to profile the molecular fingerprint of the most common orphan ichthyoses. Methods Gene, protein, and serum studies were performed on skin and blood samples from 29 patients (congenital ichthyosiform erythroderma, n = 9; lamellar ichthyosis, n = 8; epidermolytic ichthyosis, n = 8; and Netherton syndrome, n = 4), as well as age-matched healthy control subjects (n = 14), patients with psoriasis (n = 30), and patients with atopic dermatitis (AD; n = 16). Results Using criteria of a fold change of greater than 2 and a false discovery rate of less than 0.05, 132 differentially expressed genes were shared commonly among all ichthyoses, including many IL-17 and TNF-α–coregulated genes, which are considered hallmarks of psoriasis (defensin beta 4A, kynureninase, and vanin 3). Although striking upregulation of TH17 pathway genes (IL17F and IL36B/G) resembling that seen in patients with psoriasis was common to all patients with ichthyoses in a severity-related manner, patients with Netherton syndrome showed the greatest T-cell activation (inducible costimulator [ ICOS ]) and a broader immune phenotype with T H 1/IFN-γ, OASL, and T H 2/IL-4 receptor/IL-5 skewing, although less than seen in patients with AD (all P <.05). Ichthyoses lacked the epidermal differentiation and tight junction alterations of patients with AD (loricrin, filaggrin, and claudin 1) but showed characteristic alterations in lipid metabolism genes (ELOVL fatty acid elongase 3 and galanin), with parallel reductions in extracellular lipids and corneocyte compaction in all ichthyoses except epidermolytic ichthyosis, suggesting phenotypic variations. Transepidermal water loss, a functional barrier measure, significantly correlated with IL-17–regulated gene expression (IL17F and IL36A/IL36B/IL36G). Conclusion Similar to patients with AD and psoriasis, in whom cytokine dysregulation and barrier impairment orchestrate disease phenotypes, psoriasis-like immune dysregulation and lipid alterations characterize the ichthyoses. These data support the testing of IL-17/IL-36–targeted therapeutics for patients with ichthyosis similar to those used in patients with psoriasis. [ABSTRACT FROM AUTHOR]
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- 2019
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41. Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis.
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Guttman-Yassky, Emma, Bissonnette, Robert, Ungar, Benjamin, Suárez-Fariñas, Mayte, Ardeleanu, Marius, Esaki, Hitokazu, Suprun, Maria, Estrada, Yeriel, Xu, Hui, Peng, Xiangyu, Silverberg, Jonathan I., Menter, Alan, Krueger, James G., Zhang, Rick, Chaudhry, Usman, Swanson, Brian, Graham, Neil M.H., Pirozzi, Gianluca, Yancopoulos, George D., and D. Hamilton, Jennifer D.
- Abstract
Background Dupilumab is an IL-4 receptor α mAb inhibiting signaling of IL-4 and IL-13, key drivers of type 2–driven inflammation, as demonstrated by its efficacy in patients with atopic/allergic diseases. Objective This placebo-controlled, double-blind trial (NCT01979016) evaluated the efficacy, safety, and effects of dupilumab on molecular/cellular lesional and nonlesional skin phenotypes and systemic type 2 biomarkers of patients with moderate-to-severe atopic dermatitis (AD). Methods Skin biopsy specimens and blood were evaluated from 54 patients randomized 1:1 to weekly subcutaneous doses of 200 mg of dupilumab or placebo for 16 weeks. Results Dupilumab (vs placebo) significantly improved clinical signs and symptoms of AD, was well tolerated, and progressively shifted the lesional transcriptome toward a nonlesional phenotype (weeks 4–16). Mean improvements in a meta-analysis–derived AD transcriptome (genes differentially expressed between lesional and nonlesional skin) were 68.8% and 110.8% with dupilumab and −10.5% and 55.0% with placebo (weeks 4 and 16, respectively; P <.001). Dupilumab significantly reduced expression of genes involved in type 2 inflammation (IL13 , IL31 , CCL17 , CCL18 , and CCL26), epidermal hyperplasia (keratin 16 [K16] and MKi67), T cells, dendritic cells (ICOS , CD11c , and CTLA4), and T H 17/T H 22 activity (IL17A , IL-22 , and S100As) and concurrently increased expression of epidermal differentiation, barrier, and lipid metabolism genes (filaggrin [FLG] , loricrin [LOR] , claudins, and ELOVL3). Dupilumab reduced lesional epidermal thickness versus placebo (week 4, P =.001; week 16, P =.0002). Improvements in clinical and histologic measures correlated significantly with modulation of gene expression. Dupilumab also significantly suppressed type 2 serum biomarkers, including CCL17, CCL18, periostin, and total and allergen-specific IgEs. Conclusion Dupilumab-mediated inhibition of IL-4/IL-13 signaling through IL-4 receptor α blockade significantly and progressively improved disease activity, suppressed cellular/molecular cutaneous markers of inflammation and systemic measures of type 2 inflammation, and reversed AD-associated epidermal abnormalities. [ABSTRACT FROM AUTHOR]
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- 2019
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42. 43272 Differentiation of Therapeutic Monoclonal Antibodies Targeting IL-23 for the Treatment of Psoriatic Disease.
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Eyerich, Kilian, Krueger, James G., Sachen, Kacey, Greving, Carrie, Hammaker, Deepa, Bao, Phuc, Lacy, Eilyn, McInnes, Iain B., and Fourie, Anne
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- 2023
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43. 43019 Spesolimab for hidradenitis suppurativa: A proof-of-concept study.
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Alavi, Afsaneh, Prens, Errol, Kimball, Alexa B., Krueger, James G., Mukhopadhyay, Sutirtha, Wang, Hui, Ivanoff, Nathalie B., Hernandez Daly, Ana C., and Zouboulis, Christos C.
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- 2023
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44. Atopic dermatitis in Chinese patients shows TH2/TH17 skewing with psoriasiform features.
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Chan, Tom C., Sanyal, Riana D., Pavel, Ana B., Glickman, Jacob, Zheng, Xiuzhong, Xu, Hui, Cho, Yung-Tsu, Tsai, Tsen-Feng, Wen, Huei-Chi, Peng, Xiangyu, Cueto, Inna, Krueger, James G., and Guttman-Yassky, Emma
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- 2018
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45. Enhancement of cutaneous immunity during aging by blocking p38 mitogen-activated protein (MAP) kinase–induced inflammation.
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Vukmanovic-Stejic, Milica, Chambers, Emma S., Suárez-Fariñas, Mayte, Sandhu, Daisy, Fuentes-Duculan, Judilyn, Patel, Neil, Agius, Elaine, Lacy, Katie E., Turner, Carolin T., Larbi, Anis, Birault, Veronique, Noursadeghi, Mahdad, Mabbott, Neil A., Rustin, Malcolm H.A., Krueger, James G., and Akbar, Arne N.
- Abstract
Background Immunity decreases with age, which leads to reactivation of varicella zoster virus (VZV). In human subjects age-associated immune changes are usually measured in blood leukocytes; however, this might not reflect alterations in tissue-specific immunity. Objectives We used a VZV antigen challenge system in the skin to investigate changes in tissue-specific mechanisms involved in the decreased response to this virus during aging. Methods We assessed cutaneous immunity based on the extent of erythema and induration after intradermal VZV antigen injection. We also performed immune histology and transcriptomic analyses on skin biopsy specimens taken from the challenge site in young (<40 years) and old (>65 years) subjects. Results Old human subjects exhibited decreased erythema and induration, CD4 + and CD8 + T-cell infiltration, and attenuated global gene activation at the site of cutaneous VZV antigen challenge compared with young subjects. This was associated with increased sterile inflammation in the skin in the same subjects related to p38 mitogen-activated protein kinase–related proinflammatory cytokine production ( P < .0007). We inhibited systemic inflammation in old subjects by means of pretreatment with an oral small-molecule p38 mitogen-activated protein kinase inhibitor (Losmapimod; GlaxoSmithKline, Brentford, United Kingdom), which reduced both serum C-reactive protein levels and peripheral blood monocyte secretion of IL-6 and TNF-α. In contrast, cutaneous responses to VZV antigen challenge were increased significantly in the same subjects ( P < .0003). Conclusion Excessive inflammation in the skin early after antigen challenge retards antigen-specific immunity. However, this can be reversed by inhibition of inflammatory cytokine production that can be used to promote vaccine efficacy and the treatment of infections and malignancy during aging. [ABSTRACT FROM AUTHOR]
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- 2018
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46. Early-onset pediatric atopic dermatitis is characterized by TH2/TH17/TH22-centered inflammation and lipid alterations.
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Brunner, Patrick M., Israel, Ariel, Zhang, Ning, Leonard, Alexandra, Wen, Huei-Chi, Huynh, Thy, Tran, Gary, Lyon, Sarah, Rodriguez, Giselle, Immaneni, Supriya, Wagner, Annette, Zheng, Xiuzhong, Estrada, Yeriel D., Xu, Hui, Krueger, James G., Paller, Amy S., and Guttman-Yassky, Emma
- Abstract
Background Although atopic dermatitis (AD) often starts in early childhood, detailed tissue profiling of early-onset AD in children is lacking, hindering therapeutic development for this patient population with a particularly high unmet need for better treatments. Objective We sought to globally profile the skin of infants with AD compared with that of adults with AD and healthy control subjects. Methods We performed microarray, RT-PCR, and fluorescence microscopy studies in infants and young children (<5 years old) with early-onset AD (<6 months disease duration) compared with age-matched control subjects and adults with longstanding AD. Results Transcriptomic analyses revealed profound differences between pediatric patients with early-onset versus adult patients with longstanding AD in not only lesional but also nonlesional tissues. Although both patient populations harbored T H 2-centered inflammation, pediatric AD also showed significant T H 17/T H 22 skewing but lacked the T H 1 upregulation that characterizes adult AD. Pediatric AD exhibited relatively normal expression of epidermal differentiation and cornification products, which is downregulated in adults with AD. Defects in the lipid barrier (eg, ELOVL fatty acid elongase 3 [ELOVL3] and diacylglycerol o-acyltransferase 2 [DGAT2]) and tight junction regulation (eg, claudins 8 and 23) were evident in both groups. However, some lipid-associated mediators (eg, fatty acyl-CoA reductase 2 and fatty acid 2-hydroxylase) showed preferential downregulation in pediatric AD, and lipid barrier genes (FA2H and DGAT2) showed inverse correlations with transepidermal water loss, a functional measure of the epidermal barrier. Conclusions Skin samples from children and adult patients with AD share lipid metabolism and tight junction alterations, but epidermal differentiation complex defects are only present in adult AD, potentially resulting from chronic immune aberration that is not yet present in early-onset disease. [ABSTRACT FROM AUTHOR]
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- 2018
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47. Atopic dermatitis and psoriasis: two different immune diseases or one spectrum?
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Guttman-Yassky, Emma and Krueger, James G
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ATOPIC dermatitis treatment , *PSORIASIS treatment , *IMMUNOSUPPRESSIVE agents , *CYTOKINES , *INTERLEUKIN-17 , *HISTOPATHOLOGY - Abstract
Psoriasis and atopic dermatitis (AD) are common T-cell mediated inflammatory diseases of the skin that can be treated by specific cytokine antagonists or more broad immunosuppressive drugs. The diseases are similar in that epidermal keratinocytes respond to T-cell derived cytokines by altering growth and differentiation responses, accounting for major parts of the overall disease phenotype. When studied across European-American populations, psoriasis and AD display differing T-cell polarity and different arrays of cytokines. Psoriasis is a disease largely driven by Th17 T-cells and associated IL-17 activation, while AD has a strong Th2 component associated with IL-4 and IL-13 over-production, and both diseases have activation of Th22 T-cells and Th1 pathways with increased IL-22 and IFNγ production, respectively. AD is a disease frequently associated with increased IgE production and overt allergies or asthma, most likely due to increased Th2 activation, which is largely lacking in psoriasis. Hence, psoriasis and AD can be viewed as distinct diseases with differing clinical, tissue, and molecular disease phenotypes, but this view does not account for specific subtypes of AD, including Asian-origin, intrinsic, and pediatric AD, that have a prominent IL-17 component and also tissue patterning that overlaps with distinctive psoriasis histopathology. Hence, when considering the range of AD phenotypes, a case can be made that psoriasis and AD exist across a spectrum where polar T-cell axes can be variably present and create some overlapping disease characteristics. Today, ∼90% of psoriasis patients have extremely controlled disease by targeting the IL-23/Th17 T-cell axis with IL-23 or IL-17-targeting antibodies. An outstanding question is whether targeting a single cytokine axis in AD, for example, Th2 axis, will lead to disease suppression in the majority of patients and across all subtypes, including those with higher IL-17 expression, or whether it is necessary to personalize therapies and target multiple T-cell axes to attain similar disease improvement to psoriasis. [ABSTRACT FROM AUTHOR]
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- 2017
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48. 769 GUSELKUMAB, AN IL-23P19 SUBUNIT-SPECIFIC MONOCLONAL ANTIBODY, BINDS CD64+ MYELOID CELLS AND POTENTLY NEUTRALIZES IL-23 PRODUCED FROM THE SAME CELLS.
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Abreu, Maria T., Atreya, Raja, Krueger, James G., Eyerich, Kilian, Sachen, Kacey, Greving, Carrie, Hammaker, Deepa, Bao, Phuc, Lacy, Eilyn, Sarabia, Indra, Deming, Janise, Elloso, M. Merle, Ritchlin, Christopher, McInnes, Iain B., Allez, Matthieu, and Fourie, Anne
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- 2023
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49. Psoriasis pathogenesis and the development of novel targeted immune therapies.
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Hawkes, Jason E., Chan, Tom C., and Krueger, James G.
- Abstract
Psoriasis is caused by a complex interplay between the immune system, psoriasis-associated susceptibility loci, autoantigens, and multiple environmental factors. Over the last 2 decades, research has unequivocally shown that psoriasis represents a bona fide T cell–mediated disease primarily driven by pathogenic T cells that produce high levels of IL-17 in response to IL-23. The discovery of the central role for the IL-23/type 17 T-cell axis in the development of psoriasis has led to a major paradigm shift in the pathogenic model for this condition. The activation and upregulation of IL-17 in prepsoriatic skin produces a “feed forward” inflammatory response in keratinocytes that is self-amplifying and drives the development of mature psoriatic plaques by inducing epidermal hyperplasia, epidermal cell proliferation, and recruitment of leukocyte subsets into the skin. Clinical trial data for mAbs against IL-17 signaling (secukinumab, ixekizumab, and brodalumab) and newer IL-23p19 antagonists (tildrakizumab, guselkumab, and risankizumab) underscore the central role of these cytokines as predominant drivers of psoriatic disease. Currently, we are witnessing a translational revolution in the treatment and management of psoriasis. Emerging bispecific antibodies offer the potential for even better disease control, whereas small-molecule drugs offer future alternatives to the use of biologics and less costly long-term disease management. [ABSTRACT FROM AUTHOR]
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- 2017
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50. Novel concepts of prevention and treatment of atopic dermatitis through barrier and immune manipulations with implications for the atopic march.
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Czarnowicki, Tali, Krueger, James G., and Guttman-Yassky, Emma
- Abstract
Skin barrier abnormalities have been suggested to play an essential role in initiation of early atopic dermatitis (AD). Antigen penetration through a compromised barrier likely leads to increased innate immune responses, antigen-presenting cell stimulation, and priming of overt cutaneous disease. In a T H 2-promoting environment, T-cell/B-cell interactions occurring in regional lymph nodes lead to excessive IgE switch. Concurrent redistribution of memory T cells into the circulation not only leads to exacerbation of AD through T-cell skin infiltration but also spreads beyond the skin to initiate the atopic march, which includes food allergy, asthma, and allergic rhinitis. Possible primary interventions to prevent AD are focusing on improving skin barrier integrity, including supplementing barrier function with moisturizers. As for secondary prophylaxis in children with established AD, this can be stratified into prevention of disease exacerbations by using proactive approaches (with either topical corticosteroids or topical calcineurin inhibitors) in mild AD cases or the prevention of other atopic disorders that will probably mandate systemic immunosuppression in severe AD cases. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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