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Gu X, Weng R, Deng Q, Rao J, Zhao J, Hou J, Liu S. Interleukin-17D accelerates atherosclerosis through promoting endothelial cells ferroptosis via CD93/miR-181a-5p/SLC7A11 signaling. Int Immunopharmacol 2024; 143:113558. [PMID: 39510035 DOI: 10.1016/j.intimp.2024.113558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 10/30/2024] [Accepted: 10/30/2024] [Indexed: 11/15/2024]
Abstract
IL-17D has been found to induce inflammatory cytokines in endothelial cells, but its exact role in atherosclerosis (AS) is unclear. This study aims to explore IL-17D' function in AS development. The expression of IL-17D was examined in AS patients and mice, and its clinical significance was evaluated in patients with acute coronary syndrome (ACS). Apolipoprotein E and IL-17D deficient mice (ApoE-/-IL-17D-/-) were generated for this study. The inflammation response and ferroptosis status in vascular endothelial cells were assessed following IL-17D treatment. Flow cytometry was used to identify the functional receptor of IL-17D. Additionally, RNA-seq was utilized to analyze the miRNA expression profiles induced by IL-17D. Plasma levels of IL-17D were elevated in both AS patients and mice, and were correlated with an increased incidence of major adverse cardiovascular events (MACEs). ApoE-/-IL-17D-/- mice displayed reduced inflammation and fewer atherosclerotic lesions. Treatment with IL-17D resulted in elevated levels of IL-6, IL-8, and ROS, as well as impaired cell viability and GSH production in endothelial cells. Ferroptosis inhibitor (Fer-1) suppressed the proinflammatory effects by IL-17D. Furthermore, CD93 was identified as the functional receptor for IL-17D in endothelial cells. The inhibition of miR-181a-5p led to a significant increase in cell viability and GSH levels, alongside a reduction in ROS and IL-6/IL-8 levels, while the suppression of SLC7A11 abolished these effects. Our findings suggest that IL-17D promotes endothelial inflammation by causing ferroptosis via CD93/miR-181a-5p/SLC7A11 signaling pathway. These insights advance our understanding of the pathophysiology of AS and identify a potential target for therapeutic intervention.
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Affiliation(s)
- Xiaodong Gu
- Meizhou Clinical Institute, Shantou University Medical College, Meizhou 514000, PR China; Institute of Basic Medical Sciences, Meizhou People's Hospital (Huangtang Hospital), Meizhou 514000, China; Guangdong Engineering Technology Research Center of Molecular Diagnostics for Cardiovascular Diseases, Meizhou 514000, PR China
| | - Ruiqiang Weng
- Meizhou Clinical Institute, Shantou University Medical College, Meizhou 514000, PR China; Institute of Basic Medical Sciences, Meizhou People's Hospital (Huangtang Hospital), Meizhou 514000, China; Guangdong Engineering Technology Research Center of Molecular Diagnostics for Cardiovascular Diseases, Meizhou 514000, PR China
| | - Qiaoting Deng
- Meizhou Clinical Institute, Shantou University Medical College, Meizhou 514000, PR China; Institute of Basic Medical Sciences, Meizhou People's Hospital (Huangtang Hospital), Meizhou 514000, China; Guangdong Engineering Technology Research Center of Molecular Diagnostics for Cardiovascular Diseases, Meizhou 514000, PR China
| | - Jiawei Rao
- Meizhou Clinical Medical School, Guangdong Medical University, Meizhou 514000, PR China
| | - Junli Zhao
- Meizhou Clinical Institute, Shantou University Medical College, Meizhou 514000, PR China
| | - Jingyuan Hou
- Meizhou Clinical Institute, Shantou University Medical College, Meizhou 514000, PR China; Guangdong Engineering Technology Research Center of Molecular Diagnostics for Cardiovascular Diseases, Meizhou 514000, PR China; Cardiovascular Disease Research Institute, Meizhou People's Hospital (Huangtang Hospital), Meizhou 514000, China.
| | - Sudong Liu
- Meizhou Clinical Institute, Shantou University Medical College, Meizhou 514000, PR China; Institute of Basic Medical Sciences, Meizhou People's Hospital (Huangtang Hospital), Meizhou 514000, China; Guangdong Engineering Technology Research Center of Molecular Diagnostics for Cardiovascular Diseases, Meizhou 514000, PR China.
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Krygere L, Jukna P, Jariene K, Drejeriene E. Diagnostic Potential of Cytokine Biomarkers in Endometriosis: Challenges and Insights. Biomedicines 2024; 12:2867. [PMID: 39767772 PMCID: PMC11673701 DOI: 10.3390/biomedicines12122867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2024] [Revised: 12/15/2024] [Accepted: 12/16/2024] [Indexed: 01/11/2025] Open
Abstract
Endometriosis is a common gynecological condition affecting approximately 10% of women of reproductive age, characterized by the abnormal presence of endometrial-like tissue outside the uterus. Although endometriosis was first described over 300 years ago, its underlying mechanisms remain poorly understood, and accurate, prompt diagnosis continues to be challenging. Currently, there is a lack of effective, non-invasive diagnostic methods, and available treatments often come with significant side effects and high recurrence rates. This has spurred interest in investigating the role of pro- and anti-inflammatory molecules, particularly cytokines, in endometriosis, as these molecules play a key role in its progression by influencing cell growth and differentiation. Previous studies suggest that various cytokines could serve as potential biomarkers for diagnosing endometriosis, as they are detectable in both serum and peritoneal fluid. This review provides an overview of the expression, origin, function, and regulation of specific cytokines in endometriosis, along with a brief discussion on their potential clinical implications for diagnosis. Due to the complexity of endometriosis, a panel of multiple biomarkers may ultimately be necessary for accurate diagnosis. It is essential to consider factors such as patient selection, sample collection, and analytical variability when initiating or evaluating biomarker studies.
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Affiliation(s)
- Laura Krygere
- Department of Obstetrics and Gynaecology, Medical Academy, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania; (L.K.); (P.J.); (K.J.)
| | - Povilas Jukna
- Department of Obstetrics and Gynaecology, Medical Academy, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania; (L.K.); (P.J.); (K.J.)
- Department of Obstetrics and Gynaecology, Hospital of Lithuanian University of Health Sciences Kauno Klinikos, LT-50161 Kaunas, Lithuania
| | - Kristina Jariene
- Department of Obstetrics and Gynaecology, Medical Academy, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania; (L.K.); (P.J.); (K.J.)
- Department of Obstetrics and Gynaecology, Hospital of Lithuanian University of Health Sciences Kauno Klinikos, LT-50161 Kaunas, Lithuania
| | - Egle Drejeriene
- Department of Obstetrics and Gynaecology, Medical Academy, Lithuanian University of Health Sciences, LT-50161 Kaunas, Lithuania; (L.K.); (P.J.); (K.J.)
- Department of Obstetrics and Gynaecology, Hospital of Lithuanian University of Health Sciences Kauno Klinikos, LT-50161 Kaunas, Lithuania
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Yang Y, Gong Z, Yang J, Cai Y, Hong S, Mao W, Guo Z, Qiu M, Fan Z, Cui B. Exploring shared mechanisms between ulcerative colitis and psoriasis and predicting therapeutic natural compounds through bioinformatics and molecular docking. Heliyon 2024; 10:e37624. [PMID: 39309918 PMCID: PMC11416260 DOI: 10.1016/j.heliyon.2024.e37624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 08/05/2024] [Accepted: 09/06/2024] [Indexed: 09/25/2024] Open
Abstract
Introduction Previous studies have suggested a potential correlation between psoriasis (PS) and ulcerative colitis (UC). However, studies exploring the shared mechanisms of both diseases remain limited. Current treatments primarily involve using immunosuppressive drugs, which can lead to potential side effects and drug resistance. Traditional Chinese medicine has demonstrated favorable efficacy in treating UC and PS with fewer side effects. This study aims to elucidate the shared biological mechanisms underlying UC and PS and to predict natural compounds effective for treating both disorders. Method We collected and validated differentially expressed genes associated with UC and PS from the Gene Expression Omnibus database. A protein-protein interaction network was constructed using the STRING database, aiding in identifying core targets. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes databases were utilized to analyze the functions and genomic enrichment of the identified core targets. The CIBERSORT method was employed to assess the correlation of core targets with immune cells. Compounds with potential therapeutic values were selected from the Coremine and TCMSP databases, and their therapeutic efficacy was predicted via molecular docking. Results In UC and PS, 20 common core targets were identified, with matrix metalloproteinase 9 (MMP9), matrix metalloproteinase 1 (MMP1), cluster of differentiation 274 (CD274), C-X-C motif chemokine ligand 10 (CXCL10), and topoisomerase II alpha (TOP2A) emerging as the most relevant targets shared between both conditions. Elevated levels of macrophages and dendritic cells were observed in UC and PS, with CXCL10 exhibiting the closest association with macrophages. UC and PS shared common signaling pathways, including IL-17, TNF, and chemokine signaling pathways, among others. Molecular docking revealed that quercetin, baicalen, irisolidone, rutaecarpine, epigallocatechin-3-gallate, and others held potential as natural compounds for treating both disorders. Conclusion MMP9, MMP1, and CXCL10, central mediators in the inflammatory pathways of UC and PS, establish a shared mechanism by triggering cytokine and chemokine activation, leading to tissue damage and positioning them as promising therapeutic targets for both conditions. Compounds such as quercetin, luteolin, irisolidone, rutaecarpine, and so on may be key drugs for treating both conditions. These findings suggest the potential advancement of therapeutic strategies and the enhancement of patient care by exploring shared mechanisms and predicting promising natural compounds for treating UC and PS.
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Affiliation(s)
- Yixuan Yang
- Department of Dermatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Zhuozhi Gong
- Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing, 100102, China
| | - Jiao Yang
- Department of Dermatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Ying Cai
- Jiangsu Province Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Shengwei Hong
- Jiangsu Province Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Wenjun Mao
- Jiangsu Province Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Zijian Guo
- Department of Dermatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Mengting Qiu
- Jiangsu Province Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China
| | - Zhu Fan
- Department of Dermatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
| | - Bingnan Cui
- Department of Dermatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China
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Kronborg L, Hansen EO, Bertelsen T, Rittig AH, Emmanuel T, Jørgensen S, Hjuler KF, Iversen L, Johansen C. ERAP1 and ERAP2 gene variants as potential clinical biomarkers of anti-interleukin-17A response in psoriasis vulgaris. Clin Exp Dermatol 2024; 49:1171-1178. [PMID: 38616723 DOI: 10.1093/ced/llae128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 12/01/2023] [Accepted: 04/01/2024] [Indexed: 04/16/2024]
Abstract
BACKGROUND Interleukin (IL)-17A is a proinflammatory cytokine that plays an essential role in the development of psoriasis. Although treatment with anti-IL-17A monoclonal antibodies has demonstrated high efficacy in patients with psoriasis, not all patients respond equally well, highlighting the need for biomarkers to predict treatment response. Specific single-nucleotide polymorphisms (SNPs) in the genes encoding endoplasmic reticulum aminopeptidases 1 and 2 (ERAP1 and ERAP2) have been associated with psoriasis and other immune-mediated diseases. OBJECTIVES To investigate the association between the ERAP1 and ERAP2 genotypes and response to secukinumab treatment in patients with psoriasis. METHODS In total, 75 patients with plaque psoriasis were included. All patients were genotyped for the ERAP1 rs27524, rs27044, rs30187, rs2287987 and rs26653 SNPs, the ERAP2 rs2248374 SNP, and the status of the human leucocyte antigen HLA-C*06:02 gene. RESULTS Our results demonstrated that individuals with specific ERAP1 and ERAP2 genotypes had a considerably lower response rate to secukinumab treatment. Patients with the ERAP2 rs2248374 GG genotype had a more than sixfold increased risk of treatment failure compared with patients with the rs2248374 AG or AA genotypes. Stratifying for HLA-C*06:02 status, the ERAP2 GG genotype pointed towards an increased risk of treatment failure among HLA-C*06:02-positive patients, although this was not statistically significant. CONCLUSIONS Taken together, this unique study breaks new ground by identifying distinct ERAP1 and ERAP2 gene variants that may serve as potential biomarkers for predicting the treatment response to secukinumab in patients with psoriasis. Notably, our data extend existing knowledge by linking specific ERAP1 and ERAP2 gene variants to treatment outcome.
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Affiliation(s)
- Lasse Kronborg
- Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Emma Oxlund Hansen
- Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Trine Bertelsen
- Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Anne Hald Rittig
- Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Thomas Emmanuel
- Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Sofie Jørgensen
- Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Kasper Fjellhaugen Hjuler
- Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Lars Iversen
- Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - Claus Johansen
- Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
- Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
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Blauvelt A, Langley RG, Branigan PJ, Liu X, Chen Y, DePrimo S, Ma K, Scott B, Campbell K, Muñoz-Elías EJ, Papp KA. Guselkumab Reduces Disease- and Mechanism-Related Biomarkers More Than Adalimumab in Patients with Psoriasis: A VOYAGE 1 Substudy. JID INNOVATIONS 2024; 4:100287. [PMID: 39114670 PMCID: PMC11305298 DOI: 10.1016/j.xjidi.2024.100287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 04/22/2024] [Accepted: 04/24/2024] [Indexed: 08/10/2024] Open
Abstract
Background Psoriasis is an immune-mediated inflammatory disease characterized by activation of IL-23-driven IL-17-producing T cell and other IL-23 receptor-positive IL-17-producing cell responses. Selective blockade of IL-23p19 with guselkumab was superior to blockade of TNF-α with adalimumab (ADA) in treating moderate-to-severe psoriasis. Objective: Pharmacodynamic responses of guselkumab versus ADA were compared in patients with psoriasis in VOYAGE 1. Design Inflammatory cytokine serum levels were assessed (n = 118), and lesional and nonlesional skin biopsies were collected (n = 38) in patient subsets at baseline and 4, 24, and 48 weeks after treatment to evaluate pharmacodynamic responses of guselkumab versus those of ADA. Results Guselkumab provided rapid reductions in serum IL-17A, IL-17F, and IL-22 levels by week 4 versus at baseline, which were maintained through weeks 24 and 48 (P < .001). The magnitude of reduction of IL-17A and IL-22 at week 48 and IL-17F at weeks 4, 24, and 48 were greater with guselkumab than with ADA (all P < .05). In the skin, guselkumab reduced the expression of IL-23/IL-17 pathway-associated and psoriasis-associated genes. Conclusion These data provide extensive characterization of pharmacodynamic anti-inflammatory responses to IL-23p19 and TNF-α inhibition in human blood and tissue over time with FDA-approved doses of guselkumab and ADA. Trial registration:ClinicalTrials.govClinicalTrials.gov (NCT02207231).
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Affiliation(s)
| | - Richard G. Langley
- Division of Dermatology, Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
| | - Patrick J. Branigan
- Immunology, Janssen Research & Development, LLC, Spring House, Pennsylvania, USA
| | - Xuejun Liu
- Immunology, Janssen Research & Development, LLC, San Diego, California, USA
| | - Yanqing Chen
- Immunology, Janssen Research & Development, LLC, San Diego, California, USA
| | - Samuel DePrimo
- Immunology, Janssen Research & Development, LLC, San Diego, California, USA
| | - Keying Ma
- Immunology, Janssen Research & Development, LLC, Spring House, Pennsylvania, USA
| | - Brittney Scott
- Immunology, Janssen Research & Development, LLC, Spring House, Pennsylvania, USA
| | - Kim Campbell
- Immunology, Janssen Research & Development, LLC, Spring House, Pennsylvania, USA
| | | | - Kim A. Papp
- K. Papp Alliance Clinical Trials and Probity Medical Research, Waterloo, ON, Canada
- University of Toronto, Toronto, ON, Canada
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Kong B, Lai Y. IL-17 family cytokines in inflammatory or autoimmune skin diseases. Adv Immunol 2024; 163:21-49. [PMID: 39271258 DOI: 10.1016/bs.ai.2024.07.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/15/2024]
Abstract
As potent pro-inflammatory mediators, IL-17 family cytokines play crucial roles in the pathogenesis of various inflammatory and autoimmune skin disorders. Although substantial progress has been achieved in understanding the pivotal role of IL-17A signaling in psoriasis, leading to the development of highly effective biologics, the functions of other IL-17 family members in inflammatory or autoimmune skin diseases remain less explored. In this review, we provide a comprehensive overview of IL-17 family cytokines and their receptors, with a particular focus on the recent advancements in identifying cellular sources, receptors and signaling pathways regulated by these cytokines. At the end, we discuss how the aberrant functions of IL-17 family cytokines contribute to the pathogenesis of diverse inflammatory or autoimmune skin diseases.
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Affiliation(s)
- Baida Kong
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, P.R. China; Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, School of Life Sciences, East China Normal University, Shanghai, P.R. China
| | - Yuping Lai
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, P.R. China; Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, School of Life Sciences, East China Normal University, Shanghai, P.R. China.
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Elahi R, Nazari M, Mohammadi V, Esmaeilzadeh K, Esmaeilzadeh A. IL-17 in type II diabetes mellitus (T2DM) immunopathogenesis and complications; molecular approaches. Mol Immunol 2024; 171:66-76. [PMID: 38795686 DOI: 10.1016/j.molimm.2024.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Revised: 03/06/2024] [Accepted: 03/19/2024] [Indexed: 05/28/2024]
Abstract
Chronic inflammation has long been considered the characteristic feature of type II diabetes mellitus (T2DM) Immunopathogenesis. Pro-inflammatory cytokines are considered the central drivers of the inflammatory cascade leading to β-cell dysfunction and insulin resistance (IR), two major pathologic events contributing to T2DM. Analyzing the cytokine profile of T2DM patients has also introduced interleukin-17 (IL-17) as an upstream regulator of inflammation, regarding its role in inducing the nuclear factor-kappa B (NF-κB) pathway. In diabetic tissues, IL-17 induces the expression of inflammatory cytokines and chemokines. Hence, IL-17 can deteriorate insulin signaling and β-cell function by activating the JNK pathway and inducing infiltration of neutrophils into pancreatic islets, respectively. Additionally, higher levels of IL-17 expression in patients with diabetic complications compared to non-complicated individuals have also proposed a role for IL-17 in T2DM complications. Here, we highlight the role of IL-17 in the Immunopathogenesis of T2DM and corresponding pathways, recent advances in preclinical and clinical studies targeting IL-17 in T2DM, and corresponding challenges and possible solutions.
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Affiliation(s)
- Reza Elahi
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mahdis Nazari
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Vahid Mohammadi
- School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Kimia Esmaeilzadeh
- Department of Medical Nanotechnology, Faculty of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Abdolreza Esmaeilzadeh
- Department of Immunology, Zanjan University of Medical Sciences, Zanjan, Iran; Cancer Gene Therapy Research Center (CGRC), Zanjan University of Medical Sciences, Zanjan, Iran.
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Mease PJ, Gladman DD, Merola JF, Nash P, Grieve S, Laliman-Khara V, Willems D, Taieb V, Prickett AR, Coates LC. Comparative efficacy and safety of bimekizumab in psoriatic arthritis: a systematic literature review and network meta-analysis. Rheumatology (Oxford) 2024; 63:1779-1789. [PMID: 38218744 PMCID: PMC11215990 DOI: 10.1093/rheumatology/kead705] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 11/09/2023] [Accepted: 12/02/2023] [Indexed: 01/15/2024] Open
Abstract
OBJECTIVES To understand the relative efficacy and safety of bimekizumab, a selective inhibitor of IL-17F in addition to IL-17A, vs other biologic and targeted synthetic DMARDs (b/tsDMARDs) for PsA using network meta-analysis (NMA). METHODS A systematic literature review (most recent update conducted on 1 January 2023) identified randomized controlled trials (RCTs) of b/tsDMARDs in PsA. Bayesian NMAs were conducted for efficacy outcomes at Weeks 12-24 for b/tsDMARD-naïve and TNF inhibitor (TNFi)-experienced patients. Safety at Weeks 12-24 was analysed in a mixed population. Odds ratios (ORs) and differences of mean change with the associated 95% credible interval (CrI) were calculated for the best-fitting models, and the surface under the cumulative ranking curve (SUCRA) values were calculated to determine relative rank. RESULTS The NMA included 41 RCTs for 22 b/tsDMARDs. For minimal disease activity (MDA), bimekizumab ranked 1st in b/tsDMARD-naïve patients and 2nd in TNFi-experienced patients. In b/tsDMARD-naïve patients, bimekizumab ranked 6th, 5th and 3rd for ACR response ACR20/50/70, respectively. In TNFi-experienced patients, bimekizumab ranked 1st, 2nd and 1st for ACR20/50/70, respectively. For Psoriasis Area and Severity Index 90/100, bimekizumab ranked 2nd and 1st in b/tsDMARD-naïve patients, respectively, and 1st and 2nd in TNFi-experienced patients, respectively. Bimekizumab was comparable to b/tsDMARDs for serious adverse events. CONCLUSION Bimekizumab ranked favourably among b/tsDMARDs for efficacy on joint, skin and MDA outcomes, and showed comparable safety, suggesting it may be a beneficial treatment option for patients with PsA.
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Affiliation(s)
- Philip J Mease
- Swedish Medical Center and Providence St. Joseph Health, University of Washington, Seattle, WA, USA
| | - Dafna D Gladman
- Schroeder Arthritis Institute, Krembil Research Institute, Toronto Western Hospital, University Health Network, University of Toronto, ON, Canada
| | - Joseph F Merola
- Department of Dermatology, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA
- Division of Rheumatology, Department of Medicine, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA, USA
| | - Peter Nash
- School of Medicine, Griffith University, Brisbane, QLD, Australia
| | - Stacy Grieve
- Department of RWA Health Economics, Cytel, Inc, Waltham, MA, USA
| | | | | | | | | | - Laura C Coates
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science, University of Oxford and Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford, UK
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Siebert S, Coates LC, Schett G, Raychaudhuri SP, Chen W, Gao S, Seridi L, Chakravarty SD, Shawi M, Lavie F, Sharaf M, Zimmermann M, Kollmeier AP, Xu XL, Rahman P, Mease PJ, Deodhar A. Modulation of Interleukin-23 Signaling With Guselkumab in Biologic-Naive Patients Versus Tumor Necrosis Factor Inhibitor-Inadequate Responders With Active Psoriatic Arthritis. Arthritis Rheumatol 2024; 76:894-904. [PMID: 38253404 DOI: 10.1002/art.42803] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Revised: 01/08/2024] [Accepted: 01/16/2024] [Indexed: 01/24/2024]
Abstract
OBJECTIVE We assessed and compared immunologic differences and associations with clinical response to guselkumab, a fully human interleukin (IL)-23p19 subunit inhibitor, in participants with active psoriatic arthritis (PsA) who were biologic-naive or had inadequate response to tumor necrosis factor inhibitors (TNFi-IR). METHODS Serum biomarker levels at baseline and after treatment with guselkumab 100 mg every 8 weeks were compared between biologic-naive (n = 251) and TNFi-IR (n = 93) subgroups identified in the pooled DISCOVER-1/DISCOVER-2/COSMOS data set. Baseline biomarker levels determined by achievement of week 24 clinical responses (≥75%/90% improvement in Psoriasis Area and Severity Index [PASI 75/90], Investigator's Global Assessment [IGA] of psoriasis score 0/1 and ≥2-point improvement], ≥20% improvement in American College of Rheumatology criteria [ACR20]) were compared between prior treatment subgroups. RESULTS Baseline IL-22, TNFα, and beta defensin-2 (BD-2) levels were significantly lower in biologic-naive than in TNFi-IR participants. With guselkumab, week 24 IL-17A, IL-17F, IL-22, serum amyloid A, C-reactive protein, IL-6, and BD-2 levels were significantly reduced from baseline in biologic-naive and TNFi-IR participants (≥1.4-fold difference, nominal P < 0.05). Clinical responders to guselkumab exhibited significantly higher baseline levels of several biomarkers than nonresponders (IL-17A, IL-17F, BD-2 in biologic-naive PASI 90 responders; IL-17A, BD-2 in TNFi-IR IGA 0/1 responders; IL-22, BD-2 in TNFi-IR PASI 90 responders [nominal P < 0.05]) and trended higher in TNFi-IR ACR20 responders. CONCLUSION Guselkumab modulates IL-23 signaling and provides consistent pharmacodynamic effects in both biologic-naive and TNFi-IR PsA patients. Significantly elevated baseline IL-22, TNFα, and BD-2 levels and associations between baseline IL-22, IL-17A, and BD-2 levels and skin responses to guselkumab suggest greater dysregulation of IL-23/Th17 signaling in patients with TNFi-IR.
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Affiliation(s)
| | | | - Georg Schett
- Friedrich-Alexander Universität Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany
| | - Siba P Raychaudhuri
- University of California Davis and Veterans Affairs Northern California Health Care System, Mather, California
| | - Warner Chen
- Janssen Research & Development, LLC, Spring House, Pennsylvania
| | - Sheng Gao
- Janssen Research & Development, LLC, Spring House, Pennsylvania
| | - Loqmane Seridi
- Janssen Research & Development, LLC, Spring House, Pennsylvania
| | - Soumya D Chakravarty
- Janssen Scientific Affairs, LLC, Horsham, Pennsylvania, and Drexel University College of Medicine, Philadelphia, Pennsylvania
| | - May Shawi
- Janssen Research & Development, LLC, Titusville, New Jersey
| | - Frederic Lavie
- Global Medical Affairs, Janssen Pharmaceutical Companies of Johnson & Johnson, Issy les Moulineaux, France
| | | | | | | | - Xie L Xu
- Janssen Research & Development, LLC, San Diego, California
| | - Proton Rahman
- Memorial University of Newfoundland, St. John's, Newfoundland, Canada
| | - Philip J Mease
- Swedish Medical Center/Providence St. Joseph Health and University of Washington, Seattle, Washington
| | - Atul Deodhar
- Oregon Health & Science University, Portland, Oregon
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10
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Bernardini N, Dattola A, Caldarola G, Orsini D, Assorgi C, D’Amore A, Maretti G, Richetta AG, Tolino E, Skroza N, Potenza C. Rapid response on facial psoriasis to bimekizumab: case series. Drugs Context 2024; 13:2024-1-4. [PMID: 38817804 PMCID: PMC11139169 DOI: 10.7573/dic.2024-1-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2024] [Accepted: 04/03/2024] [Indexed: 06/01/2024] Open
Abstract
Psoriasis is a chronic inflammatory disease that can affect any part of the body but, when it appears in certain areas, like the face, it can have a very significant psychological impact. Biologics, in particular IL-17 and IL-23 drug inhibitors, have shown relevant clinical efficacy in the management of psoriatic lesions in difficult-to-treat areas. In post hoc analysis of phase III trials in plaque psoriasis, bimekizumab has shown safety and complete clearance of high-impact areas. However, these studies did not focus on the effect of bimekizumab on facial lesions. Therefore, this case series represents the first clinical real-life experience of rapid and successful management of facial psoriasis with bimekizumab in six patients.
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Affiliation(s)
- Nicoletta Bernardini
- Dermatology Unit “Daniele Innocenzi”, ASL Latina, Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Polo Pontino, Italy
| | - Annunziata Dattola
- Dermatology Unit, Department of Clinical Internal, Anesthesiological and Cardiovascular Science, University of La Sapienza, Rome, Italy
| | - Giacomo Caldarola
- UOC of Dermatology, Department of Medical and Surgical Sciences, Fondazione Policlinico Universitario A. Gemelli – IRCCS, Rome, Italy
| | - Diego Orsini
- Clinical Dermatology Unit IFO-San Gallicano Dermatological Institute-IRCCS Rome, Italy
| | - Chiara Assorgi
- Section of Dermatology, Department of Clinical Medicine and Surgery University of Naples Federico II, Naples, Italy
| | - Alessandra D’Amore
- Dermatology, Department of Translational Medicine and Surgery, Catholic University of the Sacred Heart, Rome, Italy
| | - Giulia Maretti
- Dermatology Unit, Department of Clinical Internal, Anesthesiological and Cardiovascular Science, University of La Sapienza, Rome, Italy
| | - Antonio Giovanni Richetta
- Dermatology Unit, Department of Clinical Internal, Anesthesiological and Cardiovascular Science, University of La Sapienza, Rome, Italy
| | - Ersilia Tolino
- Dermatology Unit “Daniele Innocenzi”, ASL Latina, Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Polo Pontino, Italy
| | - Nevena Skroza
- Dermatology Unit “Daniele Innocenzi”, ASL Latina, Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Polo Pontino, Italy
| | - Concetta Potenza
- Dermatology Unit “Daniele Innocenzi”, ASL Latina, Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Polo Pontino, Italy
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11
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Garcia EM, Lenz JD, Schaub RE, Hackett KT, Salgado-Pabón W, Dillard JP. IL-17C is a driver of damaging inflammation during Neisseria gonorrhoeae infection of human Fallopian tube. Nat Commun 2024; 15:3756. [PMID: 38704381 PMCID: PMC11069574 DOI: 10.1038/s41467-024-48141-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 04/19/2024] [Indexed: 05/06/2024] Open
Abstract
The human pathogen Neisseria gonorrhoeae ascends into the upper female reproductive tract to cause damaging inflammation within the Fallopian tubes and pelvic inflammatory disease (PID), increasing the risk of infertility and ectopic pregnancy. The loss of ciliated cells from the epithelium is thought to be both a consequence of inflammation and a cause of adverse sequelae. However, the links between infection, inflammation, and ciliated cell extrusion remain unresolved. With the use of ex vivo cultures of human Fallopian tube paired with RNA sequencing we defined the tissue response to gonococcal challenge, identifying cytokine, chemokine, cell adhesion, and apoptosis related transcripts not previously recognized as potentiators of gonococcal PID. Unexpectedly, IL-17C was one of the most highly induced genes. Yet, this cytokine has no previous association with gonococcal infection nor pelvic inflammatory disease and thus it was selected for further characterization. We show that human Fallopian tubes express the IL-17C receptor on the epithelial surface and that treatment with purified IL-17C induces pro-inflammatory cytokine secretion in addition to sloughing of the epithelium and generalized tissue damage. These results demonstrate a previously unrecognized but critical role of IL-17C in the damaging inflammation induced by gonococci in a human explant model of PID.
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Affiliation(s)
- Erin M Garcia
- Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, USA
| | - Jonathan D Lenz
- Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, USA
| | - Ryan E Schaub
- Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, USA
| | - Kathleen T Hackett
- Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, USA
| | - Wilmara Salgado-Pabón
- Department of Pathobiological Sciences, University of Wisconsin-Madison, Madison, WI, USA
| | - Joseph P Dillard
- Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI, USA.
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12
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Sieminska I, Pieniawska M, Grzywa TM. The Immunology of Psoriasis-Current Concepts in Pathogenesis. Clin Rev Allergy Immunol 2024; 66:164-191. [PMID: 38642273 PMCID: PMC11193704 DOI: 10.1007/s12016-024-08991-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/01/2024] [Indexed: 04/22/2024]
Abstract
Psoriasis is one of the most common inflammatory skin diseases with a chronic, relapsing-remitting course. The last decades of intense research uncovered a pathological network of interactions between immune cells and other types of cells in the pathogenesis of psoriasis. Emerging evidence indicates that dendritic cells, TH17 cells, and keratinocytes constitute a pathogenic triad in psoriasis. Dendritic cells produce TNF-α and IL-23 to promote T cell differentiation toward TH17 cells that produce key psoriatic cytokines IL-17, IFN-γ, and IL-22. Their activity results in skin inflammation and activation and hyperproliferation of keratinocytes. In addition, other cells and signaling pathways are implicated in the pathogenesis of psoriasis, including TH9 cells, TH22 cells, CD8+ cytotoxic cells, neutrophils, γδ T cells, and cytokines and chemokines secreted by them. New insights from high-throughput analysis of lesional skin identified novel signaling pathways and cell populations involved in the pathogenesis. These studies not only expanded our knowledge about the mechanisms of immune response and the pathogenesis of psoriasis but also resulted in a revolution in the clinical management of patients with psoriasis. Thus, understanding the mechanisms of immune response in psoriatic inflammation is crucial for further studies, the development of novel therapeutic strategies, and the clinical management of psoriasis patients. The aim of the review was to comprehensively present the dysregulation of immune response in psoriasis with an emphasis on recent findings. Here, we described the role of immune cells, including T cells, B cells, dendritic cells, neutrophils, monocytes, mast cells, and innate lymphoid cells (ILCs), as well as non-immune cells, including keratinocytes, fibroblasts, endothelial cells, and platelets in the initiation, development, and progression of psoriasis.
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Affiliation(s)
- Izabela Sieminska
- University Centre of Veterinary Medicine, University of Agriculture in Krakow, Krakow, Poland
| | - Monika Pieniawska
- Institute of Human Genetics, Polish Academy of Sciences, Poznań, Poland
| | - Tomasz M Grzywa
- Laboratory of Immunology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Warsaw, Poland.
- Department of Methodology, Medical University of Warsaw, Warsaw, Poland.
- The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, USA.
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13
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Tanaka Y, Shaw S. Bimekizumab for the treatment of psoriatic arthritis. Expert Rev Clin Immunol 2024; 20:155-168. [PMID: 37909894 DOI: 10.1080/1744666x.2023.2277266] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 10/26/2023] [Indexed: 11/03/2023]
Abstract
INTRODUCTION Interleukin (IL)-17A and IL-17F have overlapping roles in pro-inflammatory signaling and have been implicated in the pathogenesis of psoriatic disease. Bimekizumab is the first human monoclonal antibody to selectively inhibit IL-17F in addition to IL-17A. Bimekizumab has been studied in several phase II/III trials and has been approved for the treatment of patients with psoriatic arthritis (PsA) in the EU and UK. AREAS COVERED A literature search identified clinical trials examining the efficacy and safety of bimekizumab for PsA, which were critically appraised. EXPERT OPINION Clinical trials of bimekizumab in PsA have demonstrated rapid and sustained treatment responses and depth of response across the multiple disease domains. High levels of efficacy were sustained to 152 weeks in phase IIb trials, and to 52 weeks in phase III trials. Bimekizumab was generally well tolerated. As expected, due to the role of IL-17 in the immune response to fungal pathogens, there was an increase in mild-to-moderate, localized fungal infections with bimekizumab treatment, very few of which led to discontinuation. Studies over longer time periods, with relevant comparators from the IL-17A inhibitor class, and real-world data will be important to further define the role of bimekizumab among currently available treatments for PsA. [Figure: see text].
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Affiliation(s)
- Yoshiya Tanaka
- The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Fukuoka, Japan
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14
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Koh CH, Kim BS, Kang CY, Chung Y, Seo H. IL-17 and IL-21: Their Immunobiology and Therapeutic Potentials. Immune Netw 2024; 24:e2. [PMID: 38455465 PMCID: PMC10917578 DOI: 10.4110/in.2024.24.e2] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2023] [Revised: 12/26/2023] [Accepted: 01/07/2024] [Indexed: 03/09/2024] Open
Abstract
Studies over the last 2 decades have identified IL-17 and IL-21 as key cytokines in the modulation of a wide range of immune responses. IL-17 serves as a critical defender against bacterial and fungal pathogens, while maintaining symbiotic relationships with commensal microbiota. However, alterations in its levels can lead to chronic inflammation and autoimmunity. IL-21, on the other hand, bridges the adaptive and innate immune responses, and its imbalance is implicated in autoimmune diseases and cancer, highlighting its important role in both health and disease. Delving into the intricacies of these cytokines not only opens new avenues for understanding the immune system, but also promises innovative advances in the development of therapeutic strategies for numerous diseases. In this review, we will discuss an updated view of the immunobiology and therapeutic potential of IL-17 and IL-21.
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Affiliation(s)
- Choong-Hyun Koh
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea
| | - Byung-Seok Kim
- Division of Life Sciences, College of Life Science and Bioengineering, Incheon National University, Incheon 22012, Korea
| | - Chang-Yuil Kang
- Research & Development Center, Cellid Co., Ltd., Seoul 08826, Korea
| | - Yeonseok Chung
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea
| | - Hyungseok Seo
- Laboratory of Cell & Gene Therapy, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Korea
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15
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Choi H, Huang F, Flack M. The Effect of BI 730357 (Retinoic Acid-Related Orphan Receptor Gamma t Antagonist, Bevurogant) on the Pharmacokinetics of a Transporter Probe Cocktail, Including Digoxin, Furosemide, Metformin, and Rosuvastatin: An Open-Label, Non-randomized, 2-Period Fixed-Sequence Trial in Healthy Subjects. Clin Pharmacol Drug Dev 2024; 13:197-207. [PMID: 37960990 DOI: 10.1002/cpdd.1344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 10/25/2023] [Indexed: 11/15/2023]
Abstract
Evaluating Drug-Drug Interactions (DDIs) for new investigational compounds requires several trials evaluating different drugs with different transporter specificities. By using a cocktail of drugs with different transporter specificities, a single trial could evaluate the pharmacokinetics (PKs) of each cocktail drug simultaneously, reducing the number of clinical DDI trials required for clinical development. We aimed to investigate the effect of steady-state Boehringer Ingelheim (BI) 730357 (bevurogant) on the PKs of a validated and optimized 4-component transporter cocktail. This open-label, non-randomized, 2-period fixed-sequence phase I trial compared transporter cocktail (0.25 mg digoxin/1 mg furosemide/10 mg metformin hydrochloride/10 mg rosuvastatin) with and without BI 730357 in healthy subjects aged 18-55 years with body mass index 18.5-29.9 kg/m2 . During reference treatment/period 1, transporter cocktail was administered 90 minutes after breakfast. After a washout period, during test treatment/period 2, BI 730357 was dosed twice daily for 13 days, with transporter cocktail administered on day 1. The primary endpoints were the area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞ ) and the maximum measured concentration of the analyte in plasma (Cmax ), and the secondary endpoint was the area under the concentration-time curve of the analyte in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz ). Steady-state BI 730357 increased digoxin (+48% to +94%), minimally affected metformin (-2% to -9%), furosemide (+12% to +18%), and rosuvastatin (+19% to +39%) exposure. Therefore, no clinically relevant inhibition of transporters OCT2/MATE-1/MATE-2K, OAT1/OAT3, OATP1B1/OATP1B3 was observed. Potential inhibition of breast cancer resistance protein noted as PK parameters of coproporphyrin I/III (OATP1B1/OATP1B3 biomarkers) remained within bioequivalence boundaries while rosuvastatin PK parameters (AUC0-∞ /Cmax /AUC0-tz ) exceeded the bioequivalence boundary. BI 730357 was safe and well tolerated. This trial confirms the usefulness and tolerability of the transporter cocktail consisting of digoxin, furosemide, metformin, and rosuvastatin in assessing drug-transporter interactions in vivo.
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Affiliation(s)
- HeeJae Choi
- Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA
| | - Fenglei Huang
- Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA
| | - Mary Flack
- Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA
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16
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Gao Y, Gong B, Chen Z, Song J, Xu N, Weng Z. Damage-Associated Molecular Patterns, a Class of Potential Psoriasis Drug Targets. Int J Mol Sci 2024; 25:771. [PMID: 38255845 PMCID: PMC10815563 DOI: 10.3390/ijms25020771] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 12/29/2023] [Accepted: 01/04/2024] [Indexed: 01/24/2024] Open
Abstract
Psoriasis is a chronic skin disorder that involves both innate and adaptive immune responses in its pathogenesis. Local tissue damage is a hallmark feature of psoriasis and other autoimmune diseases. In psoriasis, damage-associated molecular patterns (DAMPs) released by damaged local tissue act as danger signals and trigger inflammatory responses by recruiting and activating immune cells. They also stimulate the release of pro-inflammatory cytokines and chemokines, which exacerbate the inflammatory response and contribute to disease progression. Recent studies have highlighted the role of DAMPs as key regulators of immune responses involved in the initiation and maintenance of psoriatic inflammation. This review summarizes the current understanding of the immune mechanism of psoriasis, focusing on several important DAMPs and their mechanisms of action. We also discussed the potential of DAMPs as diagnostic and therapeutic targets for psoriasis, offering new insights into the development of more effective treatments for this challenging skin disease.
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Affiliation(s)
| | | | | | | | - Na Xu
- Shenzhen Key Laboratory of Systems Medicine for Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (Y.G.); (B.G.); (Z.C.); (J.S.)
| | - Zhuangfeng Weng
- Shenzhen Key Laboratory of Systems Medicine for Inflammatory Diseases, School of Medicine, Shenzhen Campus of Sun Yat-sen University, Shenzhen 518107, China; (Y.G.); (B.G.); (Z.C.); (J.S.)
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17
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Liu Y, Ouyang Y, You W, Liu W, Cheng Y, Mai X, Shen Z. Physiological roles of human interleukin-17 family. Exp Dermatol 2024; 33:e14964. [PMID: 37905720 DOI: 10.1111/exd.14964] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Revised: 10/08/2023] [Accepted: 10/13/2023] [Indexed: 11/02/2023]
Abstract
Interleukin-17 s (IL-17s) are well-known proinflammatory cytokines, and their antagonists perform excellently in the treatment of inflammatory skin diseases such as psoriasis. However, their physiological functions have not been given sufficient attention by clinicians. IL-17s can protect the host from extracellular pathogens, maintain epithelial integrity, regulate cognitive processes and modulate adipocyte activity through distinct mechanisms. Here, we present a systematic review concerning the physiological functions of IL-17s. Our goal is not to negate the therapeutic effect of IL-17 antagonists, but to ensure their safe use and reasonably explain the possible adverse events that may occur in their application.
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Affiliation(s)
- Yucong Liu
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Ye Ouyang
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Wanchun You
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Wenqi Liu
- Department of Dermatology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Yufan Cheng
- Department of Dermatology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Xinming Mai
- Medical School, Shenzhen University, Shenzhen, China
| | - Zhu Shen
- Department of Dermatology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
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18
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Guo J, Zhang H, Lin W, Lu L, Su J, Chen X. Signaling pathways and targeted therapies for psoriasis. Signal Transduct Target Ther 2023; 8:437. [PMID: 38008779 PMCID: PMC10679229 DOI: 10.1038/s41392-023-01655-6] [Citation(s) in RCA: 68] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 09/10/2023] [Accepted: 09/14/2023] [Indexed: 11/28/2023] Open
Abstract
Psoriasis is a common, chronic, and inflammatory skin disease with a high burden on individuals, health systems, and society worldwide. With the immunological pathologies and pathogenesis of psoriasis becoming gradually revealed, the therapeutic approaches for this disease have gained revolutionary progress. Nevertheless, the mechanisms of less common forms of psoriasis remain elusive. Furthermore, severe adverse effects and the recurrence of disease upon treatment cessation should be noted and addressed during the treatment, which, however, has been rarely explored with the integration of preliminary findings. Therefore, it is crucial to have a comprehensive understanding of the mechanisms behind psoriasis pathogenesis, which might offer new insights for research and lead to more substantive progress in therapeutic approaches and expand clinical options for psoriasis treatment. In this review, we looked to briefly introduce the epidemiology, clinical subtypes, pathophysiology, and comorbidities of psoriasis and systematically discuss the signaling pathways involving extracellular cytokines and intracellular transmission, as well as the cross-talk between them. In the discussion, we also paid more attention to the potential metabolic and epigenetic mechanisms of psoriasis and the molecular mechanistic cascades related to its comorbidities. This review also outlined current treatment for psoriasis, especially targeted therapies and novel therapeutic strategies, as well as the potential mechanism of disease recurrence.
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Affiliation(s)
- Jia Guo
- Department of Dermatology, Xiangya Hospital, Central South University, No.87 Xiangya Road, Changsha, 410008, Hunan, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, 410008, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410008, Hunan, China
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China
| | - Hanyi Zhang
- Department of Dermatology, Xiangya Hospital, Central South University, No.87 Xiangya Road, Changsha, 410008, Hunan, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, 410008, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410008, Hunan, China
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China
| | - Wenrui Lin
- Department of Dermatology, Xiangya Hospital, Central South University, No.87 Xiangya Road, Changsha, 410008, Hunan, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, 410008, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410008, Hunan, China
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China
| | - Lixia Lu
- Department of Dermatology, Xiangya Hospital, Central South University, No.87 Xiangya Road, Changsha, 410008, Hunan, China
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, 410008, Hunan, China
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410008, Hunan, China
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China
| | - Juan Su
- Department of Dermatology, Xiangya Hospital, Central South University, No.87 Xiangya Road, Changsha, 410008, Hunan, China.
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, 410008, Hunan, China.
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410008, Hunan, China.
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China.
| | - Xiang Chen
- Department of Dermatology, Xiangya Hospital, Central South University, No.87 Xiangya Road, Changsha, 410008, Hunan, China.
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Changsha, 410008, Hunan, China.
- Hunan Key Laboratory of Skin Cancer and Psoriasis, Changsha, 410008, Hunan, China.
- Hunan Engineering Research Center of Skin Health and Disease, Changsha, 410008, Hunan, China.
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19
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Schäkel K, Reich K, Asadullah K, Pinter A, Jullien D, Weisenseel P, Paul C, Gomez M, Wegner S, Personke Y, Kreimendahl F, Chen Y, Angsana J, Leung MWL, Eyerich K. Early disease intervention with guselkumab in psoriasis leads to a higher rate of stable complete skin clearance ('clinical super response'): Week 28 results from the ongoing phase IIIb randomized, double-blind, parallel-group, GUIDE study. J Eur Acad Dermatol Venereol 2023; 37:2016-2027. [PMID: 37262309 DOI: 10.1111/jdv.19236] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 04/25/2023] [Indexed: 06/03/2023]
Abstract
BACKGROUND Guselkumab is an interleukin (IL)-23 inhibitor with demonstrated efficacy in patients with psoriasis. OBJECTIVES Evaluate the impact of early disease intervention on clinical responses following 28 weeks of guselkumab treatment in patients with moderate-to-severe plaque psoriasis. Correlate clinical response and disease duration data with serum biomarker data. METHODS GUIDE is a phase IIIb randomized, double-blind, parallel-group, multicentre study of adults with moderate-to-severe plaque psoriasis. In study part 1, patients with a short disease duration (SDD [≤2 years]) or a long disease duration (LDD [>2 years]) received guselkumab 100 mg at Week (W) 0, 4, 12, and 20. Those achieving complete skin clearance at W20 and W28 were defined as a super responder (SRe). A multivariable logistic regression analysed the association between baseline factors and the likelihood of becoming an SRe. The relationship between clinical response, disease duration and serum biomarker data was assessed at W0 and 4. RESULTS In total, 880 patients were enrolled (SDD/LDD = 40.6%/59.4% of patients). More SDD than LDD patients achieved absolute Psoriasis Area and Severity Index (PASI) = 0 at W28 (51.8% vs. 39.4%) and were SRes (43.7% vs. 28.1% [overall 34.4%]). SDD patients also achieved PASI = 0 quicker than LDD patients (median 141 vs. 200 days). Disease duration and prior biologic use had the greatest impact on becoming an SRe, with no strong association among these independent variables. At baseline, there were no significant differences in the serum biomarker levels of IL-17A, IL-17F, IL-22 and β-defensin 2 between SDD and LDD patients, or between SRe and non-SRe patients. Guselkumab rapidly decreased these markers of systemic inflammation across all patient groups analysed at W4. Guselkumab was well tolerated. CONCLUSIONS Guselkumab efficacy was consistent across subpopulations, on the skin and systemically. The proportion of SRes was higher in SDD than LDD patients, indicating early treatment intervention may improve clinical outcomes.
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Affiliation(s)
- K Schäkel
- Department of Dermatology, and Interdisciplinary Center for Inflammatory Diseases, Heidelberg University Hospital, Heidelberg, Germany
| | - K Reich
- Translational Research in Inflammatory Skin Diseases, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - K Asadullah
- Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, Berlin, Germany
- Prof. Dr. med. Asadullah, Dermatological Practice, Potsdam, Germany
| | - A Pinter
- University Hospital Frankfurt am Main, Frankfurt, Germany
| | - D Jullien
- Department of Dermatology, Edouard Herriot Hospital, Hospices Civils de Lyon, Lyon, France
| | | | - C Paul
- Toulouse University, Toulouse, France
| | - M Gomez
- Janssen-Cilag GmbH, Neuss, Germany
| | - S Wegner
- Janssen-Cilag GmbH, Neuss, Germany
| | | | | | - Y Chen
- Janssen R&D, LLC, San Diego, USA
| | | | | | - K Eyerich
- Department of Dermatology and Venereology, Medical Center, University of Freiburg, Freiburg im Breisgau, Germany
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20
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Cannizzaro MV, Coscarella G, Chiricozzi A. Brodalumab in the Treatment of Plaque Psoriasis Localized in Difficult-to-Treat Areas: A Narrative Review. Dermatol Pract Concept 2023; 13:e2023245. [PMID: 37557129 PMCID: PMC10412049 DOI: 10.5826/dpc.1303a245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/07/2022] [Indexed: 08/11/2023] Open
Abstract
INTRODUCTION Psoriasis is a common chronic, immune-mediated, inflammatory skin disease that in certain localization results difficult to treat. Psoriatic lesions in difficult-to-treat areas might be hardly managed as no standardized therapeutic approach and the application of topical treatments might have great limitations. Systemic agents, including biologic therapies, have been proven effective in treating this subgroup of patients. In particular, current evidence has shown beneficial effects with the use of brodalumab, a fully human IgG2 monoclonal antibody antagonizing the IL-17 receptor A subunit (IL-17RA). OBJECTIVES The aim of this narrative review was to collect published data about efficacy and safety of brodalumab in the treatment of psoriasis occurring in difficult-to-treat areas. METHODS Data on brodalumab effectiveness and safety deriving from both trials and real-world setting that had been published in the last 15 years were collected for this review, together with clinical findings issued during international meetings. RESULTS In phase 3 trials, brodalumab demonstrated to be effective in promoting a rapid response in scalp psoriasis as well as in generalized pustular psoriasis and erythrodermic psoriasis. Nail psoriasis demonstrated marked clinical improvement after treatment with brodalumab. Amelioration of palmoplantar psoriasis was also described in brodalumab-treated patients. Various retrospective real-world studies reported a complete clearance of psoriatic lesions in difficult-to-treat areas, including genitalia, through short-term brodalumab treatment. CONCLUSIONS Brodalumab, combining rapid and sustained efficacy with a favorable safety profile, may be a valid therapeutic option for severe variants of psoriasis as well as for psoriasis localized in difficult-to-treat areas.
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Affiliation(s)
- Maria Vittoria Cannizzaro
- Dermatologia, Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Giulia Coscarella
- Dermatologia, Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Dermatologia, Dipartimento Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Andrea Chiricozzi
- Dermatologia, Dipartimento Universitario di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
- Dermatologia, Dipartimento Scienze Mediche e Chirurgiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
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21
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Park A, Heo TH. IL-17A-targeting fenofibrate attenuates inflammation in psoriasis by inducing autophagy. Life Sci 2023:121755. [PMID: 37236601 DOI: 10.1016/j.lfs.2023.121755] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 04/27/2023] [Accepted: 05/02/2023] [Indexed: 05/28/2023]
Abstract
IL-17A is a critical pro-inflammatory cytokine in autoimmune diseases such as psoriasis. Targeting of IL-17A is an effective strategy to treat patients with autoimmune diseases; however, relevant small molecule therapeutics have not yet been developed. Here, the small molecule drug fenofibrate was validated as an inhibitor of IL-17A through ELISA and surface plasmon resonance (SPR) assays. We further confirmed that fenofibrate blocked IL-17A signalings including the mitogen-activated protein kinase (MAPK) and NF-κB signaling pathways, in IL-17A-treated HaCaT cells, HEKa (human primary epidermal keratinocytes) and imiquimod (IMQ)-induced psoriasis mouse model. Fenofibrate attenuated systemic inflammation by suppressing Th17 populations and inflammatory cytokines, such as IL-1β, IL-6, IL-17A, and tumor necrosis factor (TNF). Surprisingly, fenofibrate upregulated LC3 and p62 in the psoriatic mouse group. The autophagy changes were caused by ULK1 pathway in hIL-17A-treated HaCaT and HEKa. In addition, the enhancement of autophagy by fenofibrate exerted anti-inflammatory effects, as demonstrated by the suppression of IL-6 and IL-8 in the IL-17A-treated keratinocytes. Thus, IL-17A-targeting fenofibrate can be a potential therapeutic for psoriasis and other autoimmune diseases via regulating autophagy.
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Affiliation(s)
- Aeri Park
- Laboratory of PharmacoImmunology, Integrated Research Institute of Pharmaceutical Sciences and BK21 FOUR Team for Advanced Program for SmartPharma Leaders, College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Bucheon-si, Gyeonggi-do 14662, Republic of Korea
| | - Tae-Hwe Heo
- Laboratory of PharmacoImmunology, Integrated Research Institute of Pharmaceutical Sciences and BK21 FOUR Team for Advanced Program for SmartPharma Leaders, College of Pharmacy, The Catholic University of Korea, 43, Jibong-ro, Bucheon-si, Gyeonggi-do 14662, Republic of Korea.
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22
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Brembilla NC, Boehncke WH. Revisiting the interleukin 17 family of cytokines in psoriasis: pathogenesis and potential targets for innovative therapies. Front Immunol 2023; 14:1186455. [PMID: 37283755 PMCID: PMC10239979 DOI: 10.3389/fimmu.2023.1186455] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Accepted: 05/09/2023] [Indexed: 06/08/2023] Open
Abstract
Psoriasis is a common chronic inflammatory skin disease, associated with substantial comorbidity. TH17 lymphocytes, differentiating under the influence of dendritic cell-derived IL-23, and mediating their effects via IL-17A, are believed to be central effector cells in psoriasis. This concept is underlined by the unprecedented efficacy of therapeutics targeting this pathogenetic axis. In recent years, numerous observations made it necessary to revisit and refine this simple "linear" pathogenetic model. It became evident that IL-23 independent cells exist that produce IL-17A, that IL-17 homologues may exhibit synergistic biological effects, and that the blockade of IL-17A alone is clinically less effective compared to the inhibition of several IL-17 homologues. In this review, we will summarize the current knowledge around IL-17A and its five currently known homologues, namely IL-17B, IL-17C, IL-17D, IL-17E (also known as IL-25) and IL-17F, in relation to skin inflammation in general and psoriasis in particular. We will also re-visit the above-mentioned observations and integrate them into a more comprehensive pathogenetic model. This may help to appreciate current as well as developing anti-psoriatic therapies and to prioritize the selection of future drugs' mode(s) of action.
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Affiliation(s)
| | - Wolf-Henning Boehncke
- Divison of Dermatology and Venereology, Geneva University Hospitals, Geneva, Switzerland
- Department of Pathology and Immunology, Faculty of Medicine, University of Geneva, Geneva, Switzerland
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23
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Shah AM, Zamora R, Vodovotz Y. Interleukin-17 as a spatiotemporal bridge from acute to chronic inflammation: Novel insights from computational modeling. WIREs Mech Dis 2023; 15:e1599. [PMID: 36710253 PMCID: PMC10176872 DOI: 10.1002/wsbm.1599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 01/12/2023] [Indexed: 01/31/2023]
Abstract
A systematic review of several acute inflammatory diseases ranging from sepsis and trauma/hemorrhagic shock to the relevant pathology of the decade, COVID-19, points to the cytokine interleukin (IL)-17A as being centrally involved in the propagation of inflammation. We summarize the role of IL-17A in acute inflammation, leveraging insights made possible by biological network analysis and novel computational methodologies aimed at defining the spatiotemporal spread of inflammation in both experimental animal models and humans. These studies implicate IL-17A in the cross-tissue spread of inflammation, a process that appears to be in part regulated through neural mechanisms. Although acute inflammatory diseases are currently considered distinct from chronic inflammatory pathologies, we suggest that chronic inflammation may represent repeated, cyclical episodes of acute inflammation driven by mechanisms involving IL-17A. Thus, insights from computational modeling of acute inflammatory diseases may improve diagnosis and treatment of chronic inflammation; in turn, therapeutics developed for chronic/autoimmune disease may be of benefit in acute inflammation. This article is categorized under: Immune System Diseases > Computational Models.
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Affiliation(s)
- Ashti M Shah
- Physician Scientist Training Program, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Ruben Zamora
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Center for Inflammation and Regeneration Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Yoram Vodovotz
- Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Center for Inflammation and Regeneration Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
- Center for Systems Immunology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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24
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Crawford MP, Borcherding N, Karandikar NJ. IL-17 cytokines preferentially act on naïve CD4+ T cells with the IL-17AF heterodimer inducing the greatest functional changes. PLoS One 2023; 18:e0285166. [PMID: 37115755 PMCID: PMC10146571 DOI: 10.1371/journal.pone.0285166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 04/17/2023] [Indexed: 04/29/2023] Open
Abstract
CD4+ T-helper 17 (Th17) T cells are a key population in protective immunity during infection and in self-tolerance/autoimmunity. Through the secretion of IL-17, Th17 cells act in promotion of inflammation and are thus a major potential therapeutic target in autoimmune disorders. Recent reports have brought to light that the IL-17 family cytokines, IL-17A, IL-17F and IL-17AF, can directly act on CD4+ T-cells, both in murine and human systems, inducing functional changes in these cells. Here we show that this action is preferentially targeted toward naïve, but not memory, CD4+ T-cells. Naïve cells showed transcriptome changes as early as 48 hours post-IL-17 exposure, whereas memory cells remained unaffected as late as 7 days. These functional differences occurred despite similar IL-17 receptor expression on these subsets and were maintained in co-culture/transwell systems, with each subset maintaining its functional response to IL-17. Importantly, there were differences in downstream transcriptional signaling by the three IL-17 cytokines, with the IL-17AF heterodimer conferring both the greatest transcriptional change and most altered functional consequences. Detailed transcriptome analysis provides important insights into the genes and pathways that are modulated as a result of IL-17-mediated signaling and may serve as targets of future therapies.
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Affiliation(s)
- Michael P Crawford
- Department of Pathology, University of Iowa Health Care, Iowa City, Iowa, United States of America
- Iowa City Veterans Administration Medical Center, Iowa City, IA, United States of America
| | - Nicholas Borcherding
- Department of Pathology, University of Iowa Health Care, Iowa City, Iowa, United States of America
| | - Nitin J Karandikar
- Department of Pathology, University of Iowa Health Care, Iowa City, Iowa, United States of America
- Iowa City Veterans Administration Medical Center, Iowa City, IA, United States of America
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25
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Wang P, Li T, Niu C, Sun S, Liu D. ROS-activated MAPK/ERK pathway regulates crosstalk between Nrf2 and Hif-1α to promote IL-17D expression protecting the intestinal epithelial barrier under hyperoxia. Int Immunopharmacol 2023; 116:109763. [PMID: 36736221 DOI: 10.1016/j.intimp.2023.109763] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2022] [Revised: 01/12/2023] [Accepted: 01/18/2023] [Indexed: 02/04/2023]
Abstract
Reactive oxygen species (ROS) damage to the intestinal barrier is a side effect of prolonged hyperoxia therapy in neonates, which impairs growth and development of the intestine and promotes intestinal diseases. However, the research on clinical prevention and treatment is lacking. Therefore, we investigated the molecular mechanisms of the neonate intestinal response against hyperoxia-derived ROS to find targets for intestinal barrier damage prevention. Human intestinal epithelial cells were incubated under hyperoxia (85% oxygen) to build an in vitro model. ROS and the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway were inhibited to detect the MAPK/ERK pathway, nuclear factor erythroid factor 2-related factor 2 (Nrf2), hypoxia-inducible factor-1α (Hif-1α), and interleukin-17D (IL-17D) expression. Nrf2 was inhibited to detect Hif-1α and IL-17D expression. Hif-1α was inhibited to detect Nrf2, IL-17D, and tight junction proteins expression and apoptosis. Cells were treated with human recombinant IL-17D to detect TNF-α, IL-1β, IL-10, and tight junction proteins expression. ROS, Nrf2, Hif-1α, and IL-17D were upregulated and the MAPK/ERK pathway was activated under hyperoxia. But ROS inhibition downregulated the MAPK/ERK pathway, Nrf2, Hif-1α, and IL-17D. MAPK/ERK pathway inhibition downregulated Nrf2, Hif-1α, and IL-17D. Nrf2 inhibition downregulated Hif-1α and IL-17D. Hif-1α inhibition downregulated Nrf2, IL-17D, tight junction proteins, and exacerbated apoptosis. The recombinant IL-17D downregulated TNF-α, IL-1β, but upregulated IL-10 and tight junction proteins. We concluded that Hyperoxia-generated ROS activated the MAPK/ERK pathway to regulate Nrf2, Hif-1α, and IL-17D expression. Nrf2 and Hif-1α were interdependent and promoted IL-17D. Importantly, Hif-1α and IL-17D expression protected the intestinal epithelial barrier.
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Affiliation(s)
- Pingchuan Wang
- ShengJing Hospital of China Medical University, Department of Gastroenterology and Medical Research Center, Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, SanHao Street No.36, HePing District, ShenYang, Liaoning 110000, China
| | - Tianming Li
- ShengJing Hospital of China Medical University, Department of Gastroenterology and Medical Research Center, Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, SanHao Street No.36, HePing District, ShenYang, Liaoning 110000, China
| | - Changping Niu
- ShengJing Hospital of China Medical University, Department of Gastroenterology and Medical Research Center, Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, SanHao Street No.36, HePing District, ShenYang, Liaoning 110000, China
| | - Siyu Sun
- ShengJing Hospital of China Medical University, Department of Gastroenterology, SanHao Street No.36, HePing District, ShenYang, Liaoning 110000, China
| | - Dongyan Liu
- ShengJing Hospital of China Medical University, Department of Gastroenterology and Medical Research Center, Liaoning Key Laboratory of Research and Application of Animal Models for Environmental and Metabolic Diseases, SanHao Street No.36, HePing District, ShenYang, Liaoning 110000, China.
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26
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Asahina A, Okubo Y, Morita A, Tada Y, Igarashi A, Langley RG, Deherder D, Matano M, Vanvoorden V, Wang M, Ohtsuki M, Nakagawa H. Bimekizumab Efficacy and Safety in Japanese Patients with Plaque Psoriasis in BE VIVID: A Phase 3, Ustekinumab and Placebo-Controlled Study. Dermatol Ther (Heidelb) 2023; 13:751-768. [PMID: 36648594 PMCID: PMC9984664 DOI: 10.1007/s13555-022-00883-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 12/21/2022] [Indexed: 01/18/2023] Open
Abstract
INTRODUCTION Bimekizumab treatment resulted in improved clinical outcomes in patients with moderate-to-severe plaque psoriasis in BE VIVID, a 52-week, phase 3, randomized, ustekinumab and placebo-controlled study. We present data from the BE VIVID Japan patient subpopulation. METHODS Globally, patients were randomized to receive bimekizumab 320 mg every 4 weeks (Q4W), ustekinumab (45/90 mg weight-based at baseline and week 4, then every 12 weeks), or placebo (Q4W through week 16, then bimekizumab 320 mg Q4W). Efficacy endpoints included week 16 Psoriasis Area and Severity Index (PASI) 90 and Investigator's Global Assessment (IGA) 0/1, and other outcomes [PASI 100, PASI 75, IGA 0, Dermatology Life Quality Index (DLQI) 0/1, absolute PASI, scalp IGA, Psoriasis Symptoms and Impacts Measure (P-SIM) responses]. Safety analyses were conducted. RESULTS There were 108 Japanese randomized patients (bimekizumab: 62; ustekinumab: 29; placebo: 17). At week 16, bimekizumab-treated patients had a higher clinical response versus ustekinumab and placebo (PASI 90: 85.5% versus 51.7% and 5.9%; IGA 0/1: 82.3% versus 48.3% and 0.0%). Over 52 weeks, improved clinical response was maintained with bimekizumab, including patients switching from placebo at week 16. Overall, the safety profile in Japanese patients was consistent with that observed in the global population. CONCLUSION Bimekizumab resulted in improved clinical response versus ustekinumab and placebo, and was well-tolerated in Japanese patients. TRIAL REGISTRATION NCT03370133.
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Affiliation(s)
- Akihiko Asahina
- grid.411898.d0000 0001 0661 2073Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan
| | - Yukari Okubo
- grid.410793.80000 0001 0663 3325Department of Dermatology, Tokyo Medical University, Tokyo, Japan
| | - Akimichi Morita
- grid.260433.00000 0001 0728 1069Department of Geriatric and Environmental Dermatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Yayoi Tada
- grid.264706.10000 0000 9239 9995Department of Dermatology, Teikyo University School of Medicine, Tokyo, Japan
| | - Atsuyuki Igarashi
- grid.414992.3Department of Dermatology, NTT Medical Center Tokyo, Tokyo, Japan
| | - Richard G. Langley
- grid.55602.340000 0004 1936 8200Division of Clinical Dermatology and Cutaneous Science, Department of Medicine, Dalhousie University, Halifax, NS Canada
| | - Delphine Deherder
- grid.421932.f0000 0004 0605 7243UCB Pharma, Braine L’alleud, Belgium
| | - Mizuho Matano
- UCB Pharma, UCB Japan Co., Ltd, 8-17-1 Nishi-Shinjuku, Shinjuku-Ku, Tokyo, 160-0023, Japan.
| | - Veerle Vanvoorden
- grid.421932.f0000 0004 0605 7243UCB Pharma, Braine L’alleud, Belgium
| | | | - Mamitaro Ohtsuki
- grid.410804.90000000123090000Department of Dermatology, Jichi Medical University, Tochigi, Japan
| | - Hidemi Nakagawa
- grid.411898.d0000 0001 0661 2073Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan
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27
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Costache RS, Georgescu M, Ghilencea A, Feroiu O, Tiplica SG, Costache DO. The Role of Inflammation in the Pathogenesis of Psoriasis. ROMANIAN JOURNAL OF MILITARY MEDICINE 2023. [DOI: 10.55453/rjmm.2023.126.3.2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/06/2023]
Abstract
"Psoriasis is a chronic inflammatory skin condition with genetic determinism characterized by the presence of welldefined, erythematous plaques, covered by white, pearly, stratified scales, located on the extension areas, the skin of the scalp, intertriginous regions. The origin of psoriasis is multifactorial, involving hereditary and environmental pathogenic mechanisms. It is triggered by various risk factors involving a variety of processes, such as inflammation, antigen presentation, cell signaling, and transcriptional regulation. "
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Affiliation(s)
- Raluca S. Costache
- Discipline of Internal Medicine, Carol Davila University Central Emergency Military Hospital, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Mihaela Georgescu
- Dermatology Clinic, Carol Davila University Central Emergency Military Hospital, Bucharest, Romania
| | - Adelina Ghilencea
- Dermatology Clinic, Carol Davila University Central Emergency Military Hospital, Bucharest, Romania
| | - Oana Feroiu
- Dermatology Clinic, Carol Davila University Central Emergency Military Hospital, Bucharest, Romania
| | - Sorin G. Tiplica
- Discipline of Dermatology, Colentina Clinical Hospital & Carol Davila University Central Emergency Military Hospital, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Daniel O. Costache
- Discipline of Dermatology, Colentina Clinical Hospital & Carol Davila University Central Emergency Military Hospital, Faculty of Medicine, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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28
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Merola JF, Landewé R, McInnes IB, Mease PJ, Ritchlin CT, Tanaka Y, Asahina A, Behrens F, Gladman DD, Gossec L, Gottlieb AB, Thaçi D, Warren RB, Ink B, Assudani D, Bajracharya R, Shende V, Coarse J, Coates LC. Bimekizumab in patients with active psoriatic arthritis and previous inadequate response or intolerance to tumour necrosis factor-α inhibitors: a randomised, double-blind, placebo-controlled, phase 3 trial (BE COMPLETE). Lancet 2023; 401:38-48. [PMID: 36495881 DOI: 10.1016/s0140-6736(22)02303-0] [Citation(s) in RCA: 83] [Impact Index Per Article: 41.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/21/2022] [Accepted: 11/03/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F and IL-17A. This study compared the efficacy and safety of bimekizumab with placebo over 16 weeks in patients with active psoriatic arthritis and previous inadequate response or intolerance to tumour necrosis factor-α (TNFα) inhibitors. METHODS BE COMPLETE was a phase 3, multicentre, randomised, double-blind, placebo-controlled trial conducted across 92 sites (including hospitals, clinics, and research centres) in 11 countries (Australia, Canada, Czech Republic, Germany, Hungary, Italy, Japan, Poland, Russia, the UK, and the USA). Eligible patients were aged 18 years or older with adult-onset psoriatic arthritis (meeting the Classification Criteria for Psoriatic Arthritis for at least 6 months before screening) with a history of inadequate response or intolerance to treatment with one or two TNFα inhibitors for either psoriatic arthritis or psoriasis. We stratified patients with active psoriatic arthritis by region and previous TNFα inhibitor use. Patients were randomly assigned (2:1) to receive subcutaneous bimekizumab 160 mg every 4 weeks or placebo by an interactive-voice and web-response system on the basis of a predetermined randomisation schedule. The primary endpoint was the proportion of patients with 50% or greater improvement in American College of Rheumatology criteria (ACR50) at week 16 (non-responder imputation). Efficacy analyses were done in the randomised population. The safety analysis set comprised patients who received one or more doses of study treatment. This trial was registered at ClinicalTrials.gov, NCT03896581, and is completed. FINDINGS Between March 28, 2019, and Feb 14, 2022, 556 patients were screened and 400 patients were randomly assigned to bimekizumab 160 mg every 4 weeks (n=267) or placebo (n=133). The primary and all hierarchical secondary endpoints were met at week 16. 116 (43%) of 267 patients receiving bimekizumab reached ACR50, compared with nine (7%) of 133 patients receiving placebo (adjusted odds ratio [OR] 11·1 [95% CI 5·4-23·0], p<0·0001). 121 (69%) of 176 patients with psoriasis affecting at least 3% body surface area at baseline who received bimekizumab reached 90% or greater improvement in the Psoriasis Area and Severity Index (PASI90), compared with six (7%) of 88 patients who received placebo (adjusted OR 30·2 [12·4-73·9], p<0·0001). Treatment-emergent adverse events up to week 16 were reported in 108 (40%) of 267 patients receiving bimekizumab and 44 (33%) of 132 patients receiving placebo. There were no new safety signals and no deaths. INTERPRETATION Bimekizumab treatment led to superior improvements in joint and skin efficacy outcomes at week 16 compared with placebo in patients with psoriatic arthritis and inadequate response or intolerance to TNFα inhibitors. The safety profile of bimekizumab was consistent with previous phase 3 studies in patients with plaque psoriasis, and studies of IL-17A inhibitors. FUNDING UCB Pharma.
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Affiliation(s)
- Joseph F Merola
- Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA
| | - Robert Landewé
- Amsterdam Rheumatology and Clinical Immunology Center, Amsterdam, Netherlands; Zuyderland MC, Heerlen, Netherlands
| | - Iain B McInnes
- College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
| | - Philip J Mease
- Swedish Medical Center and Providence St Joseph Health and University of Washington, Seattle, WA, USA
| | | | - Yoshiya Tanaka
- The First Department of Internal Medicine, University of Occupational and Environmental Health, Japan, Kitakyushu, Japan
| | - Akihiko Asahina
- Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan
| | - Frank Behrens
- Division of Rheumatology, University Hospital and Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Goethe University, Frankfurt am Main, Germany
| | - Dafna D Gladman
- Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, University of Toronto, ON, Canada
| | - Laure Gossec
- Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France; Rheumatology Department, AP-HP, Pitié-Salpêtrière Hospital, Paris, France
| | - Alice B Gottlieb
- Department of Dermatology, The Icahn School of Medicine at Mt Sinai, New York, NY, USA
| | - Diamant Thaçi
- Institute and Comprehensive Center for Inflammation Medicine, University of Lübeck, Lübeck, Germany
| | - Richard B Warren
- Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester NIHR Biomedical Research Centre, University of Manchester, Manchester, UK
| | | | | | | | | | | | - Laura C Coates
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Diseases University of Oxford, Oxford, UK; Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, Oxford, UK
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29
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Non-invasive diagnosis of endometriosis: Immunologic and genetic markers. Clin Chim Acta 2023; 538:70-86. [PMID: 36375526 DOI: 10.1016/j.cca.2022.11.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 11/07/2022] [Accepted: 11/07/2022] [Indexed: 11/13/2022]
Abstract
Endometriosis, a benign gynecologic and chronic inflammatory disease, is defined by the presence of endometrial tissue outside the uterus characterized mainly by pelvic pain and infertility. Because endometriosis affects approximately 10% of females, it represents a significant socioeconomic burden worldwide having tremendous impact on daily quality of life. Accurate and prompt diagnosis is crucial for the management of this debilitating disorder. Unfortunately, diagnosis is typically delayed to lack of specific symptoms and readily accessible biomarkers. Although histopathologic examination remains the current gold standard, this approach is highly invasive and not applicable for early screening. Recent work has focused on the identification of reliable biomarkers including immunologic, ie, immune cells, antibodies and cytokines, as well as genetic and biochemical markers, ie, microRNAs, lncRNAs, circulating and mitochondrial nucleic acids, along with some hormones, glycoproteins and signaling molecules. Confirmatory research studies are, however, needed to more fully establish these markers in the diagnosis, progression and staging of these endometrial lesions.
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30
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Klint S, Feldwisch J, Gudmundsdotter L, Dillner Bergstedt K, Gunneriusson E, Höidén Guthenberg I, Wennborg A, Nyborg AC, Kamboj AP, Peloso PM, Bejker D, Frejd FY. Izokibep: Preclinical development and first-in-human study of a novel IL-17A neutralizing Affibody molecule in patients with plaque psoriasis. MAbs 2023; 15:2209920. [PMID: 37184136 PMCID: PMC10187109 DOI: 10.1080/19420862.2023.2209920] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 04/28/2023] [Indexed: 05/16/2023] Open
Abstract
Psoriasis, an immune-mediated inflammatory disease, affects nearly 125 million people globally. The interleukin (IL)-17A homodimer is a key driver of psoriasis and other autoimmune diseases, including psoriatic arthritis, axial spondyloarthritis, hidradenitis suppurativa, and uveitis. Treatment with monoclonal antibodies (mAbs) against IL-17A provides an improvement in the Psoriasis Area and Severity Index compared to conventional systemic agents. In this study, the AffibodyⓇ technology was used to identify and optimize a novel, small, biological molecule comprising three triple helical affinity domains, izokibep (previously ABY-035), for the inhibition of IL-17A signaling. Preclinical studies show that izokibep, a small 18.6 kDa IL-17 ligand trap comprising two IL-17A-specific Affibody domains and one albumin-binding domain, selectively inhibits human IL-17A in vitro and in vivo with superior potency and efficacy relative to anti-IL-17A mAbs. A Phase 1 first-in-human study was conducted to establish the safety, pharmacokinetics, and preliminary efficacy of izokibep, when administered intravenously and subcutaneously as single doses to healthy subjects, and as single intravenous and multiple subcutaneous doses to patients with psoriasis (NCT02690142; EudraCT No: 2015-004531-13). Izokibep was well tolerated with no meaningful safety concerns identified in healthy volunteers and patients with psoriasis. Rapid efficacy was seen in all psoriasis patients after one dose which further improved in patients receiving multiple doses. A therapeutic decrease in joint pain was also observed in a single patient with concurrent psoriatic arthritis. The study suggests that izokibep has the potential to safely treat IL17A-associated diseases such as psoriasis, psoriatic arthritis, axial spondyloarthritis, hidradenitis suppurativa, and uveitis.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | - Fredrik Y. Frejd
- Affibody AB, Solna, Sweden
- Department of Immunology, Genetics and Pathology, IGP, Uppsala University, Uppsala, Sweden
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Akhter S, Tasnim FM, Islam MN, Rauf A, Mitra S, Emran TB, Alhumaydhi FA, Khalil AA, Aljohani ASM, Al Abdulmonem W, Thiruvengadam M. Role of Th17 and IL-17 Cytokines on Inflammatory and Auto-immune Diseases. Curr Pharm Des 2023; 29:2078-2090. [PMID: 37670700 DOI: 10.2174/1381612829666230904150808] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 06/21/2023] [Accepted: 07/24/2023] [Indexed: 09/07/2023]
Abstract
BACKGROUND The IL-17 (interleukin 17) family consists of six structurally related pro-inflammatory cytokines, namely IL-17A to IL-17F. These cytokines have garnered significant scientific interest due to their pivotal role in the pathogenesis of various diseases. Notably, a specific subset of T-cells expresses IL-17 family members, highlighting their importance in immune responses against microbial infections. INTRODUCTION IL-17 cytokines play a critical role in host defense mechanisms by inducing cytokines and chemokines, recruiting neutrophils, modifying T-cell differentiation, and stimulating the production of antimicrobial proteins. Maintaining an appropriate balance of IL-17 is vital for overall health. However, dysregulated production of IL-17A and other members can lead to the pathogenesis of numerous inflammatory and autoimmune diseases. METHOD This review provides a comprehensive overview of the IL-17 family and its involvement in several inflammatory and autoimmune diseases. Relevant literature and research studies were analyzed to compile the data presented in this review. RESULTS IL-17 cytokines, particularly IL-17A, have been implicated in the development of various inflammatory and autoimmune disorders, including multiple sclerosis, Hashimoto's thyroiditis, systemic lupus erythematosus, pyoderma gangrenosum, autoimmune hepatic disorders, rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, osteoarthritis, and graft-versus-host disease. Understanding the role of IL-17 in these diseases is crucial for developing targeted therapeutic strategies. CONCLUSION The significant involvement of IL-17 cytokines in inflammatory and autoimmune diseases underscores their potential as therapeutic targets. Current treatments utilizing antibodies against IL-17 cytokines and IL-17RA receptors have shown promise in managing these conditions. This review consolidates the understanding of IL-17 family members and their roles, providing valuable insights for the development of novel immunomodulators to effectively treat inflammatory and autoimmune diseases.
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Affiliation(s)
- Saima Akhter
- Department of Pharmacy, International Islamic University Chittagong, Chittagong 4318, Bangladesh
| | - Farhin Muntaha Tasnim
- Department of Pharmacy, International Islamic University Chittagong, Chittagong 4318, Bangladesh
| | - Mohammad Nazmul Islam
- Department of Pharmacy, International Islamic University Chittagong, Chittagong 4318, Bangladesh
| | - Abdur Rauf
- Department of Chemistry, University of Swabi, Swabi, Pakistan
| | - Saikat Mitra
- Department of Pharmacy, Faculty of Pharmacy, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Talha Bin Emran
- Department of Pharmacy, BGC Trust University Bangladesh, Chittagong 4381, Bangladesh
| | - Fahad A Alhumaydhi
- Department of Medical Laboratories, College of Applied Medical Science, Qassim University, Buraydah, Saudi Arabia
| | - Anees Ahmed Khalil
- University Institute of Diet and Nutritionals Sciences, Faculty of Allied Health Sciences, The University of Lahore, Lahore, Pakistan
| | - Abdullah S M Aljohani
- Department of Veterinary Medicine, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Waleed Al Abdulmonem
- Department of Pathology, College of Medicine, Qassim University, Buraydah, Saudi Arabia
| | - Muthu Thiruvengadam
- Department of Crop Science, College of Sanghuh Life Science, Konkuk University, Seoul 05029, Republic of Korea
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Interleukin-17 Family Cytokines in Metabolic Disorders and Cancer. Genes (Basel) 2022; 13:genes13091643. [PMID: 36140808 PMCID: PMC9498678 DOI: 10.3390/genes13091643] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/04/2022] [Accepted: 09/07/2022] [Indexed: 02/07/2023] Open
Abstract
Interleukin-17 (IL-17) family cytokines are potent drivers of inflammatory responses. Although IL-17 was originally identified as a cytokine that induces protective effects against bacterial and fungal infections, IL-17 can also promote chronic inflammation in a number of autoimmune diseases. Research in the last decade has also elucidated critical roles of IL-17 during cancer development and treatment. Intriguingly, IL-17 seems to play a role in the risk of cancers that are associated with metabolic disorders. In this review, we summarize our current knowledge on the biochemical basis of IL-17 signaling, IL-17′s involvement in cancers and metabolic disorders, and postulate how IL-17 family cytokines may serve as a bridge between these two types of diseases.
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Critical role of m 6A modification in T-helper cell disorders. Mol Immunol 2022; 151:1-10. [PMID: 36058047 DOI: 10.1016/j.molimm.2022.08.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 08/08/2022] [Accepted: 08/24/2022] [Indexed: 11/20/2022]
Abstract
Diseases with T-helper cell subset imbalance involve multiple systems and organs. In addition to this, the pathogenesis of these diseases is always complex, and involves Th1, Th2, Th9, Th17, Th22, and Tfh cells. T-helper cell subset imbalance mediates immune responses to various pathogenic factors, by secreting specific cytokines. Although several studies have revealed the specific mechanisms of the occurrence and development of these diseases from different aspects, there is still a need for more comprehensive and in-depth studies that can compensate for the corresponding gaps in the diagnosis, targeted therapy, and prognosis of these diseases. N6-methyladenosine(m6A) modification is the most prevalent and abundant post-transcriptional modification in eukaryotic RNAs. In recent years, the critical role of m6A modification has been confirmed in multiple diseases with T-helper cell subset imbalance. m6A modification affects the immune cell development, inflammatory processes, biological behaviour of tumours, and immune response in these diseases. In this review, we focussed on how the enzymes involved in m6A modification, directly or indirectly, influence the pathogenesis and phenotype of various diseases with T-helper cell subset imbalance, and could therefore, serve as potential diagnostic markers and therapeutic targets for these diseases. In addition, this review also discusses the focus of future research in this area. Finally, we summarise the prospects of m6A modification in immunotherapy and chemotherapy.
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Necroptosis Plays a Crucial Role in Vascular Injury during DVT and Is Enhanced by IL-17B. J Immunol Res 2022; 2022:6909764. [PMID: 36046722 PMCID: PMC9424031 DOI: 10.1155/2022/6909764] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 07/16/2022] [Indexed: 12/16/2022] Open
Abstract
Background. This study investigated whether vascular endothelial necroptosis is involved in deep vein thrombosis (DVT) and how IL-17B facilitates necroptosis signaling. Methods. The DVT mouse model was induced by ligation of the IVC. The cross-sectional area of thrombus increases and the thrombus occupied the entire venous lumen at 48 h after ligation. Meanwhile, the increased expression of p-RIP3/RIP3 was most pronounced at 48 h after ligation, and the p-MLKL/MLKL peaked at 72 h. Results. Based on Illumina sequencing and KEGG pathway analyses, the activated RIP3/MLKL is associated with increased IL-17B. With thrombus formation, IL-17B was upregulated and enhanced the expression of RIP3 and MLKL in the IVC wall, as well as their phosphorylation levels (all
, the comparison group consisted of the control group, DVT group, DVT/IL-17B group, and DVT/anti-IL-17B group). The p-RIP3/RIP3 and p-MLKL/MLKL ratios were reduced by anti-IL-17B. Similarly, the weight and cross-sectional area of the thrombi were increased by IL-17B and decreased by the IL-17B antibody. IL-17B had a smaller effect on thrombosis in knockout mice compared with WT mice. In vitro, the IL-17B protein expression and the level of RIP3 and MLKL phosphorylation increased high in the OGD cells, accompanied by increased expression of IL-6 and TNF-α. IL-17B enhanced the expression of IL-6 and TNF-α but had little effect on the IL-6 and TNF-α after transfected with siRIP3 or siMLKL. Similarly, the plasma IL-17B, IL-6, and TNF-α were significantly increased after thrombosis in WT mice, and enhanced by IL-17B. But IL-17B did not increase the plasma IL-6 and TNF-α in knockout mice. Conclusions. In conclusion, those results suggest that vascular endothelial necroptosis plays a crucial role in vascular injury and IL-17B could enhance the necroptosis pathway.
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Tichy M, Kojanova M, Velackova B, Dolezal T, Gkalpatiotis S, Cetkovska P, Antal Z, Arenberger P, Bartonova J, Blahova L, Brodska P, Petr B, Buckova H, Cetkovsky M, Diamantova D, Duchkova H, Fialova J, Filipovska O, Gkalpakioti P, Grycova M, Horazdovsky J, Horka E, Hrazdirova K, Hrncir E, Hugo J, Janku J, Kopova R, Kovandova D, Lomicova I, Machackova R, Machovcova A, Malikova H, Matzenauer M, Necas M, Nemcova H, Neumannova R, Michaela N, Osmerova J, Pallova V, Pinkova B, Plzakova Z, Policarova M, Pospisil T, Filip R, Salavec M, Slonkova V, Smetanova A, Strouhalova I, Stuchlik D, Stumpfova A, Sevcik J, Sternbersky J, Stork J, Svarcova K, Tepla K, Tomkova H, Vantuchova Y, Vasku V, Vejrova I, Zampachova I. Efficacy of switches within the class of IL‐17 inhibitors: An analysis of data from the Czech nationwide registry of psoriatic patients receiving biological/targeted therapy (BIOREP). Dermatol Ther 2022; 35:e15772. [DOI: 10.1111/dth.15772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 07/13/2022] [Accepted: 08/15/2022] [Indexed: 11/28/2022]
Affiliation(s)
- Martin Tichy
- Department of Dermatology and Venereology, Faculty of Medicine and Dentistry Palacky University and University Hospital Olomouc Czech Republic
| | - Martina Kojanova
- Department of Dermatovenereology, First Faculty of Medicine and General University Hospital Charles University Prague Czech Republic
| | | | | | - Spyridon Gkalpatiotis
- Department of Dermatovenereology, Third Faculty of Medicine Charles University and Kralovske Vinohrady University Hospital Prague Czech Republic
| | - Petra Cetkovska
- Department of Dermatovenereology, Faculty of Medicine in Pilsen Charles University Czech Republic
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Norden A, Oulee A, Munawar L, Javadi SS, Han G, Wu JJ. Anti-drug antibodies of IL-17 inhibitors for psoriasis: a systematic review. J DERMATOL TREAT 2022; 33:3080-3085. [PMID: 35972196 DOI: 10.1080/09546634.2022.2114288] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
Biologics may elicit the production of anti-drug antibodies (ADAs), the clinical significance of which is not fully understood. ADA development in psoriasis patients on IL-17 inhibitors was evaluated by incidence, impact on efficacy, and relationship with adverse events. We systematically searched PubMed, Cochrane, and Embase databases, identifying 456 references. 17 studies met inclusion criteria. ADA incidence was: 0% to 5.5% (secukinumab), 11% to 19.4% (ixekizumab), 0% to 3.3% (brodalumab), and 19% to 39% (bimekizumab). Neutralizing antibody incidence was: 0% to 1.5% (secukinumab), 0% to 3.5% (ixekizumab), and 0% (brodalumab). ADA presence alone with secukinumab, ixekizumab, and bimekizumab did not impact drug efficacy. Brodalumab was the only one of the IL-17 inhibitors, which showed a reduction in efficacy in ADA + patients. In one analysis, high ADA titers to ixekizumab were associated with diminished treatment response. ADAs to secukinumab and bimekizumab were not associated with adverse events. There were limited data on ADAs and safety with ixekizumab or brodalumab. Overall, when monitoring patients on secukinumab, ADAs, titers, and the presence of neutralizing antibodies were not prognostic of outcomes. However, monitoring for ADAs with brodalumab and measuring titers with ixekizumab may be of value clinically.
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Affiliation(s)
- Alexandra Norden
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
| | - Aislyn Oulee
- University of California Riverside School of Medicine, Riverside, CA, USA
| | | | | | - George Han
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
| | - Jashin J Wu
- Department of Dermatology, University of Miami Miller School of Medicine
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Hari G, Kishore A, Karkala SRP. Treatments for psoriasis: A journey from classical to advanced therapies. How far have we reached? Eur J Pharmacol 2022; 929:175147. [PMID: 35820531 DOI: 10.1016/j.ejphar.2022.175147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 06/29/2022] [Accepted: 07/06/2022] [Indexed: 11/03/2022]
Abstract
Psoriasis is considered an autoimmune, inflammatory disorder with a genetic basis. The underlying aetiology is yet unclear. Evidence suggests the congregation of immune cells and their secreted inflammatory cytokines, leukocytes, and other inflammation-promoting factors in large amounts within the epidermal layers of the skin, driving an inflammatory milieu. Although psoriasis is not a fatal condition, patients experience severe pain and suffering. It has a debilitating effect on the physiological and psychological state of the patient. Its distinguishing features are inflammation, formation of plaques on the skin and hyperproliferation of keratinocytes. Therapeutic strategies for treating psoriasis witnessed a radical improvement from traditional therapies to the approval of specific therapies like biologics and small molecules. The emerging evidence about new pharmacological targets and mechanisms in psoriasis has widened the scope for expanding therapeutic strategies. Our review discusses the existing treatments for plaque psoriasis and updates on therapies based on novel pharmacological targets in clinical development.
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Affiliation(s)
- Gangadhar Hari
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Anoop Kishore
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Sreedhara Ranganath Pai Karkala
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
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Armstrong A, Fahrbach K, Leonardi C, Augustin M, Neupane B, Kazmierska P, Betts M, Freitag A, Kiri S, Taieb V, Slim M, Gomez NN, Warren RB. Efficacy of Bimekizumab and Other Biologics in Moderate to Severe Plaque Psoriasis: A Systematic Literature Review and a Network Meta-Analysis. Dermatol Ther (Heidelb) 2022; 12:1777-1792. [PMID: 35798920 PMCID: PMC9357587 DOI: 10.1007/s13555-022-00760-8] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 06/08/2022] [Indexed: 01/11/2023] Open
Abstract
INTRODUCTION Biologic treatments are increasingly being used in the management of moderate to severe plaque psoriasis (PSO). Bimekizumab is a selective inhibitor of both interleukin (IL)-17A and IL-17F approved for the treatment of moderate to severe PSO. Although bimekizumab trials provide comparisons to secukinumab, adalimumab and ustekinumab, there are no further head-to-head comparisons of bimekizumab to other biologics. This network meta-analysis (NMA) aimed to compare the short-term efficacy of bimekizumab versus other biologic systemic therapies for moderate to severe PSO. METHODS A systematic literature review was conducted to identify randomised controlled trials (RCTs) in patients with moderate to severe PSO. MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and the Database of Systematic Reviews and PsycINFO were searched on July 1, 2020. An enhanced multinomial Bayesian NMA model was used to evaluate the comparative efficacy in 50%, 75%, 90% and 100% improvement from baseline Psoriasis Area and Severity Index (PASI 50/75/90/100) at 10-16 weeks. The model was also adjusted for baseline risk, given the variable placebo responses across the trials. RESULTS Eighty-six RCTs (including 34,476 patients) were included in the NMA. IL-17 and IL-23 inhibitors were the most effective treatments across all PASI levels. At 10-16 weeks, bimekizumab had the highest probability of achieving PASI 75 (92.3%), PASI 90 (84.0%) and PASI 100 (57.8%). Bimekizumab demonstrated statistical superiority over all biologics in achieving PASI 90 and PASI 100 thresholds. For PASI 75, the benefit of bimekizumab was statistically significant compared to all other treatments except risankizumab and ixekizumab. CONCLUSION This analysis demonstrated that IL-17 and IL-23 inhibitors were highly effective in achieving short-term improvement among patients with moderate to severe PSO. Patients receiving bimekizumab were significantly more likely to achieve PASI 90 or PASI 100 within 10-16 weeks of the first injection than all other biologics.
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Affiliation(s)
- April Armstrong
- Keck School of Medicine of USC, Dermatology, Los Angeles, CA, USA
| | - Kyle Fahrbach
- Evidera, Inc, 140 Kendrick St, 3rd Floor, Needham, MA, 02494, USA.
| | - Craig Leonardi
- Central Dermatology and Saint Louis University School of Medicine, St. Louis, MO, USA
| | - Matthias Augustin
- Institute for Health Services Research in Dermatology and Nursing (IVDP), University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany
| | | | | | - Marissa Betts
- Evidera, Inc, 140 Kendrick St, 3rd Floor, Needham, MA, 02494, USA
| | | | | | | | - Mahmoud Slim
- Evidera (Evidence Synthesis), St-Laurent, Canada
| | | | - Richard B Warren
- Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester NIHR Biomedical Research Centre, The University of Manchester, Manchester, UK
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Shobeiri SS, Rezaee M, Pordel S, Haghnnavaz N, Dashti M, Moghadam M, Sankian M. Anti-IL-17A ssDNA aptamer ameliorated psoriasis skin lesions in the imiquimod-induced psoriasis mouse model. Int Immunopharmacol 2022; 110:108963. [PMID: 35724603 DOI: 10.1016/j.intimp.2022.108963] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 06/12/2022] [Accepted: 06/12/2022] [Indexed: 11/30/2022]
Abstract
OBJECTIVES IL-17 is an important player in the psoriasis pathogenesis, which recruits inflammatory cells to the psoriatic lesions, induced keratinocyte proliferation and plaque formation. Three monoclonal antibodies that block IL-17 have been approved for psoriasis treatment in the last decade. Compared to monoclonal antibodies, aptamers which are single-stranded DNA or RNA, bind with high affinity to proteins or other molecules and are more cost-effective. We previously showed that M2 and M7 anti-IL17A ssDNA aptamers could block IL-17 in vitro. The current study evaluated the therapeutic effects of M2 and M7 anti-IL17A ssDNA aptamers in the imiquimod (IMQ)-induced psoriasis mouse model. METHODS IMQ cream and Vaseline (Vas) were administered on the back skin of C57BL/6 mice as IMQ-induced psoriasis and Vas control groups, respectively. In addition, hydrogel-containing aptamers were topically administered on the back skin of the mice, 10 min before IMQ treatment. Psoriatic lesions were evaluated by histology, clinical factors, and psoriasis area severity index (PASI) score. The mRNA expression levels of inflammatory factors, including IL-17A, IL-1β, and S100a9, were assessed with quantitative reverse transcriptase-polymerase chain reaction in the mice back skin. RESULTS Application of anti-IL-17A aptamers significantly ameliorated IMQ-induced keratinocyte proliferation, psoriatic lesions cumulative PASI score, IL-17A, IL-β, and S100a9 inflammatory factors mRNA expression levels (p < 0.05). CONCLUSION According to our results, it seems that M2 in high concentration and M7 in low concentration can be appropriate candidates to alleviate psoriasis lesions.
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Affiliation(s)
- Saeideh Sadat Shobeiri
- Immunology Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - MohammadAli Rezaee
- Immunology Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Safoora Pordel
- Immunology Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Navideh Haghnnavaz
- Immunology Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammadreza Dashti
- Immunology Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Malihe Moghadam
- Immunology Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mojtaba Sankian
- Immunology Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Zhao P, Zhang J, Liu B, Tang Y, Wang L, Wang G, Wu H, Yang C, Li X, Li B. Causal Effects of Circulating Cytokines on the Risk of Psoriasis Vulgaris: A Mendelian Randomization Study. Front Genet 2022; 13:941961. [PMID: 35769988 PMCID: PMC9234291 DOI: 10.3389/fgene.2022.941961] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Accepted: 05/24/2022] [Indexed: 11/24/2022] Open
Abstract
Background: Psoriasis vulgaris is an inflammatory skin disease. Observational studies have shown associations between circulating cytokine levels and psoriasis vulgaris. But the causal relationship between circulating cytokine and psoriasis vulgaris remains elusive. Methods: To assess the causal effects of cytokine levels on the risk of psoriasis vulgaris and vice versa, we performed a two-sample Mendelian randomization (MR) study by using the inverse-variance weighted (IVW), weighted median, and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) in genome-wide association summary statistics of 41 circulating cytokines in up to 8,293 individuals and psoriasis vulgaris in 399,883 individuals. Results: We identified that increasing RANTES level induced an elevated risk of psoriasis vulgaris in IVW (β = 0.33, S.E. = 0.12, p = 0.006). This causal effect showed consistency across the weighted median (β = 0.35, S.E. = 0.15, p = 0.022) and MR-PRESSO method (β = 0.33, S.E. = 0.11, p = 0.028). Conclusions: Our results suggest a potential causal effect of elevated RANTES concentration on the increased risk of psoriasis vulgaris.
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Adverse Effect in Patients with Psoriasis Treated with Interleukin 17A Inhibitor- Secukinumab. SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2022. [DOI: 10.2478/sjecr-2022-0013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Abstract
Secukinumab is fully human monoclonal antibody, IgG-1κ, which selectively attaches to IL-17A and inhibits its effects, which subsequently leads to a decrease of local inflammatory markers. In 2015 it was approved for treatment of patients suffering from psoriasis. We can say that in comparison with other biologic medicine, such as IL-12/23 inhibitors and TNF-α inhibitors, the incidence rate of serious adverse effects related to use of secukinumab is notably lower. Serious adverse effects reported in relation to use of secukinumab were development of mucocutaneous candidiasis, neutropenia and development or aggravation of the inflammatory bowel disease conditions.
In this review study we focused on frequent adverse effects and adverse effects of special interest during the secukinumab therapy in treating psoriasis patients.
Available data on long-term safety and effects on comorbidities are relatively few. A more extensive and longer term research is needed, as well as critical reevaluation of the criteria for participation in clinical trials in order to obtain data which would be of relevance in clinical practice. A better understanding of adverse effects leads to an improved individual therapeutic approach, increases patient’s satisfaction and results in minimizing these effects.
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Sobolev VV, Denisova EV, Chebysheva SN, Geppe NA, Korsunskaya IM. IL-6 Gene Expression as a Marker of Pathological State in Psoriasis and Psoriatic Arthritis. Bull Exp Biol Med 2022; 173:77-80. [PMID: 35622251 DOI: 10.1007/s10517-022-05497-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Indexed: 11/28/2022]
Abstract
The expression of the IL-6 gene in mononuclear blood cells of 45 patients with psoriatic arthritis and 31 patients with plaque psoriasis was studied for possible differential diagnosis of the pathologies. The expression level of IL-6 in psoriatic arthritis and psoriasis surpassed that in healthy controls by 192 and 147 times, respectively. Significant differences in the gene expression were revealed between the patients with psoriatic arthritis and mild psoriasis. The level of IL-6 in patients with severe psoriasis approached that in patients with psoriatic arthritis. High level of IL-6 gene expression can be a marker of possible joint damage in patients with psoriasis and a signal for revising the therapeutic approach in a particular patient.
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Affiliation(s)
- V V Sobolev
- Center for Theoretical Problems of Physico-Chemical Pharmacology, Russian Academy of Sciences, Moscow, Russia.
| | - E V Denisova
- Center for Theoretical Problems of Physico-Chemical Pharmacology, Russian Academy of Sciences, Moscow, Russia.,Moscow Scientific and Practical Center of Dermatovenereology and Cosmetology, Moscow, Russia
| | - S N Chebysheva
- Department of Children's Diseases, N. F. Filatov Clinical Institute of Children's Health, I. M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia
| | - N A Geppe
- Department of Children's Diseases, N. F. Filatov Clinical Institute of Children's Health, I. M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia
| | - I M Korsunskaya
- Center for Theoretical Problems of Physico-Chemical Pharmacology, Russian Academy of Sciences, Moscow, Russia.,Moscow Scientific and Practical Center of Dermatovenereology and Cosmetology, Moscow, Russia
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43
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Wang Y, Zang J, Liu C, Yan Z, Shi D. Interleukin-17 Links Inflammatory Cross-Talks Between Comorbid Psoriasis and Atherosclerosis. Front Immunol 2022; 13:835671. [PMID: 35514987 PMCID: PMC9063001 DOI: 10.3389/fimmu.2022.835671] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 03/23/2022] [Indexed: 11/13/2022] Open
Abstract
Psoriasis is a chronic, systemic, immune-mediated inflammatory disorder that is associated with a significantly increased risk of cardiovascular disease (CVD). Studies have shown that psoriasis often coexists with atherosclerosis, a chronic inflammatory disease of large and medium-sized arteries, which is a major cause of CVD. Although the molecular mechanisms underlying this comorbidity are not fully understood, clinical studies have shown that when interleukin (IL)-17A inhibitors effectively improve psoriatic lesions, atherosclerotic symptoms are also ameliorated in patients with both psoriasis and atherosclerosis. Also, IL-17A levels are highly expressed in the psoriatic lesions and atherosclerotic plaques. These clinical observations implicit that IL-17A could be a crucial link for psoriasis and atherosclerosis and IL-17A-induced inflammatory responses are the major contribution to the pathogenesis of comorbid psoriasis and atherosclerosis. In this review, the current literature related to epidemiology, genetic predisposition, and inflammatory mechanisms of comorbidity of psoriasis and atherosclerosis is summarized. We focus on the immunopathological effects of IL-17A in both diseases. The goal of this review is to provide the theoretical base for future preventing or treating psoriasis patients with atherosclerosis comorbidity. The current evidence support the notion that treatments targeting IL-17 seem to be hold some promise to reduce cardiovascular risk in patients with psoriasis.
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Affiliation(s)
- Yan Wang
- College of Clinical Medicine, Jining Medical University, Jining, China
| | - Jinxin Zang
- Department of Neurology, Jining No.1 People's Hospital, Jining, China
| | - Chen Liu
- Laboratory of Medical Mycology, Jining No.1 People's Hospital, Jining, China
| | - Zhongrui Yan
- Department of Neurology, Jining No.1 People's Hospital, Jining, China
| | - Dongmei Shi
- Laboratory of Medical Mycology, Jining No.1 People's Hospital, Jining, China.,Department of Dermatology, Jining No.1 People's Hospital, Jining, China
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Moeinafshar A, Razi S, Rezaei N. Interleukin 17, the double-edged sword in atherosclerosis. Immunobiology 2022; 227:152220. [PMID: 35452921 DOI: 10.1016/j.imbio.2022.152220] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 04/07/2022] [Accepted: 04/14/2022] [Indexed: 11/05/2022]
Abstract
Cardiovascular diseases, including atherosclerosis, are the number one cause of death worldwide. These diseases have taken the place of pneumonia and other infectious diseases in the epidemiological charts. Thus, their importance should not be underestimated. Atherosclerosis is an inflammatory disease. Therefore, immunological signaling molecules and immune cells carry out a central role in its etiology. One of these signaling molecules is interleukin (IL)-17. This relatively newly discovered signaling molecule might have a dual role as acting both pro-atherogenic and anti-atherogenic depending on the situation. The majority of articles have discussed IL-17 and its action in atherosclerosis, and it may be a new target for the treatment of patients with this disease. In this review, the immunological basis of atherosclerosis with an emphasis on the role of IL-17 and a brief explanation of the role of IL-17 on atherosclerogenic disorders will be discussed.
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Affiliation(s)
- Aysan Moeinafshar
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Sepideh Razi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran; School of Medicine, Iran University of Medical Sciences, Tehran, Iran; Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Nima Rezaei
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
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45
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Zhong H, Sun X. Contribution of Interleukin-17A to Retinal Degenerative Diseases. Front Immunol 2022; 13:847937. [PMID: 35392087 PMCID: PMC8980477 DOI: 10.3389/fimmu.2022.847937] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2022] [Accepted: 02/25/2022] [Indexed: 12/26/2022] Open
Abstract
Retinal degenerative diseases are a leading cause of vision loss and blindness throughout the world, characterized by chronic and progressive loss of neurons and/or myelin. One of the common features of retinal degenerative diseases and central neurodegenerative diseases is chronic neuroinflammation. Interleukin-17A (IL-17A) is the cytokine most closely related to disease in its family. Accumulating evidence suggests that IL-17A plays a key role in human retinal degenerative diseases, including age-related macular degeneration, diabetic retinopathy and glaucoma. This review aims to provide an overview of the role of IL-17A participating in the pathogenesis of retinal degenerative diseases, which may open new avenues for potential therapeutic interventions.
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Affiliation(s)
- Huimin Zhong
- Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,National Clinical Research Center for Eye Diseases, Shanghai, China.,Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China.,Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China.,Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
| | - Xiaodong Sun
- Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.,National Clinical Research Center for Eye Diseases, Shanghai, China.,Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China.,Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China.,Shanghai Engineering Center for Precise Diagnosis and Treatment of Eye Diseases, Shanghai, China
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Mohd Noor AA, Azlan M, Mohd Redzwan N. Orchestrated Cytokines Mediated by Biologics in Psoriasis and Its Mechanisms of Action. Biomedicines 2022; 10:biomedicines10020498. [PMID: 35203707 PMCID: PMC8962336 DOI: 10.3390/biomedicines10020498] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 02/12/2022] [Accepted: 02/14/2022] [Indexed: 12/27/2022] Open
Abstract
Psoriasis is an autoimmune disease mediated by disturbed T cells and other immune cells, and is defined by deep-red, well-demarcated skin lesions. Due to its varied etiologies and indefinite standard pathogenesis, it is challenging to consider the right treatment exclusively for each psoriasis patient; thus, researchers yearn to seek even more precise treatments other than topical treatment and systemic therapy. Using biologics to target specific immune components, such as upregulated cytokines secreted by activated immune cells, is the most advanced therapy for psoriasis to date. By inhibiting the appropriate pro-inflammatory cytokines, cellular signaling can be altered and, thus, can inhibit further downstream inflammatory pathways. Herein, the roles of cytokines with their mechanisms of action in progressing psoriasis and how the usage of biologics alleviates cellular inflammation are discussed. In addition, other potential pro-inflammatory cytokines, with their mechanism of action, are presented herein. The authors hope that this gathered information may benefit future research in expanding the discovery of targeted psoriasis therapy.
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Affiliation(s)
- Aina Akmal Mohd Noor
- Immunology Department, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia;
| | - Maryam Azlan
- School of Health Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia;
| | - Norhanani Mohd Redzwan
- Immunology Department, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia;
- Correspondence: ; Tel.: +60-9767-6130
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Zhang N, Qian T, Sun S, Cao W, Wang Z, Liu D, Li P, Wu J, Li H, Yang J. IL-17 is a Potential Therapeutic Target in a Rodent Model of Otitis Media with Effusion. J Inflamm Res 2022; 15:635-648. [PMID: 35140496 PMCID: PMC8818970 DOI: 10.2147/jir.s338598] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Accepted: 01/21/2022] [Indexed: 11/23/2022] Open
Abstract
Background Otitis media with effusion (OME) is a non-suppurative inflammation of the middle ear that is characterized by middle ear effusion and hearing loss. However, the mechanisms of OME are not fully understood. The aim of this study was to determine the function and the mechanism of the IL-17 cytokine in the pathogenesis of OME and to investigate IL-17 as a potential strategy for the treatment of OME. Methods In this study, the OME rat model was induced by ovalbumin (OVA) as previously described. The severity of OME was determined with an oto-endoscope, by histochemical analysis, and by acoustic immittance. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of RNA-sequencing (RNA-seq) data was carried out to analyze the signaling pathways related to the pathogenesis of OME, which indicated that IL-17 is involved in OME. The anti-IL-17A monoclonal antibody was administrated by nasal drip to block IL-17 to treat OME in the rat model. The rats were finally injected intraperitoneally with the inhibitor of Notch signaling pathway to study the mechanisms of IL-17-induced inflammation. Serum and lavage fluid were collected for the detection of related cytokines, and middle ear tissue was collected for Western blot, quantitative real-time PCR (qRT-PCR), and immunohistochemical and immunofluorescence analysis. Results KEGG analysis of RNA-seq data suggested that the IL-17 signaling pathway might be involved in the onset of OME. IL-17 expression was confirmed to be increased in both the serum and the middle ear of the rat model. The monoclonal antibody against IL-17 neutralized IL-17, inhibited the inflammation in the middle ear, and reduced the overall severity of OME in vivo. Furthermore, the Notch signaling pathway was activated upon IL-17 upregulation in OME and was suppressed by IL-17 blockage. However, there was no change in IL-17 expression after Notch inhibitor treatment, which reduced the severity of OME in the rat middle ear. Conclusion IL-17 plays a key role in the pathogenesis of the OVA-induced OME rat model. IL-17 induced inflammatory responses via the Notch signaling pathway and targeting IL-17 might be an effective approach for OME therapy.
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Affiliation(s)
- Nanfeng Zhang
- Department of ENT, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230031, People’s Republic of China
| | - Tingting Qian
- Department of ENT Institute and Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, NHC Key Laboratory of Hearing Medicine Research, Fudan University, Shanghai, 200032, People’s Republic of China
| | - Shan Sun
- Department of ENT Institute and Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, NHC Key Laboratory of Hearing Medicine Research, Fudan University, Shanghai, 200032, People’s Republic of China
| | - Wei Cao
- Department of ENT, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230031, People’s Republic of China
| | - Zhixian Wang
- Department of ENT, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230031, People’s Republic of China
| | - Danling Liu
- Department of ENT Institute and Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, NHC Key Laboratory of Hearing Medicine Research, Fudan University, Shanghai, 200032, People’s Republic of China
| | - Peifan Li
- Department of ENT Institute and Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, NHC Key Laboratory of Hearing Medicine Research, Fudan University, Shanghai, 200032, People’s Republic of China
| | - Jingfang Wu
- Department of ENT Institute and Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, NHC Key Laboratory of Hearing Medicine Research, Fudan University, Shanghai, 200032, People’s Republic of China
| | - Huawei Li
- Department of ENT, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230031, People’s Republic of China
- Department of ENT Institute and Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology, NHC Key Laboratory of Hearing Medicine Research, Fudan University, Shanghai, 200032, People’s Republic of China
| | - Jianming Yang
- Department of ENT, Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230031, People’s Republic of China
- Correspondence: Jianming Yang; Huawei Li, Email ;
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Bolt JW, van Kuijk AW, Teunissen MBM, van der Coelen D, Aarrass S, Gerlag DM, Tak PP, van de Sande MG, Lebre MC, van Baarsen LGM. Impact of Adalimumab Treatment on Interleukin-17 and Interleukin-17 Receptor Expression in Skin and Synovium of Psoriatic Arthritis Patients with Mild Psoriasis. Biomedicines 2022; 10:biomedicines10020324. [PMID: 35203534 PMCID: PMC8869729 DOI: 10.3390/biomedicines10020324] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 01/19/2022] [Accepted: 01/24/2022] [Indexed: 02/04/2023] Open
Abstract
Interleukin (IL)-17 and tumor necrosis factor-alpha (TNF)-α are key players in psoriatic arthritis (PsA) pathogenesis. While both cytokines can be therapeutically targeted with beneficial clinical outcome, it is unclear whether inhibiting one cytokine will affect the other at sites of inflammation. If both act independently, this might provide a rationale for dual or combined inhibition of both cytokines. Here, we evaluated the effect of TNF blockade in PsA patients on IL-17 levels in both skin and synovial tissue biopsies. PsA patients with mild psoriatic skin lesions were randomized to receive either adalimumab or placebo for four weeks. Synovial and skin biopsies were obtained at weeks zero and four. Skin from healthy donors (HDs) was used for comparison. Expression of IL-17A, IL-17F, IL-17RA and IL-17RC was assessed by immunohistochemistry and analyzed with digital image analysis. We found relatively low levels of IL-17 and its receptors in the skin of PsA patients compared to HD, and only IL-17F in the dermis of lesional psoriatic skin was significantly higher compared to HD skin (p = 0.0002). Histologically IL-17A, IL-17F, IL-17RA and IL-17RC in skin and synovial tissue were not downregulated by adalimumab treatment. Thus, in this cohort of PsA patients with mild psoriasis, TNF blockade did not affect the protein levels of IL-17 cytokines and its receptors in skin and synovium, despite reduced cellular inflammation and improved clinical outcome for joint involvement.
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Affiliation(s)
- Janne W. Bolt
- Department of Rheumatology and Clinical Immunology, Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (J.W.B.); (D.v.d.C.); (S.A.); (D.M.G.); (P.P.T.); (M.G.v.d.S.)
- Department of Rheumatology, Amsterdam Rheumatology & Immunology Center (ARC)-Reade, 1040 HG Amsterdam, The Netherlands;
| | - Arno W. van Kuijk
- Department of Rheumatology, Amsterdam Rheumatology & Immunology Center (ARC)-Reade, 1040 HG Amsterdam, The Netherlands;
- Department of Rheumatology, Reade, 1056 AB Amsterdam, The Netherlands
| | - Marcel B. M. Teunissen
- Department of Dermatology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands;
| | - Dennis van der Coelen
- Department of Rheumatology and Clinical Immunology, Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (J.W.B.); (D.v.d.C.); (S.A.); (D.M.G.); (P.P.T.); (M.G.v.d.S.)
- Department of Rheumatology, Amsterdam Rheumatology & Immunology Center (ARC)-Reade, 1040 HG Amsterdam, The Netherlands;
| | - Saïda Aarrass
- Department of Rheumatology and Clinical Immunology, Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (J.W.B.); (D.v.d.C.); (S.A.); (D.M.G.); (P.P.T.); (M.G.v.d.S.)
- Department of Rheumatology, Amsterdam Rheumatology & Immunology Center (ARC)-Reade, 1040 HG Amsterdam, The Netherlands;
| | - Daniëlle M. Gerlag
- Department of Rheumatology and Clinical Immunology, Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (J.W.B.); (D.v.d.C.); (S.A.); (D.M.G.); (P.P.T.); (M.G.v.d.S.)
- Department of Rheumatology, Amsterdam Rheumatology & Immunology Center (ARC)-Reade, 1040 HG Amsterdam, The Netherlands;
| | - Paul P. Tak
- Department of Rheumatology and Clinical Immunology, Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (J.W.B.); (D.v.d.C.); (S.A.); (D.M.G.); (P.P.T.); (M.G.v.d.S.)
- Department of Rheumatology, Amsterdam Rheumatology & Immunology Center (ARC)-Reade, 1040 HG Amsterdam, The Netherlands;
- Candel Therapeutics, Needham, MA 02494, USA
- Internal Medicine, Cambridge University, Cambridge CB2 1TN, UK
| | - Marleen G. van de Sande
- Department of Rheumatology and Clinical Immunology, Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (J.W.B.); (D.v.d.C.); (S.A.); (D.M.G.); (P.P.T.); (M.G.v.d.S.)
- Department of Rheumatology, Amsterdam Rheumatology & Immunology Center (ARC)-Reade, 1040 HG Amsterdam, The Netherlands;
| | - Maria C. Lebre
- The Netherlands Cancer Institute, Division of Pharmacology, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands;
| | - Lisa G. M. van Baarsen
- Department of Rheumatology and Clinical Immunology, Amsterdam Rheumatology & Immunology Center (ARC), Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands; (J.W.B.); (D.v.d.C.); (S.A.); (D.M.G.); (P.P.T.); (M.G.v.d.S.)
- Department of Rheumatology, Amsterdam Rheumatology & Immunology Center (ARC)-Reade, 1040 HG Amsterdam, The Netherlands;
- Correspondence:
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Khalid HN, Elghobashy YAE, Elsayed AN. GNLY Gene Polymorphism: A Potential Role in Understanding Psoriasis Pathogenesis. J Cosmet Dermatol 2022; 21:4805-4809. [DOI: 10.1111/jocd.14792] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2021] [Revised: 10/28/2021] [Accepted: 01/11/2022] [Indexed: 11/30/2022]
Affiliation(s)
- Hesham Nabil Khalid
- Dermatology Andrology & STDs department Faculty of Medicine Menoufia University Menoufia Egypt
| | | | - Asmaa Nagy Elsayed
- Resident of Dermatology Andrology &STDs at Ministry of Health Al‐Mahala El‐Kobra Al‐Gharbia Egypt
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Kutwin M, Migdalska-Sęk M, Brzeziańska-Lasota E, Zelga P, Woźniacka A. An Analysis of IL-10, IL-17A, IL-17RA, IL-23A and IL-23R Expression and Their Correlation with Clinical Course in Patients with Psoriasis. J Clin Med 2021; 10:5834. [PMID: 34945130 PMCID: PMC8704681 DOI: 10.3390/jcm10245834] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 12/05/2021] [Accepted: 12/10/2021] [Indexed: 12/19/2022] Open
Abstract
Being one of the most common dermatological inflammatory disorders, psoriasis is a frequent subject of research. It is considered to be a T cell-dependent immune disease whose pathogenesis is influenced by cytokines, such as IL-10, IL-17A, IL-17RA, IL-23A and IL-23R. The present study examines whether the expression of selected genes is correlated with the clinical course of psoriasis, assessed by the PASI, BSA and DLQI scales. Skin biopsies and blood from 60 patients with psoriasis and 24 healthy controls were obtained for RNA isolation. These were subjected to RT-PCR for IL-10, IL-17A, IL-17RA, IL-23A and IL-23R genes. The results were presented as an RQ value. IL-17A and IL-23R expression levels were higher in psoriatic skin compared to controls, while IL-10 expression was lower. A positive correlation was also found between RQ for IL-23A and PASI index. Psoriatic skin is characterised by elevated expression of IL-17A and IL-23R and decreased expression of IL-10. This indicates that the selected cytokines may be one of the factors involved in the pathogenesis and pathomechanism of psoriasis, but more studies need to be made before we can elucidate the exact reason for the unbalance in cytokine expression levels.
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Affiliation(s)
- Magdalena Kutwin
- Department of Dermatology and Venereology, Medical University of Lodz, 90-647 Lodz, Poland;
| | - Monika Migdalska-Sęk
- Department of Biomedicine and Genetics, Medical University of Lodz, 92-213 Lodz, Poland; (M.M.-S.); (E.B.-L.)
| | - Ewa Brzeziańska-Lasota
- Department of Biomedicine and Genetics, Medical University of Lodz, 92-213 Lodz, Poland; (M.M.-S.); (E.B.-L.)
| | - Piotr Zelga
- Department of Surgery, University of Cambridge, Cambridge CB2 0QQ, UK;
| | - Anna Woźniacka
- Department of Dermatology and Venereology, Medical University of Lodz, 90-647 Lodz, Poland;
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