238 results on '"Guttman-Yassky, Emma"'
Search Results
2. Real-World Effectiveness of Dupilumab in Atopic Dermatitis Patients: Analysis of an Electronic Medical Records Dataset
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Eichenfield, Lawrence F, Armstrong, April, Guttman-Yassky, Emma, Lio, Peter A, Chen, Chi-Chang, Hines, Dionne M, McGuiness, Catherine B, Ganguli, Sohini, Delevry, Dimittri, Sierka, Debra, and Mallya, Usha G
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Biomedical and Clinical Sciences ,Clinical Sciences ,Aging ,Clinical Research ,Brain Disorders ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Good Health and Well Being ,Atopic dermatitis ,Body surface area affected ,Dupilumab ,Investigator global assessment ,Itch ,Real-world effectiveness ,Clinical sciences - Abstract
IntroductionWhile the efficacy of dupilumab for the treatment of adults with moderate-to-severe atopic dermatitis (AD) has been demonstrated in several clinical trials, patients in such trials may not necessarily reflect the real-world clinical practice setting. This study evaluated the real-world effectiveness of dupilumab in adults with moderate-to-severe AD based on physician global assessment, percent body surface area affected, and patient-reported itch.MethodsFrom Modernizing Medicine's Electronic Medical Assistant dermatology-specific electronic medical records, adults (≥ 18 years) were identified with a diagnosis of AD and ≥ 1 dupilumab prescription (index event) between 1 April 2017 and 31 January 2019. Three cohorts were identified based on 3-month pre-index (1) Investigator Global Assessment (IGA) score ≥ 3, (2) an itch severity numerical rating scale (NRS) score ≥ 3, and (3) body surface area (BSA) affected ≥ 10%. Changes from pre-index on the outcome within each cohort were evaluated at 4 months post-index. Patients were also stratified for evaluation of outcomes by baseline demographic (sex, age) and prior AD treatments (topical therapy only or no treatment, any systemic therapy).ResultsMore than 70% of the 435 AD patients with baseline IGA score ≥ 3 improved to an IGA score of ≤ 2 at month 4 post-dupilumab initiation, including 42.8% who achieved IGA 0/1 (clear/minimal). Among 112 patients with a pre-index itch severity NRS ≥ 3, scores were reduced from mean (SD) 7.0 (2.4) pre-index to 2.8 (2.8) at month 4 (p
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- 2022
3. Polygenic prediction of atopic dermatitis improves with atopic training and filaggrin factors
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Arehart, Christopher H, Daya, Michelle, Campbell, Monica, Boorgula, Meher Preethi, Rafaels, Nicholas, Chavan, Sameer, David, Gloria, Hanifin, Jon, Slifka, Mark K, Gallo, Richard L, Hata, Tissa, Schneider, Lynda C, Paller, Amy S, Ong, Peck Y, Spergel, Jonathan M, Guttman-Yassky, Emma, Leung, Donald YM, Beck, Lisa A, Gignoux, Christopher R, Mathias, Rasika A, and Barnes, Kathleen C
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Biomedical and Clinical Sciences ,Immunology ,Genetics ,Prevention ,Clinical Research ,Human Genome ,Aetiology ,2.1 Biological and endogenous factors ,Dermatitis ,Atopic ,Female ,Filaggrin Proteins ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Humans ,Infant ,Linkage Disequilibrium ,Loss of Function Mutation ,Male ,Phenotype ,Atopic dermatitis ,polygenic risk score ,atopic march ,allergic disease ,genetic architecture ,filaggrin ,disease prediction ,genetic predisposition ,Allergy - Abstract
BackgroundWhile numerous genetic loci associated with atopic dermatitis (AD) have been discovered, to date, work leveraging the combined burden of AD risk variants across the genome to predict disease risk has been limited.ObjectivesThis study aims to determine whether polygenic risk scores (PRSs) relying on genetic determinants for AD provide useful predictions for disease occurrence and severity. It also explicitly tests the value of including genome-wide association studies of related allergic phenotypes and known FLG loss-of-function (LOF) variants.MethodsAD PRSs were constructed for 1619 European American individuals from the Atopic Dermatitis Research Network using an AD training dataset and an atopic training dataset including AD, childhood onset asthma, and general allergy. Additionally, whole genome sequencing data were used to explore genetic scoring specific to FLG LOF mutations.ResultsGenetic scores derived from the AD-only genome-wide association studies were predictive of AD cases (PRSAD: odds ratio [OR], 1.70; 95% CI, 1.49-1.93). Accuracy was first improved when PRSs were built off the larger atopy genome-wide association studies (PRSAD+: OR, 2.16; 95% CI, 1.89-2.47) and further improved when including FLG LOF mutations (PRSAD++: OR, 3.23; 95% CI, 2.57-4.07). Importantly, while all 3 PRSs correlated with AD severity, the best prediction was from PRSAD++, which distinguished individuals with severe AD from control subjects with OR of 3.86 (95% CI, 2.77-5.36).ConclusionsThis study demonstrates how PRSs for AD that include genetic determinants across atopic phenotypes and FLG LOF variants may be a promising tool for identifying individuals at high risk for developing disease and specifically severe disease.
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- 2022
4. The translational revolution in atopic dermatitis: the paradigm shift from pathogenesis to treatment
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Facheris, Paola, Jeffery, Jane, Del Duca, Ester, and Guttman-Yassky, Emma
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- 2023
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5. Multiethnic genome-wide and HLA association study of total serum IgE level
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Daya, Michelle, Cox, Corey, Acevedo, Nathalie, Boorgula, Meher P, Campbell, Monica, Chavan, Sameer, Cho, Michael H, David, Gloria L, Kachroo, Priyadarshini, Lasky-Su, Jessica, Li, Xingnan, McHugh, Caitlin P, Qiao, Dandi, Rafaels, Nicholas, Beck, Lisa A, Bleecker, Eugene R, Caraballo, Luis, Cupples, Adrienne L, Figueiredo, Camila A, Gallo, Richard L, Hanifin, Jon, Hansel, Nadia N, Hata, Tissa R, Hersh, Craig P, Knight-Madden, Jennifer, Leung, Donald YM, Guttman-Yassky, Emma, Meyers, Deborah A, O’Connor, George, Ober, Carole, Ong, Peck Y, Ortega, Victor E, Paller, Amy S, Putcha, Nirupama, Reed, Robert M, Schneider, Lynda C, Silverman, Edwin K, Slifka, Mark K, Spergel, Jonathan M, Vasan, Ramachandran S, Viaud-Martinez, Karine A, Watson, Harold, Weiss, Scott T, Consortium, NHLBI Trans-Omics for Precision Medicine, Ruczinski, Ingo, Beaty, Terri H, Mathias, Rasika A, and Barnes, Kathleen C
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Clinical Research ,Genetics ,Lung ,Asthma ,Human Genome ,Aetiology ,2.1 Biological and endogenous factors ,Inflammatory and immune system ,Good Health and Well Being ,Adolescent ,Adult ,Aged ,Child ,Child ,Preschool ,Dermatitis ,Atopic ,Ethnicity ,Female ,Gene Frequency ,Genetic Predisposition to Disease ,Genome-Wide Association Study ,Genotype ,HLA-A2 Antigen ,HLA-DQ beta-Chains ,Humans ,Immunoglobulin E ,Male ,Middle Aged ,National Heart ,Lung ,and Blood Institute (U.S.) ,United States ,Whole Genome Sequencing ,Young Adult ,Total serum IgE ,human leukocyte antigen ,genome-wide association study ,atopic dermatitis ,asthma ,multiethnic ,NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium ,Immunology ,Allergy - Abstract
BackgroundTotal serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE.ObjectiveWe aimed to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum by leveraging data from the National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine program; the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA); and the Atopic Dermatitis Research Network (N = 21,901).MethodsWe performed genome-wide association within strata of study, disease, and ancestry groups, and we combined results via a meta-regression approach that models heterogeneity attributable to ancestry. We also tested for association between HLA alleles called from whole genome sequence data and tIgE, assessing replication of associations in HLA alleles called from genotype array data.ResultsWe identified 6 loci at genome-wide significance (P < 5 × 10-9), including 4 loci previously reported as genome-wide significant for tIgE, as well as new regions in chr11q13.5 and chr15q22.2, which were also identified in prior genome-wide association studies of atopic dermatitis and asthma. In the HLA allele association study, HLA-A∗02:01 was associated with decreased tIgE level (Pdiscovery = 2 × 10-4; Preplication = 5 × 10-4; Pdiscovery+replication = 4 × 10-7), and HLA-DQB1∗03:02 was strongly associated with decreased tIgE level in Hispanic/Latino ancestry populations (PHispanic/Latino discovery+replication = 8 × 10-8).ConclusionWe performed the largest genome-wide association study and HLA association study of tIgE focused on ancestrally diverse populations and found several known tIgE and allergic disease loci that are relevant in non-European ancestry populations.
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- 2021
6. Whole genome sequencing identifies novel genetic mutations in patients with eczema herpeticum
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Bin, Lianghua, Malley, Claire, Taylor, Patricia, Boorgula, Meher Preethi, Chavan, Sameer, Daya, Michelle, Mathias, Malaika, Shankar, Gautam, Rafaels, Nicholas, Vergara, Candelaria, Potee, Joseph, Campbell, Monica, Hanifin, Jon M, Simpson, Eric, Schneider, Lynda C, Gallo, Richard L, Hata, Tissa, Paller, Amy S, De Benedetto, Anna, Beck, Lisa A, Ong, Peck Y, Guttman‐Yassky, Emma, Richers, Brittany, Baraghoshi, David, Ruczinski, Ingo, Barnes, Kathleen C, Leung, Donald YM, and Mathias, Rasika A
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Biomedical and Clinical Sciences ,Clinical Sciences ,Genetics ,Biotechnology ,Sexually Transmitted Infections ,Human Genome ,2.1 Biological and endogenous factors ,Aetiology ,Skin ,Dermatitis ,Atopic ,Glutathione Transferase ,Herpesvirus 1 ,Human ,Humans ,Kaposi Varicelliform Eruption ,Mutation ,Nucleotide Transport Proteins ,Whole Genome Sequencing ,atopic dermatitis ,eczema herpeticum ,genetics ,herpes simplex virus ,SIDT2 ,whole genome sequencing ,SIDT2 ,Immunology ,Allergy - Abstract
BackgroundEczema herpeticum (EH) is a rare complication of atopic dermatitis (AD) caused by disseminated herpes simplex virus (HSV) infection. The role of rare and/or deleterious genetic variants in disease etiology is largely unknown. This study aimed to identify genes that harbor damaging genetic variants associated with HSV infection in AD with a history of recurrent eczema herpeticum (ADEH+).MethodsWhole genome sequencing (WGS) was performed on 49 recurrent ADEH+ (≥3 EH episodes), 491 AD without a history of eczema herpeticum (ADEH-) and 237 non-atopic control (NA) subjects. Variants were annotated, and a gene-based approach (SKAT-O) was used to identify genes harboring damaging genetic variants associated with ADEH+. Genes identified through WGS were studied for effects on HSV responses and keratinocyte differentiation.ResultsEight genes were identified in the comparison of recurrent ADEH+to ADEH-and NA subjects: SIDT2, CLEC7A, GSTZ1, TPSG1, SP110, RBBP8NL, TRIM15, and FRMD3. Silencing SIDT2 and RBBP8NL in normal human primary keratinocytes (NHPKs) led to significantly increased HSV-1 replication. SIDT2-silenced NHPKs had decreased gene expression of IFNk and IL1b in response to HSV-1 infection. RBBP8NL-silenced NHPKs had decreased gene expression of IFNk, but increased IL1b. Additionally, silencing SIDT2 and RBBP8NL also inhibited gene expression of keratinocyte differentiation markers keratin 10 (KRT10) and loricrin (LOR).ConclusionSIDT2 and RBBP8NL participate in keratinocyte's response to HSV-1 infection. SIDT2 and RBBP8NL also regulate expression of keratinocyte differentiation genes of KRT10 and LOR.
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- 2021
7. Atopic dermatitis stratification: current and future perspective on skin and blood transcriptomic and proteomic profiling.
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Hawkins, Kelly, David, Eden, Glickman, Jacob W, Del Duca, Ester, Guttman-Yassky, Emma, and Krueger, James G
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IMMUNOGLOBULIN E ,ATOPIC dermatitis ,TRANSCRIPTOMES ,BLOOD testing ,DISEASE progression - Abstract
Atopic dermatitis (AD) is a common, chronic inflammatory skin disorder driven by an intricate interplay of genetic, environmental, and immunological factors. As a clinically heterogenous condition, AD may be stratified into subtypes based on factors including, chronicity, immunoglobulin E levels, severity, age, and ethnicity. Transcriptomic and proteomic analyses in skin and blood help elucidate the underlying molecular mechanisms of these AD subtypes, referred to as AD endotypes. Further characterizing AD endotypes using reliable biomarkers can facilitate the development of more effective and personalized therapeutics and improve our tools for monitoring disease progression and therapeutic response across a diverse subset of patients. Here, we aim to provide perspective on the latest research regarding AD stratification using skin and blood-based studies and insight into the implications of these findings on the future of AD research and clinical practice. The precise stratification of AD endotypes will allow for the development of reliable biomarkers and a more personalized medical treatment approach. Clinical practice and trials will eventually be able to bridge clinical with molecular data to optimize individualized treatments and more effectively monitor treatment response. [ABSTRACT FROM AUTHOR]
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- 2024
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8. Pharmacokinetics and pharmacodynamics of itepekimab in adults with moderate‐to‐severe atopic dermatitis: Results from two terminated phase II trials.
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Kosloski, Matthew P., Guttman‐Yassky, Emma, Cork, Michael J., Worm, Margitta, Nahm, Dong‐Ho, Zhu, Xiaoping, Ruddy, Marcella K., Harel, Sivan, Kamal, Mohamed A., Goulaouic, Hélène, Xu, Christine R., Avetisova, Elena, Davis, John D., Nivens, Michael C., Shabbir, Arsalan, and Radin, Allen
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CHRONIC obstructive pulmonary disease , *EPITHELIUM , *ATOPIC dermatitis , *EPITHELIAL cells , *DUPILUMAB - Abstract
Interleukin‐33 (IL‐33) is a proinflammatory alarmin cytokine released by damaged epithelial tissue cells that initiates and amplifies both type 1 and type 2 inflammatory cascades. A role for IL‐33 in atopic dermatitis (AD; a chronic, relapsing type 2 inflammatory disease of the skin) has been proposed. Itepekimab is a novel human IgG4P monoclonal antibody against IL‐33, currently in clinical development for chronic obstructive pulmonary disease (COPD). Two global phase II studies—a dose‐ranging itepekimab monotherapy study (NCT03738423) and a proof‐of‐concept study of itepekimab alone and in combination with dupilumab (NCT03736967)—were conducted in patients with moderate‐to‐severe AD to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy; both studies were terminated following an interim analysis of the proof‐of‐concept study, which failed to demonstrate the efficacy of itepekimab. In these two studies, itepekimab exhibited linear and dose‐proportional pharmacokinetics. Pharmacodynamics of total IL‐33 indicated that itepekimab saturated binding to the target in serum at 300 mg q2w and q4w doses, and decreased blood eosinophil counts. Concentration–time profiles of itepekimab and total IL‐33 were similar for itepekimab with or without dupilumab, and between East Asian and non‐East Asian subgroups. Itepekimab was generally well tolerated, both alone and in combination with dupilumab. The lack of clinical efficacy for itepekimab observed in these studies suggests that IL‐33 may not be a key pathogenic driver in moderate‐to‐severe AD. [ABSTRACT FROM AUTHOR]
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- 2024
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9. Biologic and small-molecule therapy for treating moderate to severe atopic dermatitis: Mechanistic considerations.
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Rothenberg-Lausell, Camille, Bar, Jonathan, Dahabreh, Dante, Renert-Yuval, Yael, Del Duca, Ester, and Guttman-Yassky, Emma
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Atopic dermatitis (AD) is a complex and heterogeneous skin disease for which achieving complete clinical clearance for most patients has proven challenging through single cytokine inhibition. Current studies integrate biomarkers and evaluate their role in AD, aiming to advance our understanding of the diverse molecular profiles implicated. Although traditionally characterized as a T H 2-driven disease, extensive research has recently revealed the involvement of T H 1, T H 17, and T H 22 immune pathways as well as the interplay of pivotal immune molecules, such as OX40, OX40 ligand (OX40L), thymic stromal lymphopoietin, and IL-33. This review explores the mechanistic effects of treatments for AD, focusing on mAbs and Janus kinase inhibitors. It describes how these treatments modulate immune pathways and examines their impact on key inflammatory and barrier biomarkers. [ABSTRACT FROM AUTHOR]
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- 2024
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10. Integrated Safety Update of Abrocitinib in 3802 Patients with Moderate-to-Severe Atopic Dermatitis: Data from More than 5200 Patient-Years with Up to 4 Years of Exposure.
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Simpson, Eric L., Silverberg, Jonathan I., Nosbaum, Audrey, Winthrop, Kevin, Guttman-Yassky, Emma, Hoffmeister, Karin M., Egeberg, Alexander, Valdez, Hernan, Fan, Haiyun, Farooqui, Saleem A., Chan, Gary, Alderfer, Justine, Romero, William, and Chittuluru, Kanti
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RISK factors of pneumonia ,ATOPIC dermatitis ,RISK assessment ,HERPES zoster ,PATIENT safety ,RESEARCH funding ,SKIN tumors ,LYMPHOCYTE count ,LYMPHOPENIA ,VEINS ,SEVERITY of illness index ,ORAL drug administration ,AGE distribution ,POPULATION geography ,DESCRIPTIVE statistics ,JANUS kinases ,THROMBOEMBOLISM ,NEUROTRANSMITTER uptake inhibitors ,HERPES simplex ,MORBID obesity ,CONFIDENCE intervals ,REGRESSION analysis ,PROPORTIONAL hazards models ,DISEASE risk factors ,DISEASE complications - Abstract
Background: Abrocitinib, an oral, once-daily, Janus kinase 1-selective inhibitor, is efficacious in moderate-to-severe atopic dermatitis with a manageable long-term safety profile. Objective: We aimed to provide updated integrated long-term safety results for abrocitinib from available data accrued up to a maximum of almost 4 years in patients with moderate-to-severe atopic dermatitis from the JADE clinical development program. Methods: Analysis included 3802 patients (exposure: 5213.9 patient-years) from the phase II monotherapy study (NCT02780167) and the phase III studies JADE MONO-1 (NCT03349060), JADE MONO-2 (NCT03575871), JADE TEEN (NCT03796676), JADE COMPARE (NCT03720470), JADE DARE (NCT04345367; 200 mg only), JADE REGIMEN (NCT03627767), and JADE EXTEND (NCT03422822; data cutoff 25 September, 2021). Data from patients receiving one or more doses of abrocitinib 200 mg or 100 mg were pooled in a consistent-dose cohort (patients were allocated to receive the same abrocitinib dose throughout exposure in the qualifying parent study and/or long-term study) or a variable-dose cohort (patients received open-label abrocitinib 200 mg; responders were randomized to abrocitinib 200 mg, 100 mg, or placebo, and could then receive abrocitinib 200 mg plus topical corticosteroids as rescue therapy). Incidence rates of adverse events of special interest were assessed. Cox regression analysis of risk factors for herpes zoster and serious infections was performed. Results: Overall, this safety analysis of long-term data up to a maximum of ~ 4 years of abrocitinib exposure does not indicate any changes from the previously reported risk profile. The most frequent serious infections (per Medical Dictionary for Regulatory Activities preferred term) with consistent-dose abrocitinib 200 mg and 100 mg were herpes zoster (0.5% and 0.2%), pneumonia (0.2% with either dose), and herpes simplex (0.1% with either dose). Risk factors for herpes zoster were a history of herpes zoster, abrocitinib 200-mg dose, age ≥ 65 years, absolute lymphocyte count < 1 × 10
3 /mm3 before the event, and residing in Asia. For serious infections, > 100 kg body weight was a risk factor. Incidence rate/100 patient-years (95% confidence interval) with the consistent abrocitinib 200-mg and 100-mg dose combined was higher in older (aged ≥ 65 years) patients versus younger (aged 18 to < 65 years) patients for serious adverse events (17.6 [11.7‒25.4] vs 6.7 [5.8‒7.8]), malignancy excluding non-melanoma skin cancer (2.4 [0.6‒6.0] vs 0.1 [0.0‒0.4]), non-melanoma skin cancer (2.4 [0.6‒6.1] vs 0.2 [0.1‒0.4]), lymphopenia (3.5 [1.3‒7.6] vs 0.1 [0.0‒0.3]), and venous thromboembolism (1.7 [0.4‒5.1] vs 0.1 [0.0‒0.3]). Incident rate/100 patient-years (95% confidence interval) of non-melanoma skin cancer with the consistent abrocitinib 200-mg and 100-mg dose combined was higher in current/former smokers (0.9 [0.4‒1.6]) vs never-smokers (0.0 [0.0‒0.1]). Conclusions: This safety update showed a consistent profile for abrocitinib with no new safety signals and continues to support that abrocitinib has a manageable long-term safety profile in patients with moderate-to-severe atopic dermatitis. Risk of specific adverse events was higher in certain patient populations, especially those aged ≥ 65 years. [Video abstract available.] Clinical Trial Registration: NCT02780167; study start date: April, 2016; primary completion date: March, 2017; study completion date: April, 2017. NCT03349060; study start date: 7 December, 2017; study completion date: 26 March, 2019. NCT03575871; study start date: 29 June, 2018; study completion date: 13 August, 2019. NCT03720470; study start date: 29 October, 2018; primary completion date: 27 December, 2019; study completion date: 6 March, 2020. NCT03796676; study start date: 18 February, 2019; study completion date: 8 April, 2020. NCT03627767; study start date: 11 June, 2018; primary completion date: 2 September, 2020; study completion date: 7 October, 2020. NCT04345367; study start date: 11 June, 2020; primary completion date: 16 December, 2020; study completion date: 13 July, 2021. NCT03422822; study start date: 8 March, 2018; study completion date: ongoing (estimated completion date: 31 January, 2026). Plain Language Summary: Abrocitinib is an approved treatment for people with moderate or severe atopic dermatitis, also known as AD or atopic eczema. Abrocitinib is a tablet that is taken by mouth once a day. This safety analysis looked at the side effects of treatment in a large group of adults and adolescents with moderate or severe AD who took abrocitinib up to a maximum of almost 4 years. This analysis also looked at which people were more likely to have certain side effects after taking abrocitinib. The results from this analysis were similar to those of previous safety analyses with abrocitinib, with no new side effects. Infections such as shingles, pneumonia, or herpes simplex can occur during treatment with abrocitinib. Shingles was more likely to occur in people who previously had shingles before taking abrocitinib, or who took the higher dose of abrocitinib (200 mg), or were 65 years of age or older, or had certain blood test results, or lived in Asia. People who are 65 years of age or older and took abrocitinib were more likely to develop some types of cancer, have certain abnormal blood test results, or develop blood clots in the veins than people with AD who were younger and took abrocitinib. Current or former smokers with AD who took abrocitinib were more likely to develop skin cancer (but not melanoma) than people with AD who took abrocitinib but have never smoked. This analysis further shows that abrocitinib had manageable safety in patients with moderate-to-severe AD. Dex5AhfAxs29XQspjFnxYi Video abstract: Integrated safety update of abrocitinib in 3802 patients with moderate-to-severe atopic dermatitis: data from more than 5200 patient-years with up to 4 years of exposure (MP4 63720 KB) [ABSTRACT FROM AUTHOR]- Published
- 2024
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11. Targeting IL‐13 with tralokinumab normalizes type 2 inflammation in atopic dermatitis both early and at 2 years.
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Guttman‐Yassky, Emma, Kabashima, Kenji, Staumont‐Salle, Delphine, Nahm, Walter K., Pauser, Sylvia, Da Rosa, Joel Correa, Martel, Britta Cathrina, Madsen, Daniel Elenius, Røpke, Mads, Arlert, Petra, Steffensen, Louise, Blauvelt, Andrew, and Reich, Kristian
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ATOPIC dermatitis , *GENE expression , *INFLAMMATION , *SKIN inflammation , *AMINO acid sequence - Abstract
Background: Tralokinumab is a monoclonal antibody that specifically neutralizes interleukin (IL)‐13, a key driver of skin inflammation and barrier abnormalities in atopic dermatitis (AD). This study evaluated early and 2‐year impacts of IL‐13 neutralization on skin and serum biomarkers following tralokinumab treatment in adults with moderate‐to‐severe AD. Methods: Skin biopsies and blood samples were evaluated from a subset of patients enrolled in the Phase 3 ECZTRA 1 (NCT03131648) and the long‐term extension ECZTEND (NCT03587805) trials. Gene expression was assessed by RNA sequencing; protein expression was assessed by immunohistochemistry and immunoassay. Results: Tralokinumab improved the transcriptomic profile of lesional skin by Week 4. Mean improvements in the expression of genes dysregulated in AD were 39% at Week 16 and 85% at 2 years with tralokinumab, with 15% worsening at Week 16 with placebo. At Week 16, tralokinumab significantly decreased type 2 serum biomarkers (CCL17/TARC, periostin, and IgE), reduced epidermal thickness versus placebo, and increased loricrin coverage versus baseline. Two years of tralokinumab treatment significantly reduced expression of genes in the Th2 (IL4R, IL31, CCL17, and CCL26), Th1 (IFNG), and Th17/Th22 (IL22, S100A7, S100A8, and S100A9) pathways as well as increased expression of epidermal differentiation and barrier genes (CLDN1 and LOR). Tralokinumab also shifted atherosclerosis signaling pathway genes (SELE, IL‐37, and S100A8) toward non‐lesional expression. Conclusion: Tralokinumab treatment improved epidermal pathology, reduced systemic markers of type 2 inflammation, and shifted expression of key AD biomarkers in skin towards non‐lesional levels, further highlighting the key role of IL‐13 in the pathogenesis of AD. Clinical Trial Registration: NCT03131648, NCT03587805. [ABSTRACT FROM AUTHOR]
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- 2024
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12. Mapping the immune cell landscape of severe atopic dermatitis by single‐cell RNA‐seq.
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Jin, Seon‐Pil, Lee, Kyungchun, Bang, Yoon Ji, Jeon, Yun‐Hui, Jung, Sunyoung, Choi, So‐Jung, Lee, Ji Su, Kim, Junhan, Guttman‐Yassky, Emma, Park, Chung‐Gyu, Kim, Hyun Je, Hong, Seunghee, and Lee, Dong Hun
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ATOPIC dermatitis ,MONONUCLEAR leukocytes ,INNATE lymphoid cells ,ECZEMA ,TH2 cells ,RNA sequencing - Abstract
Background: Efforts to profile atopic dermatitis (AD) tissues have intensified, yet comprehensive analysis of systemic immune landscapes in severe AD remains crucial. Methods: Employing single‐cell RNA sequencing, we analyzed over 300,000 peripheral blood mononuclear cells from 12 severe AD patients (Eczema area and severity index (EASI) > 21) and six healthy controls. Results: Results revealed significant immune cell shifts in AD patients, including increased Th2 cell abundance, reduced NK cell clusters with compromised cytotoxicity, and correlated Type 2 innate lymphoid cell proportions with disease severity. Moreover, unique monocyte clusters reflecting activated innate immunity emerged in very severe AD (EASI > 30). While overall dendritic cells (DCs) counts decreased, a distinct Th2‐priming subset termed "Th2_DC" correlated strongly with disease severity, validated across skin tissue data, and flow cytometry with additional independent severe AD samples. Beyond the recognized role of Th2 adaptive immunity, our findings highlight significant innate immune cell alterations in severe AD, implicating their roles in disease pathogenesis and therapeutic potentials. Conclusion: Apart from the widely recognized role of Th2 adaptive immunity in AD pathogenesis, alterations in innate immune cells and impaired cytotoxic cells have also been observed in severe AD. The impact of these alterations on disease pathogenesis and the effectiveness of potential therapeutic targets requires further investigation. [ABSTRACT FROM AUTHOR]
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- 2024
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13. Effect of abrocitinib on skin biomarkers in patients with moderate‐to‐severe atopic dermatitis.
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Guttman‐Yassky, Emma, Facheris, Paola, Gomez‐Arias, Pedro Jesus, Del Duca, Ester, Da Rosa, Joel Correa, Weidinger, Stephan, Bissonnette, Robert, Armstrong, April W., Seneschal, Julien, Eyerich, Kilian, Estrada, Yeriel D., Bose, Swaroop N., Xu, Dan, Chen, Allshine, Tatulych, Svitlana, Güler, Erman, Chan, Gary, Page, Karen M., and Kerkmann, Urs
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ATOPIC dermatitis , *BIOMARKERS , *GENE expression , *MATRIX metalloproteinases , *CARRIER proteins - Abstract
Background: This is the first report on the effects of abrocitinib, a Janus kinase 1–selective inhibitor, on the expression of skin biomarkers in patients with moderate‐to‐severe atopic dermatitis (AD). Methods: JADE MOA (NCT03915496) was a double‐blind Phase 2a trial. Adults were randomly assigned 1:1:1 to receive monotherapy with once‐daily abrocitinib 200 mg, abrocitinib 100 mg, or placebo for 12 weeks. The primary endpoint was change from baseline in markers of inflammation (matrix metalloproteinase [MMP]‐12), epidermal hyperplasia (keratin‐16 [KRT16]), T‐helper 2 (Th2) immune response (C‐C motif chemokine ligand [CCL]17, CCL18, and CCL26), and Th22 immune response (S100 calcium binding protein A8, A9, and A12 [S100A8, S100A9, and S100A12]) in skin through 12 weeks. Results: A total of 46 patients received abrocitinib 200 mg (n = 14), abrocitinib 100 mg (n = 16), or placebo (n = 16). Abrocitinib improved AD clinical signs and reduced itch. Gene expression of MMP‐12, KRT16, S100A8, S100A9, and S100A12 was significantly decreased from baseline with abrocitinib 200 mg (at Weeks 2, 4, and 12) and abrocitinib 100 mg (at Weeks 4 and 12) in a dose‐dependent manner. Abrocitinib 200 mg resulted in significant decreases from baseline in CCL17 expression at Week 12 and CCL18 expression at Weeks 2, 4, and 12; no significant decreases were observed for CCL26. Conclusions: Alongside improvements in clinical signs and symptoms of AD, 12 weeks of abrocitinib treatment resulted in downregulation of genes associated with inflammation, epidermal hyperplasia, and Th2 and Th22 immune responses in the skin of patients with moderate‐to‐severe AD. [ABSTRACT FROM AUTHOR]
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- 2024
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14. Proteomic alterations in patients with atopic dermatitis.
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Obi, Ashley, Rothenberg-Lausell, Camille, Levit, Sophia, Del Duca, Ester, and Guttman-Yassky, Emma
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Atopic Dermatitis (AD) is the most common inflammatory skin disease with a complex and multifactorial pathogenesis. The use of proteomics in understanding AD has yielded the discovery of novel biomarkers and may further expand therapeutic options. This review summarizes the most recent proteomic studies and the methodologies used in AD. It describes novel biomarkers that may monitor disease course and therapeutic response. The review also highlights skin and blood biomarkers characterizing different AD phenotypes and differentiates AD from other inflammatory skin disorders. A literature search was conducted by querying Scopus, Google Scholar, Pubmed/Medline, and Clinicaltrials.gov up to June 2023. The integration of proteomics into research efforts in atopic dermatitis has broadened our understanding of the molecular profile of AD through the discovery of new biomarkers. In addition, proteomics may contribute to the development of targeted treatments ultimately improving personalized medicine. An increasing number of studies are utilizing proteomics to explore this heterogeneous disease. [ABSTRACT FROM AUTHOR]
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- 2024
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15. OX40 in the Pathogenesis of Atopic Dermatitis—A New Therapeutic Target.
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Croft, Michael, Esfandiari, Ehsanollah, Chong, Camilla, Hsu, Hailing, Kabashima, Kenji, Kricorian, Greg, Warren, Richard B., Wollenberg, Andreas, and Guttman-Yassky, Emma
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ATOPIC dermatitis ,SKIN diseases ,T cells ,NECROSIS ,IMMUNOGLOBULINS ,CELLULAR signal transduction ,CHRONIC diseases ,ITCHING ,QUALITY of life ,INFLAMMATION ,CELL receptors ,IMMUNOLOGIC diseases - Abstract
Atopic dermatitis (AD) is a chronic, heterogeneous, inflammatory disease characterized by skin lesions, pruritus, and pain. Patients with moderate-to-severe AD experience chronic symptoms, intensified by unpredictable flares, and often have comorbidities and secondary complications, which can result in significant clinical burden that impacts the patient's overall quality of life. The complex interplay of immune dysregulation and skin barrier disruption drives AD pathogenesis, of which T-cell-dependent inflammation plays a critical role in patients with AD. Despite new targeted therapies, many patients with moderate-to-severe AD fail to achieve or sustain their individual treatment goals and/or may not be suitable for or tolerate these therapies. There remains a need for a novel, efficacious, well-tolerated therapeutic option that can deliver durable benefits across a heterogeneous AD patient population. Expression of OX40 [tumor necrosis factor receptor superfamily, member 4 (TNFRSF4)], a prominent T-cell co-stimulatory molecule, and its ligand [OX40L; tumor necrosis factor superfamily, member 4 (TNFSF4)] is increased in AD. As the OX40 pathway is critical for expansion, differentiation, and survival of effector and memory T cells, its targeting might be a promising therapeutic approach to provide sustained inhibition of pathogenic T cells and associated inflammation and broad disease control. Antibodies against OX40 [rocatinlimab (AMG 451/KHK4083) and telazorlimab (GBR 830)] or OX40L [amlitelimab (KY1005)] have shown promising results in early-phase clinical studies of moderate-to-severe AD, highlighting the importance of OX40 signaling as a new therapeutic target in AD. [ABSTRACT FROM AUTHOR]
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- 2024
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16. Clinical and molecular effects of oral CCR4 antagonist RPT193 in atopic dermatitis: A Phase 1 study.
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Bissonnette, Robert, DuBois, Janet, Facheris, Paola, Del Duca, Ester, Kim, Madeline, Correa Da Rosa, Joel, Trujillo, Damian L., Bose, Swaroop, Pagan, Angel D., Wustrow, David, Brockstedt, Dirk G., Wong, Brian, Kassner, Paul D., Jankicevic, Jasmina, Ho, William, Cheng, Laurence E., and Guttman‐Yassky, Emma
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CHEMOKINE receptors ,ATOPIC dermatitis ,END of treatment ,SMALL molecules ,INTERFERON beta-1a ,SKIN diseases - Abstract
Background: RPT193 is an orally administered small molecule antagonist of the human C‐C motif chemokine receptor 4 (CCR4) that inhibits the migration and downstream activation of T‐helper Type 2 (Th2) cells. We investigated single‐ and multiple‐ascending doses of RPT193 in healthy subjects, and multiple doses of RPT193 in subjects with moderate‐to‐severe atopic dermatitis (AD). Methods: This was a first‐in‐human randomized, placebo‐controlled Phase 1a/1b monotherapy study (NCT04271514) to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and CCR4 surface receptor occupancy in eligible healthy subjects and subjects with moderate‐to‐severe AD. Clinical efficacy and skin biomarker effects of RPT193 monotherapy were assessed as exploratory endpoints in AD subjects. Results: In healthy (n = 72) and AD subjects (n = 31), once‐daily RPT193 treatment was generally well tolerated, with no serious adverse events reported and all treatment‐emergent adverse events reported as mild/moderate. In AD subjects, numerically greater improvements in clinical efficacy endpoints were observed with RPT193 monotherapy versus placebo up to the end of the treatment period (Day 29), with statistically significant improvement, compared to Day 29 and placebo, observed 2 weeks after the end of treatment (Day 43) on several endpoints (p <.05). Moreover, significant changes in the transcriptional profile were seen in skin biopsies of RPT193‐treated versus placebo‐treated subjects at Day 29, which were also significantly correlated with improvements in clinical efficacy measures. Conclusions: To our knowledge, this is the first clinical study with an oral CCR4 antagonist that showed clinical improvement coupled with modulation of the cutaneous transcriptomic profile in an inflammatory skin disease. [ABSTRACT FROM AUTHOR]
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- 2024
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17. Two‐sample Mendelian randomization analysis identifies a causal association between atopic dermatitis and impetigo.
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Diaz, Michael J., O'Hagan, Ross, Tran, Jasmine T., Guttman‐Yassky, Emma, and Ungar, Benjamin
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ZINC-finger proteins ,RANDOM effects model ,GENOME-wide association studies ,SINGLE nucleotide polymorphisms ,LINKAGE disequilibrium - Abstract
A study published in the International Journal of Dermatology has found a causal relationship between atopic dermatitis (AD) and an increased risk of impetigo, a bacterial infection. The study used a two-sample Mendelian randomization analysis to investigate this association. The researchers identified specific genetic variants that were strongly associated with impetigo risk. However, further research is needed to validate these findings and understand the biological implications. These findings could potentially inform preventative interventions for both AD and impetigo. [Extracted from the article]
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- 2024
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18. 627 - A checklist to aid in identifying patients with atopic dermatitis who are candidates for systemic therapy.
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Silverberg, Jonathan, Augustin, Matthias, Eichenfield, Lawrence, Lio, Peter, Guttman-Yassky, Emma, Atwater, Amber Reck, Pierce, Evangeline, Rueda, Maria Jose, Li, Alvin, Maldonado, Yolanda Munoz, and Simpson, Eric
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ATOPIC dermatitis ,MEDICAL registries ,CONFIDENCE intervals ,ECZEMA ,ADULTS - Abstract
Introduction The decision to initiate systemic therapy (ST) in patients with atopic dermatitis (AD) is complex, with no criteria that are globally agreed upon. To aid dermatology providers in this decision-making, the "When to Start Systemic Therapy Checklist" was developed. The checklist comprises three components: (A) clinical severity, (B) subjective burden, and (C) lack of treatment response, each with several criteria. Systemic therapy is indicated when at least one criterion in each component is fulfilled. Objectives To corroborate the validity of this checklist, we evaluated the agreement between the decision to initiate ST using the checklist, against the reference, CorEvitas AD Registry patients prescribed a ST. Methods Adults with moderate-to-severe AD from the prospective, longitudinal CorEvitas AD registry were included in this descriptive analysis (July 2020 – August 2023). Patients were included if they were initiating ST at enrollment (ST group) or not initiating ST at enrollment (non-ST group) but had vIGA-AD® ≥3 and Eczema Area Severity Index ≥12. The checklist criteria were compared against registry outcome measures; when a criterion did not match a measure, either a proxy measure was selected or that part of the questionnaire was excluded. Overall percentage agreement (accord between checklist criteria and ST initiation status [reference standard]) with corresponding 95% confidence intervals (CIs) was calculated. Results In the ST group (n=1488), 97.0% of patients met at least one criterion from section A, 94.1% from section B, and 92.1% for either section A or B. In the non-ST group (n=208), 100% of patients met at least one criterion from section A, 92.3% from section B, and 92.3% from either section A or B. Among patients in the ST group who met at least one criterion each from section A and B, overall percentage agreement was 81.7% (95% CI: 79.8%, 83.5%). Section C, which addresses "lack of treatment response" could not be evaluated due to the absence of relevant data in the registry. Conclusions Nearly all patients initiating ST met at least one criterion from both section A and B of the "When to Start Systemic Therapy Checklist", demonstrating a strong alignment between the checklist sections A and B and disease burden of AD patients in the registry. Subsequent research is needed to assess section C due to registry limitations. Future analyses should examine why some patients with high disease burden and severity remain untreated with systemics. [ABSTRACT FROM AUTHOR]
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- 2024
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19. Qualitative Assessment of Adult Patients’ Perception of Atopic Dermatitis Using Natural Language Processing Analysis in a Cross-Sectional Study
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Falissard, Bruno, Simpson, Eric L., Guttman-Yassky, Emma, Papp, Kim A., Barbarot, Sebastien, Gadkari, Abhijit, Saba, Grece, Gautier, Laurene, Abbe, Adeline, and Eckert, Laurent
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- 2020
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20. The vIGA‐AD scale for atopic dermatitis: Uptake in the past 5 years and position of the International Eczema Council.
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Bissonnette, Robert, Simpson, Eric, Eichenfield, Lawrence F., Guttman‐Yassky, Emma, Silverberg, Jonathan I., Beck, Lisa A., Mija, Lorena, Thyssen, Jacob P., Bieber, Thomas, Kabashima, Kenji, Siegfried, Elaine, Stingl, Georg, van de Kerkhof, Peter, Yosipovitch, Gil, Paul, Carle, and Paller, Amy S.
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ATOPIC dermatitis ,ECZEMA ,EMPLOYEE ownership - Abstract
The article discusses the adoption and use of the vIGA-AD scale, a validated scale for measuring the severity of atopic dermatitis (AD). The scale was developed in 2016 to provide a standardized and representative measure of AD severity. The study analyzed data from ClinicalTrials.gov and PubMed to assess the scale's uptake in the AD research community. The results showed an increase in the proportion of studies and publications using the vIGA-AD scale over the years. The article also highlights the limitations of the scale and suggests using it in combination with other outcome measures. The authors conclude that the vIGA-AD scale has been widely adopted by researchers and sponsors as a validated measure of AD severity. [Extracted from the article]
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- 2024
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21. CLA+ memory T cells in atopic dermatitis: CLA+ T cells and atopic dermatitis.
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Nicolàs, Lídia Sans‐de San, Czarnowicki, Tali, Akdis, Mübeccel, Pujol, Ramon M., Lozano‐Ojalvo, Daniel, Leung, Donald Y. M., Guttman‐Yassky, Emma, and Santamaria‐Babí, Luis F.
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ATOPIC dermatitis ,T cells ,IMMUNOLOGIC memory ,LYMPHOID tissue ,SKIN diseases - Abstract
Circulating skin‐homing cutaneous lymphocyte‐associated antigen (CLA)+ T cells constitute a small subset of human memory T cells involved in several aspects of atopic dermatitis: Staphylococcus aureus related mechanisms, the abnormal Th2 immune response, biomarkers, clinical aspects of the patients, pruritus, and the mechanism of action of targeted therapies. Superantigens, IL‐13, IL‐31, pruritus, CCL17 and early effects on dupilumab‐treated patients have in common that they are associated with the CLA+ T cell mechanisms in atopic dermatitis patients. The function of CLA+ T cells corresponds with the role of T cells belonging to the skin‐associated lymphoid tissue and could be a reason why they reflect different mechanisms of atopic dermatitis and many other T cell mediated skin diseases. The goal of this review is to gather all this translational information of atopic dermatitis pathology. [ABSTRACT FROM AUTHOR]
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- 2024
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22. Intrapatient comparison of atopic dermatitis skin transcriptome shows differences between tape‐strips and biopsies.
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Del Duca, Ester, He, Helen, Liu, Ying, Pagan, Angel D., David, Eden, Cheng, Julia, Carroll, Britta, Renert‐Yuval, Yael, Bar, Jonathan, Estrada, Yeriel D., Maari, Catherine, Proulx, Etienne Saint‐Cyr, Krueger, James G., Bissonnette, Robert, and Guttman‐Yassky, Emma
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ATOPIC dermatitis ,ITCHING ,FALSE discovery rate ,SKIN biopsy ,TRANSCRIPTOMES ,BIOPSY - Abstract
Background: Our knowledge of etiopathogenesis of atopic dermatitis (AD) is largely derived from skin biopsies, which are associated with pain, scarring and infection. In contrast, tape‐stripping is a minimally invasive, nonscarring technique to collect skin samples. Methods: To construct a global AD skin transcriptomic profile comparing tape‐strips to whole‐skin biopsies, we performed RNA‐seq on tape‐strips and biopsies taken from the lesional skin of 20 moderate‐to‐severe AD patients and the skin of 20 controls. Differentially expressed genes (DEGs) were defined by fold‐change (FCH) ≥2.0 and false discovery rate <0.05. Results: We detected 4104 (2513 Up; 1591 Down) and 1273 (546 Up; 727 Down) DEGs in AD versus controls, in tape‐strips and biopsies, respectively. Although both techniques captured dysregulation of key immune genes, tape‐strips showed higher FCHs for innate immunity (IL‐1B, IL‐8), dendritic cell (ITGAX/CD11C, FCER1A), Th2 (IL‐13, CCL17, TNFRSF4/OX40), and Th17 (CCL20, CXCL1) products, while biopsies showed higher upregulation of Th22 associated genes (IL‐22, S100As) and dermal cytokines (IFN‐γ, CCL26). Itch‐related genes (IL‐31, TRPV3) were preferentially captured by tape‐strips. Epidermal barrier abnormalities were detected in both techniques, with terminal differentiation defects (FLG2, PSORS1C2) better represented by tape‐strips and epidermal hyperplasia changes (KRT16, MKI67) better detected by biopsies. Conclusions: Tape‐strips and biopsies capture overlapping but distinct features of the AD molecular signature, suggesting their respective utility for monitoring specific AD‐related immune, itch, and barrier abnormalities in clinical trials and longitudinal studies. [ABSTRACT FROM AUTHOR]
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- 2024
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23. Treat‐to‐target in dermatology: A scoping review and International Eczema Council survey on the approach in atopic dermatitis.
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Renert‐Yuval, Yael, Del Duca, Ester, Arents, Bernd, Bissonnette, Robert, Drucker, Aaron M., Flohr, Carsten, Guttman‐Yassky, Emma, Hijnen, Dirkjan, Kabashima, Kenji, Leshem, Yael A., Paller, Amy S., Silverberg, Jonathan I., Simpson, Eric L., Spuls, Phyllis, Vestergaard, Christian, Wollenberg, Andreas, Irvine, Alan D., and Thyssen, Jacob P.
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PEDIATRIC dermatology ,ATOPIC dermatitis ,ITCHING ,ECZEMA ,CHILD patients ,DERMATOLOGY ,SKIN diseases - Abstract
Treat‐to‐target (T2T) is a pragmatic therapeutic strategy being gradually introduced into dermatology after adoption in several other clinical areas. Atopic dermatitis (AD), one of the most common inflammatory skin diseases, may also benefit from this structured and practical therapeutic approach. We aimed to evaluate existing data regarding the T2T approach in dermatology, with a specific focus on AD, as well as the views of International Eczema Council (IEC) members on the potential application of a T2T approach to AD management. To do so, we systematically searched for peer‐reviewed publications on the T2T approach for any skin disease in the PubMed and Scopus databases up to February 2022 and conducted a survey among IEC members regarding various components to potentially include in a T2T approach in AD. We identified 21 relevant T2T‐related reports in dermatology, of which 14 were related to psoriasis, five to AD, one for juvenile dermatomyositis and one for urticaria. In the IEC member survey, respondents proposed treatable traits (with itch, disease severity and sleep problems getting the highest scores), relevant comorbidities (with asthma being selected most commonly, followed by anxiety and depression in adults), recommended specialists that should define the approach in AD (dermatologists, allergists and primary care physicians were most commonly selected in adults), and applicable assessment tools (both physician‐ and patient‐reported), in both adult and paediatric patients, for potential future utilization of the T2T approach in AD. In conclusion, while the T2T approach may become a useful tool to simplify therapeutic goals and AD management, its foundation in AD is only starting to build. A multidisciplinary approach, including a wide range of stakeholders, including patients, is needed to further define the essential components needed to utilize T2T in AD. [ABSTRACT FROM AUTHOR]
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- 2024
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24. The Unique Molecular Signatures of Contact Dermatitis and Implications for Treatment
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Leonard, Alexandra and Guttman-Yassky, Emma
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- 2019
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25. Upadacitinib treatment withdrawal and retreatment in patients with moderate‐to‐severe atopic dermatitis: Results from a phase 2b, randomized, controlled trial.
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Guttman‐Yassky, Emma, Silverberg, Jonathan I., Thaçi, Diamant, Papp, Kim A., Ständer, Sonja, Beck, Lisa A., Kim, Brian S., Hu, Xiaofei, Liu, Jianzhong, Calimlim, Brian M., Vigna, Namita, Crowley, Jameson T., Teixeira, Henrique D., and Thyssen, Jacob P.
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TERMINATION of treatment , *ITCHING , *ATOPIC dermatitis , *TREATMENT effectiveness , *ORAL drug administration , *SKIN diseases - Abstract
Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by pruritic eczematous lesions. The effect of treatment withdrawal after response to upadacitinib oral treatment is not fully characterized. Objectives: Assess the effect of upadacitinib withdrawal on skin clearance and itch improvement in adult patients with moderate‐to‐severe AD and evaluate the kinetics of recovery on rescue treatment. Methods: Data from a phase 2b randomized, placebo‐controlled trial (NCT02925117) of upadacitinib in patients with moderate‐to‐severe AD were analysed. Patients were randomized 1:1:1:1 to receive upadacitinib 7.5 mg, 15 mg, 30 mg or placebo, and then at Week 16, patients were re‐randomized 1:1 to receive the same dose of upadacitinib (upadacitinib 30 mg for patients initialized to placebo) or placebo. From Week 20, those who experienced loss of response defined as Eczema Area and Severity Index <50% improvement from baseline (EASI 50) received rescue treatment with upadacitinib 30 mg. Results: Patients who withdrew from upadacitinib experienced a rapid loss of skin clearance response, while those who switched from placebo to upadacitinib gained response. Loss of skin clearance response occurred within 4 weeks and worsening of itch occurred within 5 days. In patients who originally received placebo or a lower dose of upadacitinib leading to a loss of EASI response, rescue treatment with upadacitinib 30 mg resulted in rapid recovery or improvement of both skin and itch responses; most patients who were re‐randomized to placebo achieved EASI 75 and IGA 0/1 by 8 weeks of rescue treatment. No new safety risks were observed. Conclusions: Continuous treatment with upadacitinib is suggested to maintain skin clearance and antipruritic effects. [ABSTRACT FROM AUTHOR]
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- 2023
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26. The role of Janus kinase signaling in the pathology of atopic dermatitis.
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Guttman-Yassky, Emma, Irvine, Alan D., Brunner, Patrick M., Kim, Brian S., Boguniewicz, Mark, Parmentier, Julie, Platt, Andrew M., and Kabashima, Kenji
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Atopic dermatitis (AD) is a heterogeneous, chronic, relapsing, inflammatory skin disease associated with considerable physical, psychological, and economic burden. The pathology of AD includes complex interactions involving abnormalities in immune and skin barrier genes, skin barrier disruption, immune dysregulation, microbiome disturbance, and other environmental factors. Many of the cytokines involved in AD pathology, including IL-4, IL-13, IL-22, IL-31, thymic stromal lymphopoietin, and IFN-γ, signal through the Janus kinase (JAK)–signal transducer and activation of transcription (STAT) pathway. The JAK family includes JAK1, JAK2, JAK3, and tyrosine kinase 2; the STAT family includes STAT1, STAT2, STAT3, STAT4, STAT5A/B, and STAT6. Activation of the JAK-STAT pathway has been implicated in the pathology of several immune-mediated inflammatory diseases, including AD. However, the exact mechanisms of JAK-STAT involvement in AD have not been fully characterized. This review aims to discuss current knowledge about the role of the JAK-STAT signaling pathway and, specifically, the role of JAK1 in the pathology and symptomology of AD. [ABSTRACT FROM AUTHOR]
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- 2023
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27. Tralokinumab therapy for moderate‐to‐severe atopic dermatitis: Clinical outcomes with targeted IL‐13 inhibition.
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Simpson, Eric L., Guttman‐Yassky, Emma, Eichenfield, Lawrence F., Boguniewicz, Mark, Bieber, Thomas, Schneider, Shannon, Guana, Adriana, and Silverberg, Jonathan I.
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ATOPIC dermatitis , *ALLERGIC conjunctivitis , *CLINICAL trials , *TREATMENT effectiveness , *MONOCLONAL antibodies , *SYMPTOMS - Abstract
Atopic dermatitis (AD) is a chronic, inflammatory, intensely pruritic skin disorder associated with significant patient burden. Interleukin (IL)‐13 is a cytokine that acts as a driver of immune dysregulation, skin‐barrier dysfunction, and microbiome dysbiosis that characterizes AD, and is consistently overexpressed in AD skin. Tralokinumab is a fully human immunoglobulin (Ig) G4 monoclonal antibody that binds specifically to IL‐13 with high affinity, thereby inhibiting subsequent downstream IL‐13 signaling. Three pivotal phase 3 clinical trials demonstrated that tralokinumab 300 mg every other week, as monotherapy or in combination with topical corticosteroids as needed, provides significant improvements in signs and symptoms of moderate‐to‐severe AD, as measured by Investigator's Global Assessment 0/1 (clear/almost clear) and Eczema Area and Severity Index‐75 at Week 16. Improvements were observed soon after tralokinumab initiation and were maintained over 52 weeks of therapy. Tralokinumab significantly improved patient‐reported outcomes such as itch and sleep, and demonstrated a safety profile comparable with placebo; conjunctivitis during tralokinumab therapy was generally mild. Similar results were observed in a phase 3 adolescent trial. The role of IL‐13 in the pathophysiology of AD justifies a targeted approach and a wealth of clinical data supports tralokinumab as a new therapeutic option for people with moderate‐to‐severe AD. [ABSTRACT FROM AUTHOR]
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- 2023
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28. Oral difelikefalin reduces moderate to severe pruritus and expression of pruritic and inflammatory biomarkers in subjects with atopic dermatitis.
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Guttman-Yassky, Emma, Facheris, Paola, Da Rosa, Joel Correa, Rothenberg-Lausell, Camille, del Duca, Ester, David, Eden, Estrada, Yeriel, Liu, Ying, Bose, Swaroop, Chowdhury, Mashkura, Munera, Catherine, Goncalves, Joana, Nograles, Kristine, Kim, Brian S., and Lebwohl, Mark
- Abstract
Pruritus is the most common and burdensome symptom of atopic dermatitis (AD). Pruritus-targeted treatments in AD are lacking, particularly for patients with milder skin disease. We sought to evaluate the impact of the selective κ-opioid receptor agonist difelikefalin (DFK) on pruritus intensity and pruritus- and immune-related biomarkers in subjects with moderate to severe AD-related pruritus. A phase 2 clinical trial investigated the efficacy and safety of oral DFK 0.25, 0.5, and 1.0 mg in subjects with moderate to severe AD-related pruritus. A biomarker substudy evaluated the effects of DFK on the expression of pruritus, T H 2-associated genes, and skin barrier–related genes. In the clinical trial (N = 401), all DFK doses reduced itch versus placebo; however, the results were not statistically significant at week 12. In a subgroup of subjects in the trial with mild to moderate skin inflammation and moderate to severe itch (itch-dominant AD phenotype), DFK reduced itch at week 12 versus placebo. In the biomarker substudy, DFK downregulated the expression of key pruritus-related genes (eg, IL-31 and TRPV1) and the AD phenotype (eg, CCL17). Gene set variation analysis confirmed that DFK, but not placebo, downregulated pruritus-related genes and T H 2 pathways. DFK improved skin barrier integrity markers and upregulated the expression of claudins and lipid metabolism–associated genes (eg, SEC14L6, ELOVL3, CYP1A2, and AKR1D1). DFK treatment reduced itch in subjects with moderate to severe AD-related pruritus, particularly those with an "itch-dominant" AD phenotype, and had an impact on the expression of pruritus, T H 2-associated genes, and skin barrier–related genes. DFK is a promising therapy for AD-related pruritus; further clinical studies are warranted. [ABSTRACT FROM AUTHOR]
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- 2023
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29. Difelikefalin suppresses itch and reduces scratching independent of inflammation in a murine model of atopic dermatitis.
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Tamari, Masato, Zamidar, Lydia, Ver Heul, Aaron M., Nograles, Kristine, Goncalves, Joana, Guttman-Yassky, Emma, Lebwohl, Mark, and Kim, Brian S.
- Abstract
Therapies specifically targeting nonhistaminergic pruritus are largely lacking. Difelikefalin (DFK) has been found to reduce itch in various chronic pruritic conditions, including atopic dermatitis (AD). We sought to investigate the ability of DFK to impact scratching behavior, inflammatory mediators, and neuronal signaling in a murine model of AD. The ears of C57BL/6 mice were topically treated with MC903 for 12 consecutive days to induce AD-like inflammation and itch. Before MC903 treatment, mice were treated with either DFK (0.5 mg/kg, intraperitoneal injection twice daily) or vehicle (saline). Skin ear thickness, histological analysis, flow cytometry, RNA-sequencing, and differential gene expression analyses of mouse ear skin were used to examine the effect of DFK on skin inflammation. Scratching behavior was quantified to measure itch behavior in mice that were topically treated with MC903 for 6 consecutive days; then, mice received a single injection of either DFK (1.0 mg/kg, intraperitoneal injection) or saline. Calcium imaging and single-cell RNA-sequencing were used in mouse dorsal root ganglia neurons to determine the size of the neurons activated with DFK treatment. Statistical significance was determined by Mann-Whitney test, unless otherwise noted. DFK rapidly suppressed itch without altering AD-like skin inflammation in MC903 (calcipotriol)-treated mice. In vitro Ca
2+ influx trace of dorsal root ganglia suggested that a major target for DFK is the larger-diameter mechanoreceptors (eg, Aꞵ-fibers), rather than small-diameter pruriceptive C-fibers. These studies support a potential neuromodulatory role of DFK for reducing itch associated with AD in mice. [ABSTRACT FROM AUTHOR]- Published
- 2023
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30. Lack of effect of benralizumab on signs and symptoms of moderate‐to‐severe atopic dermatitis: Results from the phase 2 randomized, double‐blind, placebo‐controlled HILLIER trial.
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Guttman‐Yassky, E., Bahadori, L., Brooks, L., Clark, K. L., Grindebacke, H., Ho, C. N., Katial, R., Pham, T.‐H., Walton, C., Datto, C. J., Guttman‐Yassky, Emma, Arias, Pedro Jesús Gómez, Alpizar, Ricardo, Alpizar, Sady, Asrenberger, Petr, Azib, Selma, Badia, Anais, Beck, Lisa, Bran, Eduardo Lopez, and Breneman, Debra
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ATOPIC dermatitis ,SYMPTOMS ,ITCHING - Abstract
Data underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure. Lack of effect of benralizumab on signs and symptoms of moderate-to-severe atopic dermatitis: Results from the phase 2 randomized, double-blind, placebo-controlled HILLIER trial Ninety-six patients (including 26 adolescents) and 98 patients (27 adolescents) were randomized into the benralizumab and placebo groups, respectively. [Extracted from the article]
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- 2023
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31. Association between alopecia areata and atopic dermatitis: A nested case-control study of the All of Us database.
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Diaz, Michael J., Haq, Zaim, Abdi, Parsa, Tran, Jasmine T., Guttman-Yassky, Emma, and Ungar, Benjamin
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- 2024
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32. Crisaborole reverses dysregulation of the mild to moderate atopic dermatitis proteome toward nonlesional and normal skin.
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Kim, Madeline, Del Duca, Ester, Cheng, Julia, Carroll, Britta, Facheris, Paola, Estrada, Yeriel, Cha, Amy, Werth, John, Bissonnette, Robert, Nocka, Karl, Zang, Chuanbo, Pavel, Ana B., and Guttman-Yassky, Emma
- Abstract
Safe and effective long-term topical treatments for atopic dermatitis (AD) remain limited. In this phase 2a, single-center, intrapatient, and vehicle-controlled study, we examine the mechanism of action of crisaborole 2% ointment, a topical nonsteroidal PDE4 (phosphodiesterase-4) inhibitor, in a proteomic analysis of 40 adults with mild to moderate AD and 20 healthy subjects. Within the AD cohort, 2 target lesions were randomized in an intrapatient (1:1) manner to double-blind crisaborole/vehicle applied twice daily for 14 days. Punch biopsy specimens were collected for biomarker analysis at baseline from all participants, then from AD patients only at day 8 (optional) and day 15. Compared to the vehicle, crisaborole significantly reversed dysregulation of the overall lesional proteome and of key markers and pathways (eg, Th2, Th17/Th22, and T-cell activation) associated with AD pathogenesis toward both nonlesional and normal skin. Significant clinical correlations were observed with markers associated with nociception and Th2, Th17, and neutrophilic activation. Study limitations include predominance of white patients in the cohort, relatively short treatment time, and regimented administration of crisaborole. Our results demonstrate crisaborole-induced normalization of the AD proteome toward a nonlesional molecular phenotype and further support topical PDE4 inhibition in the treatment of mild to moderate AD. [ABSTRACT FROM AUTHOR]
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- 2023
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33. Age of onset defines two distinct profiles of atopic dermatitis in adults.
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Facheris, Paola, Da Rosa, Joel Correa, Pagan, Angel D., Angelov, Michael, Del Duca, Ester, Rabinowitz, Grace, Gómez‐Arias, Pedro Jesús, Rothenberg‐Lausell, Camille, Estrada, Yeriel D., Bose, Swaroop, Chowdhury, Mashkura, Shemer, Avner, Pavel, Ana B., and Guttman‐Yassky, Emma
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ATOPIC dermatitis ,AGE of onset ,BLOOD proteins ,SKIN inflammation ,RNA sequencing - Abstract
Background: The incidence of adult‐onset atopic dermatitis (AOAD) is increasing. However, the unique characteristics of AOAD compared to pediatric‐onset AD persisting into adulthood (POAD) are underexplored, hampering the development of targeted‐therapeutics for this growing population. We thus assessed the profile of AOAD in skin and blood compared to that of POAD. Methods: We collected skin biopsies and blood from adults with AOAD, POAD, and healthy controls (n = 15 in each group). Skin samples were analyzed by RNA sequencing, qRT‐PCR, and immunohistochemistry, and Olink Proseek multiplex assay was used to identify the serum proteomic profile. Results: Compared to healthy controls, both AOAD and POAD showed cutaneous immune and barrier dysregulations with a shared Th2/Th22 hyperactivation. Overall, POAD showed greater inflammation in lesional skin, with more prominent expression of Th2/Th17/Th22 markers (CCL17/22, S100A8/9, IL‐36A, PI3/Elafin, DEFB4) in POAD compared to AOAD (p‐value <.05). In contrast, higher Th1‐(IFN‐γ, IL‐2, IL‐15, CCL5) upregulation and Th1‐skewing were seen in AOAD. The epidermal barrier was also more compromised in POAD, with greater epidermal hyperplasia and lower expression of markers related to terminal differentiation, lipids, and cell adhesion. In parallel with increased rates of cardiovascular comorbidities, AOAD demonstrated many more significantly dysregulated proteins in serum (n = 148) compared to POAD (n = 86), including pro‐inflammatory and cardiovascular‐risk markers. Th1‐related products showed significant correlations between their skin and blood expressions only in AOAD subjects. Conclusion: Age‐of‐onset delineates two distinct endophenotypes in adult AD potentially suggesting the need for broader (beyond Th2) therapeutic targeting in AOAD. [ABSTRACT FROM AUTHOR]
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- 2023
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34. Efficacy and safety of etrasimod, a sphingosine 1‐phosphate receptor modulator, in adults with moderate‐to‐severe atopic dermatitis (ADVISE).
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Silverberg, Jonathan I., Bissonnette, Robert, Kircik, Leon, Murrell, Dedee F., Selfridge, Andrew, Liu, Kris, Ahluwalia, Gurpreet, and Guttman‐Yassky, Emma
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ATOPIC dermatitis ,SPHINGOSINE ,BODY surface area - Abstract
Background: Etrasimod is an oral, selective, sphingosine 1‐phosphate (S1P) receptor1,4,5 modulator in development for immune‐mediated inflammatory disorders. Efficacy and safety of orally administered S1P receptor modulation in atopic dermatitis (AD) have not yet been examined. Objective: To assess the efficacy and safety of etrasimod monotherapy in adults with moderate‐to‐severe AD. Methods: In this phase 2, randomized, double‐blind, placebo‐controlled trial, participants (≥18 years) with moderate‐to‐severe AD defined as baseline validated Investigator's Global Assessment (vIGA‐AD) score ≥ 3, Eczema Area and Severity Index (EASI) score ≥ 16, and body surface area involvement ≥10% were randomized 1:1:1 to once‐daily oral etrasimod 1 mg, 2 mg or placebo for 12 weeks. The primary outcome was percent change in EASI score from baseline at week 12, assessed in the Full Analysis Set (all randomized participants). Key secondary outcomes were achievement of a vIGA‐AD score of 0 or 1 with a ≥2‐point improvement from baseline and EASI‐75 response at Week 12. Safety was assessed during the double‐blind period. Results: One hundred and forty participants were randomized to etrasimod 2 mg (n = 47), 1 mg (n = 47) or placebo (n = 46). At Week 12, percent change in EASI score was −57.2% in the etrasimod 2‐mg group versus −48.4% in the placebo group (p = 0.18). A significantly greater proportion of participants receiving etrasimod 2 mg achieved vIGA‐AD scores of 0 or 1 with a ≥2‐point improvement at Week 12 versus placebo (29.8% vs. 13.0%; p = 0.045); however, EASI‐75 response was not statistically significant versus placebo. Treatment‐emergent adverse events (AEs) occurred in 59.6%, 40.4% and 47.8% of participants receiving etrasimod 2 mg, 1 mg and placebo, respectively. There were no serious AEs or deaths. Conclusions: The primary outcome was not met, although efficacy was observed for etrasimod 2 mg on several clinician‐ and patient‐assessed measures, and both 1‐ and 2‐mg doses were well tolerated, warranting further clinical investigation in AD. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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35. Systemic Therapy of Atopic Dermatitis: When, How, for How Long?
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Malik, Kunal and Guttman-Yassky, Emma
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- 2017
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36. 679 - Rocatinlimab significantly improves clinical responses in patients with moderate-to-severe atopic dermatitis by week 2 in a randomized double-blind placebo-controlled phase 2b study.
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Guttman-Yassky, Emma, Esfandiari, Ehsanollah, Mano, Hirotaka, Arai, Takahiro, and Kabashima, Kenji
- Subjects
- *
ATOPIC dermatitis , *LEAST squares , *QUALITY of life , *ITCHING , *ECZEMA - Abstract
Introduction/Background Moderate-to-severe atopic dermatitis (msAD) can cause chronic cycles of pruritus and scratching, impacting quality of life. Objectives To evaluate rocatinlimab for the treatment of msAD To investigate the onset of action of rocatinlimab on pruritis Numerical Rating scale (pNRS) and Eczema Area and Severity Index (EASI) in adults with msAD Methods A multicenter, randomized, double-blind, placebo-controlled Phase 2b trial (NCT03703102) evaluated rocatinlimab (anti-OX40 monoclonal antibody) for msAD. Primary endpoint achievement (Percent change from baseline to week 16 in EASI) has been presented. Randomized patients (1:1:1:1:1) received subcutaneous rocatinlimab 150mg/600mg every 4 weeks (Q4W) or 300mg/600mg every 2 weeks (Q2W) for 36 weeks, or placebo (Weeks 0–18) followed by rocatinlimab (600mg Q2W Weeks 18–36). All cohorts had 20-week off-treatment follow-up. Results Clinical response onset with rocatinlimab was evaluated post-hoc (N=267; rocatinlimab: n=210; placebo: n=57) by investigating pNRS and EASI between baseline and Week 16. Difference in least squares mean of percent change from baseline between rocatinlimab cohorts and placebo were assessed. Pruritus was significantly improved with rocatinlimab by Week 2 in all cohorts (−18.40% to −21.96%; p≤0.018) except 600mg Q4W (−9.66%; p=0.208), and in all cohorts by Week 4 (−15.70% to −27.19%; p≤0.045); EASI improvements were significant in all rocatinlimab cohorts by Week 6 (−20.50% to −32.13%; p≤0.001) compared with placebo, and the 300mg and 600mg Q2W cohorts by Week 2 (−13.27% and −13.66%; p≤0.028). Further improvements with rocatinlimab continued to Week 16 compared with placebo; improvements from baseline continued in all active cohorts to Week 36 and were maintained for 20 weeks off-treatment, suggesting rocatinlimab may have potential for disease modification in adults with msAD. Conclusion Rocatinlimab improved pNRS and EASI by Week 2; improvements continued and were maintained off-treatment until the end of study. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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37. 628 - Clinical measures of improvement in atopic dermatitis are correlated with reductions in relevant biomarkers in patients treated with lebrikizumab.
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Guttman-Yassky, Emma, Okragly, Angela, Sun, Zhe, Nickoloff, Brian J, Natalie, Chitra R, Gallo, Gaia, Wolf, Eric, Eyerich, Kilian, Aparici, Monica, and Benschop, Robert J
- Subjects
- *
ATOPIC dermatitis , *PERIOSTIN , *RANK correlation (Statistics) , *SYMPTOMS , *BIOMARKERS - Abstract
Introduction In ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967), lebrikizumab demonstrated statistical superiority vs. placebo in patients with moderate-to-severe atopic dermatitis (AD). The objective of this analysis is to test for correlations between improvements in clinical outcomes and reductions in AD-relevant serum biomarkers during ADvocate1 and ADvocate2. Objectives To assess the correlation between clinical measures of atopic dermatitis (AD) and AD-specific biomarkers at baseline; and to assess the correlation between clinical measures of AD and changes in AD-specific biomarkers after treatment with lebrikizumab. Methods Full details of these studies were previously reported. Protein biomarkers were determined in available serum samples from patients receiving lebrikizumab 250 mg every 2 weeks (n=72) or placebo (n=36). Tested biomarkers included: IL-13 (baseline only), CCL2, CCL4, CCL11, CCL13, CCL17 (TARC), CCL22, CCL26 (eotaxin-3), CXCL10, total IgE, IL-4, IL-5, and periostin. Baseline biomarker levels and baseline clinical endpoints were compared using a Spearman correlation. A repeated measures correlation analysis was used to characterize paired measurement of within-patient biomarker levels and clinical endpoints at baseline, week 4, week 16, and week 52. Clinical measures of AD included Investigator's Global Assessment (IGA), Eczema Area and Severity Index (EASI), and Pruritus Numeric Rating Scale (NRS). Results At baseline, EASI score was positively correlated with IL-13, periostin, IL-5, IgE, CCL13, CCL17, CCL22 and CCL26 (correlation coefficient>0.3, p<0.05), but not IL-4. During the studies, improvements in EASI, IGA, and Pruritus NRS were each correlated with reductions in periostin, CCL13, CCL17, CCL22, and CCL26 (correlation coefficient>0.3, p<0.05). Improvement in IGA was also correlated with a reduction in IgE (correlation coefficient>0.3, p<0.05). Conclusions Clinical measures of improvement in the signs and symptoms of AD are correlated with reductions in AD biomarkers in patients treated with lebrikizumab. [ABSTRACT FROM AUTHOR]
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- 2024
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38. Comorbidities of atopic dermatitis-what does the evidence say?
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Thyssen, Jacob P., Halling, Anne Sofie, Schmid-Grendelmeier, Peter, Guttman-Yassky, Emma, and Silverberg, Jonathan I.
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comorbidity ,Immunology ,atopy ,Immunology and Allergy ,epidemiology ,asthma ,Atopic dermatitis ,burden - Abstract
Atopic dermatitis (AD) is a common disease that is associated with atopic and nonatopic comorbidities. There has been a growing interest in this area of AD, because presence or risk of comorbidities can in many ways impact the management of patients with AD. Thus, some treatments for AD may improve its comorbidities as well, whereas others may increase their risk. In this review article, we discuss various comorbidities of AD mostly on the basis of the results of recent multiple systematic reviews and meta-analyses to update readers about this rapidly developing area of dermatology. We emphasize the important information provided by studies presenting both relative risk and absolute risk, and show that AD is associated with, among others, atopic comorbidities such as asthma, rhinitis, and food allergy, nonatopic comorbidities such as ocular, psychiatric, infectious, endocrine, autoimmune, and cardiovascular diseases, and certain cancers. Clinicians need to be aware of these and be cognizant about positive and negative effects of existing and new treatments for AD.
- Published
- 2022
39. Efficacy and safety of lebrikizumab in moderate-to-severe atopic dermatitis: 52-week results of two randomized double-blinded placebo-controlled phase III trials.
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Blauvelt, Andrew, Thyssen, Jacob P, Guttman-Yassky, Emma, Bieber, Thomas, Serra-Baldrich, Esther, Simpson, Eric, Rosmarin, David, Elmaraghy, Hany, Meskimen, Eric, Natalie, Chitra R, Liu, Zhuqing, Xu, Chenjia, Pierce, Evangeline, Morgan-Cox, MaryAnn, Gil, Esther Garcia, and Silverberg, Jonathan I
- Subjects
CLINICAL trials ,ATOPIC dermatitis ,ECZEMA ,MISSING data (Statistics) ,MONOCLONAL antibodies - Abstract
Background Lebrikizumab is a novel, high-affinity monoclonal antibody that selectively binds to interleukin (IL)-13. Objectives To evaluate the efficacy and safety of lebrikizumab monotherapy in adolescent and adult patients with moderate-to-severe atopic dermatitis (AD) over 52 weeks of treatment in ADvocate1 (NCT04146363) and ADvocate2 (NCT04178967). Methods Patients who responded to lebrikizumab 250 mg every 2 weeks (Q2W) at the end of the 16-week induction period were re-randomized 2 : 2 : 1 to receive lebrikizumab Q2W, lebrikizumab 250 mg every 4 weeks (Q4W) or placebo Q2W (lebrikizumab withdrawal) for 36 additional weeks. Response at week 16 was defined as achieving a 75% reduction in Eczema Area Severity Index (EASI 75) or an Investigator's Global Assessment (IGA) of 0 or 1, with a ≥ 2-point improvement and no rescue medication use. Multiple imputation was used to handle missing data. Intermittent use of topical therapy was permitted during the maintenance period. Results After 52 weeks, an IGA of 0 or 1 with a ≥ 2 point improvement was maintained by 71.2% of patients treated with lebrikizumab Q2W, 76.9% of patients treated with lebrikizumab Q4W and 47.9% of patients in the lebrikizumab withdrawal arm. EASI 75 was maintained by 78.4% of patients treated with lebrikizumab Q2W, 81.7% of patients treated with lebrikizumab Q4W and 66.4% of patients in the lebrikizumab withdrawal arm at week 52. Across treatment arms, proportions of patients using any rescue therapy were 14.0% (ADvocate1) and 16.4% (ADvocate2). During the combined induction and maintenance periods of ADvocate1 and ADvocate2, 63.0% of lebrikizumab-treated patients reported any treatment emergent adverse event, with most events (93.1%) being mild or moderate in severity. Conclusions After a 16-week induction period with lebrikizumab Q2W, lebrikizumab Q2W and Q4W maintained similar improvement of the signs and symptoms of moderate-to-severe AD, with a safety profile consistent with previously published data. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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40. 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]
- Published
- 2023
- Full Text
- View/download PDF
41. Comorbidities of atopic dermatitis—what does the evidence say?
- Author
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Thyssen, Jacob P., Halling, Anne-Sofie, Schmid-Grendelmeier, Peter, Guttman-Yassky, Emma, and Silverberg, Jonathan I.
- Abstract
Atopic dermatitis (AD) is a common disease that is associated with atopic and nonatopic comorbidities. There has been a growing interest in this area of AD, because presence or risk of comorbidities can in many ways impact the management of patients with AD. Thus, some treatments for AD may improve its comorbidities as well, whereas others may increase their risk. In this review article, we discuss various comorbidities of AD mostly on the basis of the results of recent multiple systematic reviews and meta-analyses to update readers about this rapidly developing area of dermatology. We emphasize the important information provided by studies presenting both relative risk and absolute risk, and show that AD is associated with, among others, atopic comorbidities such as asthma, rhinitis, and food allergy, nonatopic comorbidities such as ocular, psychiatric, infectious, endocrine, autoimmune, and cardiovascular diseases, and certain cancers. Clinicians need to be aware of these and be cognizant about positive and negative effects of existing and new treatments for AD. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
42. Scalp biomarkers during dupilumab treatment support Th2 pathway pathogenicity in alopecia areata.
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Renert‐Yuval, Yael, Pavel, Ana B., Del Duca, Ester, Facheris, Paola, Pagan, Angel D., Bose, Swaroop, Gómez‐Arias, Pedro J., Angelov, Michael, Bares, Jennifer, Chima, Margo, Estrada, Yeriel D., Garcet, Sandra, Lebwohl, Mark G., Krueger, James G., and Guttman‐Yassky, Emma
- Subjects
DUPILUMAB ,ALOPECIA areata ,SCALP ,BIOMARKERS ,CLINICAL immunology - Abstract
Background: The mechanisms driving alopecia areata (AA) are still unclear, hindering development of targeted therapeutics. Specific Th2 targeting with dupilumab in AA provides a unique opportunity to dissect its pathogenesis and explore the role of Th2 pathway. Methods: We evaluated changes in scalp biomarkers in AA patients (with and without concomitant atopy) randomized to weekly dupilumab or placebo for 24 weeks, followed by open‐label dupilumab for 24 weeks. Changes in biomarker levels were measured at weeks 12, 24, and 48 and were also correlated with clinical hair regrowth. Results: At week 24, preceding clinical hair regrowth outcomes, only dupilumab‐treated patients presented significant suppression of cellular infiltrates, and multiple Th2‐related, markers (CCL13/MCP‐4, CCL18/PARC, CCL26/eotaxin‐3, CCL24/Eotaxin‐2), coupled with significant upregulation in the hair keratins. Th1‐related suppression was evident later (week 48) when all patients received open‐label dupilumab. Results were more pronounced in atopic AA patients, that showed 48% and 97% improvements in the lesional AA scalp profile at weeks 24 and 48, respectively, while 2% worsening was seen in the placebo arm at week 24. Moreover, placebo‐treated patients presented 54% worsening in hair keratins when compared with baseline at week 24. At week 24, increases in hair keratins showed significant correlations only with decreases in Th2‐related markers. Conclusions: Scalp biomarkers provide evidence of dupilumab efficacy in AA, detected even prior to clinical response, with exclusive correlations between early suppression of Th2 markers and increased hair keratins. These findings strengthen previous reports suggesting a possible role for Th2 cytokines as AA drivers. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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43. Skin microbiome and its association with host cofactors in determining atopic dermatitis severity.
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Rauer, Luise, Reiger, Matthias, Bhattacharyya, Madhumita, Brunner, Patrick M., Krueger, James G., Guttman-Yassky, Emma, Traidl-Hoffmann, Claudia, and Neumann, Avidan U.
- Subjects
ATOPIC dermatitis ,BACTERIAL diversity ,RACE ,STAPHYLOCOCCUS aureus ,SKIN diseases - Abstract
Background: Atopic dermatitis (AD) is a heterogeneous, chronic inflammatory skin disease linked to skin microbiome dysbiosis with reduced bacterial diversity and el)evated relative abundance of Staphylococcus aureus (S. aureus). Objectives: We aimed to characterize the yet incompletely understood association between the skin microbiome and patients' demographic and clinical cofactors in relation to AD severity. Methods: The skin microbiome in 48 adult moderate-to-severe AD patients was investigated using next-generation deep sequencing (16S rRNA gene, V1–V3 re)gion) followed by denoising (DADA2) to obtain amplicon sequence variant (ASV) composition. Results: In lesional skin, AD severity was associated with S. aureus relative abun)dance (rS = 0.53, p<0.001) and slightly better with the microbiome diversity measure Evenness (rS = −0.58, p<0.001), but not with Richness. Multiple regression confirmed the association of AD severity with microbiome diversity, including Shannon (in le)sional skin, p<0.001), Evenness (in non-lesional skin, p = 0.015) or S. aureus relative abundance (p<0.012), and with patient's IgE levels (p<0.001), race (p<0.032), age (p<0.034) and sex (p = 0.012). The lesional model explained 62% of the variation in AD severity, and the non-lesional model 50% of the variation. Conclusions: Our results specify the frequently reported “reduced diversity” of the AD-related skin microbiome to reduced Evenness, which was in turn mainly driven by S. aureus relative abundance, rather than to a reduced microbiome Richness. Finding associations between AD severity, the skin microbiome and patient's cofac)tors is a key aspect in developing new personalized AD treatments, particularly those targeting the AD microbiome. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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44. Two Phase 3 Trials of Lebrikizumab for Moderate-to-Severe Atopic Dermatitis.
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Silverberg, Jonathan I., Guttman-Yassky, Emma, Thagi, Diamant, Irvine, Alan D., Stein Gold, Linda, Blauvelt, Andrew, Simpson, Eric L., Chia-Yu Chu, Zhuqing Liu, Gontijo Lima, Renata, Pillai, Sreekumar G., and Seneschal, Julien
- Subjects
- *
CLINICAL trials , *ATOPIC dermatitis , *HETERODIMERS , *MONOCLONAL antibodies - Abstract
BACKGROUND Lebrikizumab, a high-affinity IgG4 monoclonal antibody targeting interleukin-13, prevents the formation of the interleukin-4Ra-interleukin-13Ral heterodimer receptor signaling complex. METHODS We conducted two identically designed, 52-week, randomized, double-blind, placebo-controlled, phase 3 trials; both trials included a 16-week induction period and a 36-week maintenance period. Eligible patients with moderate-to-severe atopic dermatitis (adults [218 years of age] and adolescents [12 to <18 years of age, weighing >40 kg]) were randomly assigned in a 2:1 ratio to receive either lebrikizumab at a dose of 250 mg (loading dose of 500 mg at baseline and week 2) or placebo, administered subcutaneously every 2 weeks. Outcomes for the induction period were assessed up to 16 weeks and are included in this report. The primary outcome was an Investigator's Global Assessment (IGA) score of 0 or 1 (indicating clear or almost clear skin; range, 0 to 4 [severe disease]) with a reduction (indicating improvement) of at least 2 points from baseline at week 16. Secondary outcomes included a 75% improvement in the Eczema Area and Severity Index score (EASI-75 response) and assessments of itch and of itch interference with sleep. Safety was also assessed. RESULTS In trial 1, the primary outcome was met in 43.1% of 283 patients in the lebrikizumab group and in 12.7% of 141 patients in the placebo group (P<0.001); an EASI-75 response occurred in 58.8% and 16.2%, respectively (P<0.001). In trial 2, the primary outcome was met in 33.2% of 281 patients in the lebrikizumab group and in 10.8% of 146 patients in the placebo group (P<0.001); an EASI-75 response occurred in 52.1% and 18.1%, respectively (P<0.001). Measures of itch and itch interference with sleep indicated improvement with lebrikizumab therapy. The incidence of conjunctivitis was higher among patients who received lebrikizumab than among those who received placebo. Most adverse events during the induction period were mild or moderate in severity and did not lead to trial discontinuation. CONCLUSIONS In the induction period of two phase 3 trials, 16 weeks of treatment with lebrikizumab was effective in adolescents and adults with moderate-to-severe atopic dermatitis. (Funded by Dermira; ADvocatel and ADvocate2 ClinicalTrials.gov numbers, NCT04146363 and NCT04178967, respectively.) [ABSTRACT FROM AUTHOR]
- Published
- 2023
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45. Spesolimab, an anti‐interleukin‐36 receptor antibody, in patients with moderate‐to‐severe atopic dermatitis: Results from a multicentre, randomized, double‐blind, placebo‐controlled, phase IIa study.
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Bissonnette, Robert, Abramovits, William, Saint‐Cyr Proulx, Étienne, Lee, Patricia, Guttman‐Yassky, Emma, Zovko, Elizabeta, Sigmund, Ralf, Willcox, Joanne, and Bieber, Thomas
- Subjects
RECEPTOR antibodies ,ATOPIC dermatitis ,SKIN diseases ,SENSITIVITY analysis ,ECZEMA ,ANTI-NMDA receptor encephalitis - Abstract
Background: Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease, and there is increasing evidence that the interleukin (IL)‐36 pathway may play a role in the pathogenesis of AD. Objectives: To evaluate the efficacy and safety of spesolimab, a novel anti‐IL‐36 receptor antibody, in adult patients with moderate‐to‐severe AD. Methods: In this phase IIa study, 51 eligible patients were randomized 2:1 to receive intravenous doses of spesolimab 600 mg or placebo every 4 weeks. The primary endpoint was the percentage change from baseline in Eczema Area and Severity Index (EASI) score at Week 16. Results: The decrease in EASI score from baseline to Week 16 was –37.9% for spesolimab versus –12.3% for placebo (adjusted mean difference −25.6%, p = 0.149). A predefined sensitivity analysis, excluding data from patients who used restricted corticosteroids, resulted in an adjusted mean difference of −48.3% (nominal p = 0.024). Spesolimab was well tolerated, with no clinically relevant safety signals. Conclusions: This is the first study to evaluate the IL‐36 pathway inhibition in AD. Although not statistically significant, numerical improvements were observed in the primary endpoint of change from baseline in the EASI score. Spesolimab had an acceptable safety profile, with no unexcepted safety concerns. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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46. The evolving landscape of biologic therapies for atopic dermatitis: Present and future perspective.
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David, Eden, Ungar, Benjamin, Renert‐Yuval, Yael, Facheris, Paola, del Duca, Ester, and Guttman‐Yassky, Emma
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BIOTHERAPY ,ATOPIC dermatitis ,PATHOGENESIS ,THERAPEUTICS ,DUPILUMAB - Abstract
Atopic dermatitis (AD) is one of the most common, chronic inflammatory skin diseases with a significant physical, emotional and socioeconomic burden. In recent years the understanding of AD pathogenesis has expanded from the Th2‐centred perspective, with the recognition of the involvement of other immune axes. In different AD endotypes, influenced by environment, genetics and race, transcriptomic profiles have identified differing contributions of multiple immune axes such as, Th17, Th22 and Th1. The enriched pathogenic model of AD has catalysed the development of numerous biologic therapies targeting a range of key molecules implicated in disease progression. Currently, dupilumab and tralokinumab, which both target the Th2 pathway, are the only approved biologic therapies for AD in the United States and Europe. New biologic therapies in development, however, target different Th2‐pathway molecules along with cytokines in other immune axes, including Th17 and Th22, offering promise for varied treatments for this heterogeneous disease. As the biologic pipeline advances, the integration into clinical practice and approval of these experimental biologics may provide more effective, tailored therapeutic solutions and illuminate on the pathologic processes of AD across a broader, more diverse patient population. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
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47. The impact of dupilumab treatment on SARS‐CoV‐2 T cell responses in atopic dermatitis patients.
- Author
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Ungar, Benjamin, Hartzell, Susan, Lozano‐Ojalvo, Daniel, Ghalili, Sabrina, Bose, Swaroop, Golant, Alexandra K., Tan, Kathryn, Estrada, Yeriel D., Singer, Giselle K., Pavel, Ana B., Cravedi, Paolo, and Guttman‐Yassky, Emma
- Subjects
T cells ,SARS-CoV-2 ,ATOPIC dermatitis ,DUPILUMAB ,MONONUCLEAR leukocytes ,THYMIC stromal lymphopoietin - Abstract
Overall, this study suggests that Th2-inhibition with dupilumab does not hinder, and may possibly even improve, Th1-specific T cell responses to COVID-19 infection and mRNA vaccination. Fifty-five samples from patients with prior SARS-CoV-2 infection confirmed by positive anti-SARS-CoV-2 Spike IgG (unvaccinated at the time of sample collection), and 125 post-vaccination samples from different subjects were analyzed. Spike antigens were used to provide comparisons between treatment groups as a measure of T cell responses for both post-infection and post-vaccination samples (the vaccine contains only spike antigen of SARS-CoV-2). [Extracted from the article]
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- 2023
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48. Shedding light on key pharmacological knowledge and strategies for pediatric atopic dermatitis.
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Moreno, Ariana, Renert-Yuval, Yael, and Guttman-Yassky, Emma
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ATOPIC dermatitis ,AZATHIOPRINE ,CHILD patients ,ADULT development ,MYCOPHENOLIC acid ,KINASE inhibitors - Abstract
Atopic dermatitis (AD) is an inflammatory disease affecting over 20% of the pediatric population, with 85% of cases presenting before the age of five. Recently, therapeutic options in pediatric patients have evolved rapidly, following extensive development in adult treatments. This review will encompass relevant molecular drivers, along with an overlook on treatment modalities in pediatric AD, as well as a summary of pipeline treatments in clinical trials for pediatric patients from PubMed, Google Scholar, and Clinicaltrials.gov up to July 2022. Topical corticosteroids are the mainstay for AD flares in adults and children. Topical approved agents in pediatric AD are calcineurin inhibitors, crisaborolecrisaborole, and ruxolitinib. Dupilumab is the only FDA approved biologic for patients with AD from six months of age. A Janus kinase inhibitor, upadacitinib, is a systemic treatment approved for pediatric AD patients (age >12 years). Systemic immunosuppressants used in pediatric AD include methotrexate, azathioprine, cyclosporinecyclosporine, and mycophenolate mofetil. Data regarding disease prevention are conflicting, however, an abundance of research has transpired regarding amelioration of symptoms and induction of disease clearance by targeting numerous pathological mechanisms. Understanding the pediatric AD phenotype will further advance the field and the development of improved therapeutics. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
49. An anti-OX40 antibody to treat moderate-to-severe atopic dermatitis: a multicentre, double-blind, placebo-controlled phase 2b study.
- Author
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Guttman-Yassky, Emma, Simpson, Eric L, Reich, Kristian, Kabashima, Kenji, Igawa, Ken, Suzuki, Tetsuya, Mano, Hirotaka, Matsui, Takeshi, Esfandiari, Ehsanollah, and Furue, Masutaka
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ATOPIC dermatitis , *PHARYNGITIS , *BODY surface area , *TERMINATION of treatment , *CANKER sores , *IMMUNOLOGIC memory - Abstract
OX40 is crucial for T-cell differentiation and memory induction. The anti-OX40 antibody, rocatinlimab inhibits the OX40 pathway. We evaluated the efficacy and safety of rocatinlimab in adults with moderate-to-severe atopic dermatitis. This multicentre, double-blind, placebo-controlled phase 2b study was done at 65 secondary and tertiary sites in the USA, Canada, Japan, and Germany. Eligible patients were adults (aged 18 years or older) with confirmed atopic dermatitis (American Academy of Dermatology Consensus Criteria or local diagnostic criteria) with moderate-to-severe disease activity, as defined by an Eczema Area and Severity Index (EASI) score of 16 or more, validated Investigator's Global Assessment for Atopic Dermatitis score of 3 (moderate) or 4 (severe), and affected body surface area 10% or higher at both screening and baseline, with documented history (within 1 year) of inadequate response to topical medications or if topical treatments were medically inadvisable. Patients were randomly assigned (1:1:1:1:1) to receive subcutaneous rocatinlimab every 4 weeks (150 mg or 600 mg) or every 2 weeks (300 mg or 600 mg) or subcutaneous placebo up to week 18, with an 18-week active-treatment extension and 20-week follow-up. Percentage change from baseline in EASI score was assessed as the primary endpoint at week 16 and during the active extension and follow-up in all randomly assigned patients exposed to study drug with a post-baseline EASI score at week 16 or earlier according to the group they were randomly assigned to. Safety was assessed in all randomly assigned patients exposed to study drug; patients were analysed according to the group they were randomly assigned to. The study is registered with ClinicalTrials.gov , NCT03703102. Between Oct 22, 2018, and Oct 21, 2019, 274 patients (114 [42%] women, 160 [58%] men; mean age 38·0 years [SD 14·5]) were randomly assigned to one of the rocatinlimab groups (217 [79%] patients) or to the placebo group (57 [21%] patients). Compared with placebo (−15·0 [95% CI −28·6 to −1·4]), significant least-squares mean percent reductions in EASI score at week 16 were observed in all rocatinlimab groups (rocatinlimab 150 mg every 4 weeks −48·3 [−62·2 to −34·0], p=0·0003; rocatinlimab 600 mg every 4 weeks −49·7 [−64·3 to −35·2], p=0·0002; rocatinlimab 300 mg every 2 weeks −61·1 [−75·2 to −47·0], p<0·0001; and rocatinlimab 600 mg every 2 weeks −57·4 [−71·3 to −43·4], p<0·0001). The most common adverse events during the double-blind period in patients receiving rocatinlimab (adverse events ≥5% of patients in the total rocatinlimab group and more common than the placebo group) were pyrexia (36 [17%] patients), nasopharyngitis (30 [14%] patients), chills (24 [11%] patients), headache (19 [9%] patients), aphthous ulcer (15 [7%] patients), and nausea (13 [6%] patients). There were no deaths. Patients treated with rocatinlimab had progressive improvements in atopic dermatitis, which was maintained in most patients after treatment discontinuation. Treatment was well tolerated. Kyowa Kirin. [ABSTRACT FROM AUTHOR]
- Published
- 2023
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50. Safety of upadacitinib in moderate-to-severe atopic dermatitis: An integrated analysis of phase 3 studies.
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Guttman-Yassky, Emma, Thyssen, Jacob P., Silverberg, Jonathan I., Papp, Kim A., Paller, Amy S., Weidinger, Stephan, Chih-ho Hong, H., Hendrickson, Barbara, Dilley, Deanne, Tenorio, Allan R., Ladizinski, Barry, Chu, Alvina D., Liu, John, and Irvine, Alan D.
- Abstract
Upadacitinib is a selective reversible Janus kinase (JAK) inhibitor with established efficacy in moderate-to-severe atopic dermatitis (AD). We evaluated the safety of upadacitinib in patients with moderate-to-severe AD. Integrated safety data from the 16-week placebo-controlled periods of 1 phase 2b and 3 ongoing phase 3 studies (16 weeks) and longer-term safety data from patients receiving upadacitinib during the blinded extension periods of the three phase 3 studies were analyzed (all upadacitinib exposure). Treatment-emergent adverse events (TEAEs) were presented as exposure-adjusted rates per 100 patient-years (PY). Safety results were similar between the 16-week and all upadacitinib exposure groups. The latter group included 2485 patients (333 adolescents), receiving upadacitinib 15 mg (n = 1239) or 30 mg (n = 1246) for a mean duration of approximately 1 year. Upadacitinib was well tolerated by both adults and adolescents. TEAEs and discontinuation due to AEs were reported more frequently in patients receiving 30 mg upadacitinib (respectively, 311.9 and 5.7 events per 100 PY) versus 15 mg (respectively, 274.6 and 4.4 events per 100 PY). Serious adverse event rates (15/30 mg, 7.1/7.7 events per 100 PY) were similar in both groups. Acne was the most frequently reported adverse event (15/30 mg, 13.3/20.2 events per 100 PY). Serious infection rates were similar across treatment groups. Adjudicated major adverse cardiovascular event and venous thromboembolic event rates were ≤0.1 events per 100 PY. Rates of malignant neoplasms were within the expected range for the general population. Upadacitinib was well tolerated, and no new important safety risks were observed among adults and adolescents with moderate-to-severe AD treated for approximately 1 year compared to the known safety profile of upadacitinib. [ABSTRACT FROM AUTHOR]
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- 2023
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