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Yang J, Zhu J, Lu S, Qin H, Zhou W. Transdermal psoriasis treatment inspired by tumor microenvironment-mediated immunomodulation and advanced by exosomal engineering. J Control Release 2025; 382:113664. [PMID: 40147535 DOI: 10.1016/j.jconrel.2025.113664] [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: 11/10/2024] [Revised: 03/03/2025] [Accepted: 03/24/2025] [Indexed: 03/29/2025]
Abstract
Psoriasis, characterized by aberrant T cell activation and epidermal hyperplasia, lacks safe and effective localized transdermal treatments. Drawing on the divergent pathologies of psoriasis and malignancies, we explored whether immunosuppressive mechanisms from the tumor microenvironment could be repurposed for psoriasis therapy. Utilizing B16-F10 melanoma cells as a model, we found that topical application of inactivated melanoma tissue homogenate alleviated psoriatic lesions in mice, primarily mediated by melanoma-derived exosomes. These exosomes exert therapeutic effects by modulating IL-17 signaling through miRNAs, effectively reducing T cell activation and proliferation. We discovered key miRNAs, mmu-miR-320-3p and mmu-miR-126-5p, that target IL-17a. Additionally, we demonstrated that these exosomes, enriched with RhoA protein, enhance transcytosis across epidermal barriers. Based on these insights, we developed 'ExoLipo,' a biomimetic exosomal formulation incorporating RhoA and loaded with mmu-miR-320-3p, inheriting the native exosomes' transdermal and immunomodulatory capacities. This formulation exhibited significant preventive and therapeutic effects on psoriasis mice models with an excellent safety profile. Our findings highlight the potential of repurposing tumor-derived immunosuppressive strategies for inflammatory diseases and offer a groundbreaking approach for managing psoriasis.
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Affiliation(s)
- Jieru Yang
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China
| | - Jiaojiao Zhu
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China
| | - Shan Lu
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China
| | - Hong Qin
- Hunan BeautySci Biotech Co., Ltd., Hunan Province, China
| | - Wenhu Zhou
- Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410013, China; Key Laboratory of Biological Nanotechnology of National Health Commission, Changsha City 410008, Hunan Province, China; Hunan BeautySci Biotech Co., Ltd., Hunan Province, China; Hunan Key Laboratory of The Research and Development of Novel Pharmaceutical Preparations, School of Pharmaceutical Science, Changsha Medical University, Changsha 410219, China.
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Bilal H, Khan MN, Khan S, Fang W, Chang W, Yin B, Song NJ, Liu Z, Zhang D, Yao F, Wang X, Wang Q, Cai L, Hou B, Wang J, Mao C, Liu L, Zeng Y. Risk of candidiasis associated with interleukin-17 inhibitors: Implications and management. Mycology 2023; 15:30-44. [PMID: 38558839 PMCID: PMC10977001 DOI: 10.1080/21501203.2023.2265664] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Accepted: 09/27/2023] [Indexed: 04/04/2024] Open
Abstract
The application of interleukin-17 (IL-17) inhibitors, including secukinumab, ixekizumab, brodalumab, and bimekizumab, are associated with elevated risk of candidiasis. These medications interfere with the IL-17 pathway, which is essential for maintaining mucosal barriers and coordinating the immune response against Candida species. The observational data and clinical trials demonstrate the increased incidence of candidiasis in individuals treated with IL-17 inhibitors. Brodalumab and bimekizumab pose a greater risk than secukinumab in eliciting candidiasis, whereas the data regarding ixekizumab are equivocal. Higher doses and prolonged treatment duration of IL-17 inhibitors increase the risk of candidiasis by compromising the immune response against Candida species. Prior to prescribing IL-17 inhibitors, healthcare professionals should comprehensively evaluate patients' medical histories and assess their risk factors. Patients should be educated on the signs and symptoms of candidiasis to facilitate early detection and intervention. Future research should focus on identifying the risk factors associated with candidiasis in patients receiving IL-17 inhibitors. Prospective studies and long-term surveillance are required to explore the impact of specific inhibitors on the incidence and severity of candidiasis and to evaluate the effectiveness of combination therapies, such as concurrent use of IL-17 inhibitors and prophylactic antifungal agents.
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Affiliation(s)
- Hazrat Bilal
- Department of Dermatology, Second Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Muhammad Nadeem Khan
- Faculty of Biological Sciences, Department of Microbiology, Quaid-I-Azam University, Islamabad, Pakistan
| | - Sabir Khan
- Department of Dermatology, Second Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Wenjie Fang
- Department of Dermatology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Wenqiang Chang
- School of Pharmacy, Shandong University, Qingdao, Shandong, China
| | - Bin Yin
- Department of Dermatovenereology, Chengdu Second People's Hospital, Chengdu, China
| | - Ning-Jing Song
- Department of Dermatology, Tongren Hospital, Shanghai Jiao Tong University, Shanghai, China
| | - Zhongrong Liu
- Department of Dermatology, First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Dongxing Zhang
- Department of Dermatology, Meizhou Dongshan Hospital, Meizhou, Guangdong, China
- Department of Dermatology, Meizhou People's Hospital, Meizhou, Guangdong, China
| | - Fen Yao
- Department of Pharmacy, Shantou University School Medical College, Shantou, China
| | - Xun Wang
- Department of Dermatology, Second Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Qian Wang
- Department of Dermatology, Second Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Lin Cai
- Department of Dermatology, Second Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Bing Hou
- Department of Clinical Laboratory, Skin and Venereal Diseases Prevention and Control Hospital of Shantou City, Shantou, Guangdong, China
| | - Jiayue Wang
- Department of Dermatology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Chunyan Mao
- Department of Dermatology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Lingxi Liu
- Department of Dermatology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yuebin Zeng
- Department of Dermatology, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China
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Roy T, Boateng ST, Uddin MB, Banang-Mbeumi S, Yadav RK, Bock CR, Folahan JT, Siwe-Noundou X, Walker AL, King JA, Buerger C, Huang S, Chamcheu JC. The PI3K-Akt-mTOR and Associated Signaling Pathways as Molecular Drivers of Immune-Mediated Inflammatory Skin Diseases: Update on Therapeutic Strategy Using Natural and Synthetic Compounds. Cells 2023; 12:1671. [PMID: 37371141 PMCID: PMC10297376 DOI: 10.3390/cells12121671] [Citation(s) in RCA: 33] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 06/10/2023] [Accepted: 06/12/2023] [Indexed: 06/29/2023] Open
Abstract
The dysregulated phosphatidylinositol-3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling pathway has been implicated in various immune-mediated inflammatory and hyperproliferative dermatoses such as acne, atopic dermatitis, alopecia, psoriasis, wounds, and vitiligo, and is associated with poor treatment outcomes. Improved comprehension of the consequences of the dysregulated PI3K/Akt/mTOR pathway in patients with inflammatory dermatoses has resulted in the development of novel therapeutic approaches. Nonetheless, more studies are necessary to validate the regulatory role of this pathway and to create more effective preventive and treatment methods for a wide range of inflammatory skin diseases. Several studies have revealed that certain natural products and synthetic compounds can obstruct the expression/activity of PI3K/Akt/mTOR, underscoring their potential in managing common and persistent skin inflammatory disorders. This review summarizes recent advances in understanding the role of the activated PI3K/Akt/mTOR pathway and associated components in immune-mediated inflammatory dermatoses and discusses the potential of bioactive natural products, synthetic scaffolds, and biologic agents in their prevention and treatment. However, further research is necessary to validate the regulatory role of this pathway and develop more effective therapies for inflammatory skin disorders.
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Affiliation(s)
- Tithi Roy
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209, USA; (T.R.); (S.T.B.); (S.B.-M.); (R.K.Y.); (C.R.B.); (J.T.F.); (A.L.W.)
| | - Samuel T. Boateng
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209, USA; (T.R.); (S.T.B.); (S.B.-M.); (R.K.Y.); (C.R.B.); (J.T.F.); (A.L.W.)
| | - Mohammad B. Uddin
- Department of Toxicology and Cancer Biology, Center for Research on Environmental Diseases, College of Medicine, University of Kentucky, Lexington, KY 40536, USA;
| | - Sergette Banang-Mbeumi
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209, USA; (T.R.); (S.T.B.); (S.B.-M.); (R.K.Y.); (C.R.B.); (J.T.F.); (A.L.W.)
- Division for Research and Innovation, POHOFI Inc., Madison, WI 53744, USA
- School of Nursing and Allied Health Sciences, Louisiana Delta Community College, Monroe, LA 71203, USA
| | - Rajesh K. Yadav
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209, USA; (T.R.); (S.T.B.); (S.B.-M.); (R.K.Y.); (C.R.B.); (J.T.F.); (A.L.W.)
| | - Chelsea R. Bock
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209, USA; (T.R.); (S.T.B.); (S.B.-M.); (R.K.Y.); (C.R.B.); (J.T.F.); (A.L.W.)
| | - Joy T. Folahan
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209, USA; (T.R.); (S.T.B.); (S.B.-M.); (R.K.Y.); (C.R.B.); (J.T.F.); (A.L.W.)
| | - Xavier Siwe-Noundou
- Department of Pharmaceutical Sciences, School of Pharmacy, Sefako Makgatho Health Sciences University, P.O. Box 218, Pretoria 0208, South Africa;
| | - Anthony L. Walker
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209, USA; (T.R.); (S.T.B.); (S.B.-M.); (R.K.Y.); (C.R.B.); (J.T.F.); (A.L.W.)
| | - Judy A. King
- Department of Pathology and Translational Pathobiology, LSU Health Shreveport, 1501 Kings Highway, Shreveport, LA 71103, USA;
- College of Medicine, Belmont University, 900 Belmont Boulevard, Nashville, TN 37212, USA
| | - Claudia Buerger
- Department of Dermatology, Venerology and Allergology, Clinic of the Goethe University, 60590 Frankfurt am Main, Germany;
| | - Shile Huang
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA;
- Department of Hematology and Oncology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA
- Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA
| | - Jean Christopher Chamcheu
- School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209, USA; (T.R.); (S.T.B.); (S.B.-M.); (R.K.Y.); (C.R.B.); (J.T.F.); (A.L.W.)
- Department of Pathology and Translational Pathobiology, LSU Health Shreveport, 1501 Kings Highway, Shreveport, LA 71103, USA;
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Muacevic A, Adler JR, Alhowaish AK, Alshammari WS. Erythema Dyschromicum Perstans After Adalimumab Treatment. Cureus 2022; 14:e32264. [PMID: 36620779 PMCID: PMC9815781 DOI: 10.7759/cureus.32264] [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] [Accepted: 12/06/2022] [Indexed: 12/12/2022] Open
Abstract
Tumor necrosis factor (TNF) is a cytokine that regulates immunity by binding to the cytokine receptor (TNFR), which has a role in treating inflammatory, neoplastic, and autoimmune diseases. Medications, including etanercept, infliximab, and adalimumab, are examples of TNF-alpha blockers. Adalimumab is a fully human immunoglobulin monoclonal antibody approved for use in the treatment of psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease, and hidradenitis suppurativa according to the American College of Rheumatology. However, there are few reports of cases where its administration was associated with skin reactions. In the present paper, we report a case of a psoriatic male patient who developed a cutaneous reaction of the face following treatment with adalimumab.
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Kojanova M, Hugo J, Velackova B, Cetkovska P, Fialova J, Dolezal T, Tichy M, Gkalpakiotis S. Efficacy, safety, and drug survival of patients with psoriasis treated with IL-17 inhibitors – brodalumab, ixekizumab, and secukinumab: real-world data from the Czech Republic BIOREP registry. J DERMATOL TREAT 2022; 33:2827-2837. [DOI: 10.1080/09546634.2022.2082354] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Martina Kojanova
- Department of Dermatovenereology, First Faculty of Medicine and General University Hospital, Charles University, Prague, Czech Republic
| | - Jan Hugo
- 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, Prague, Czech Republic
| | - Jorga Fialova
- Department of Dermatovenereology, First Faculty of Medicine and General University Hospital, Charles University, Prague, Czech Republic
| | | | - Martin Tichy
- Department of Dermatology and Venereology, Faculty of Medicine and Dentistry, University Hospital Olomouc, Olomouc, Czech Republic
| | - Spyridon Gkalpakiotis
- Department of Dermatovenereology, Third Faculty of Medicine, Charles University and Kralovske Vinohrady University Hospital, Prague, Czech Republic
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Galluzzo M, Chiricozzi A, Cinotti E, Brunasso G, Congedo M, Esposito M, Franchi C, Malara G, Narcisi A, Piaserico S, Tiberio R, Argenziano G, Fabbrocini G, Parodi A. Tildrakizumab for treatment of moderate to severe psoriasis: an expert opinion of efficacy, safety, and use in special populations. Expert Opin Biol Ther 2022; 22:367-376. [PMID: 34607513 DOI: 10.1080/14712598.2022.1988566] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Accepted: 09/29/2021] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Tildrakizumab is a monoclonal antibody that targets the p19 subunit of IL-23, a crucial cytokine for Th17 cells. Tildrakizumab has been assessed in several Phase I, II, and III clinical trials and is approved for treatment of adults with moderate to severe plaque psoriasis who are indicated for systemic therapy. AREAS COVERED The available evidence on the efficacy, safety, and use of tildrakizumab in special populations was evaluated by 14 experts who critically reviewed the current literature. EXPERT OPINION Tildrakizumab has good efficacy that lasts for at least 5 years in patients with moderate to severe psoriasis, and appears to be safe and well tolerated in the long-term with no apparent dose-related differences in adverse events, a low incidence of discontinuation due to adverse events, and no evidence of increased risk of malignancies. The safety and the efficacy of tildrakizumab has also been confirmed in special populations such as those with inflammatory bowel disease, cardiovascular disease, metabolic syndrome, and advanced age. Early intervention with IL-23-inhibitors, such as tildrakizumab, may help to control symptoms and change the long-term course of the disease in patients affected by plaque psoriasis, while improving the quality of life and potentially minimizing the risk of developing comorbidities.
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Affiliation(s)
- Marco Galluzzo
- Dermatology Unit, Fondazione Policlinico "Tor Vergata", Rome, Italy
- Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Andrea Chiricozzi
- Dermatologia, Dipartimento Scienze Mediche E Chirurgiche, Fondazione Policlinico Universitario A. Gemelli Irccs, Rome, Italy
- Dermatologia, Dipartimento Universitario Di Medicina E Chirurgia Traslazionale, Università Cattolica Del Sacro Cuore, Rome, Italy
| | - Elisa Cinotti
- Dermatology Unit, Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy
| | | | - Maurizio Congedo
- Uosd Dermatologia E Allergologia, Ospedale Vito Fazzi, Lecce, Italy
| | - Maria Esposito
- Dermatology Unit, Department of Biotechnological Ad Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
| | | | - Giovanna Malara
- Dermatology Department, Grande Ospedale Metropolitano "Bmm", Reggio Calabria, Italy
| | | | | | | | | | - Gabriella Fabbrocini
- Section of Dermatology, Department of Clinical, Medicine and Surgery, University of Naples Federico Ii, Naples, Italy
| | - Aurora Parodi
- Dissal Dermatology Unit, University of Genoa, Genoa, Italy
- Dermatology Unit, San Martino Polyclinic Hospital IRCCS, Genoa, Italy
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Oral Candida Infection in Psoriatic Patients Treated with IL17A Inhibitors: Report of 3 Cases and a Comprehensive Review of the Literature. Diagnostics (Basel) 2021; 12:diagnostics12010003. [PMID: 35054170 PMCID: PMC8774305 DOI: 10.3390/diagnostics12010003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2021] [Revised: 12/08/2021] [Accepted: 12/10/2021] [Indexed: 12/17/2022] Open
Abstract
An intact and fully functional immune system plays a crucial role in the prevention of several infectious diseases. Interleukin (IL)17 is significantly involved in oral mucosa immunity against several antigens and microorganisms, including Candida albicans (CA). Herein, we present three cases of oral candidiasis (OC) related to the use of an IL17A inhibitor for psoriasis. Three psoriatic individuals presented for evaluation of widespread symptomatic oral lesions temporally correlated with the onset of IL17A inhibitors (secukinumab in two patients and brodalumab in one patient). Clinical examination revealed either partially removable white plaques in an erythematous background (case #1) or diffuse erythematous lesions (cases #2 and 3) involving several areas of the oral mucosa. Cytology smear, accompanied by histopathologic examination in case #1, confirmed the clinical impression of OC in all three cases. All patients received antifungal therapy with satisfactory clinical response. No discontinuation of the antipsoriatic regimen was recommended, but all patients were advised to remain under monitoring for possible OC relapses. During the last few years, new systemic biologic agents targeting IL17 have been used for the management of variable immune-mediated diseases. Few clinical trials and scarce case reports have shown that these medications place individuals at high risk of developing candidiasis. We propose that patients treated with these medications should be at close monitoring for the development of OC and, if it occurs, receive appropriate management.
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Vatsalya V, Li F, Frimodig J, Gala KS, Srivastava S, Kong M, Ramchandani VA, Feng W, Zhang X, McClain CJ. Repurposing Treatment of Wernicke-Korsakoff Syndrome for Th-17 Cell Immune Storm Syndrome and Neurological Symptoms in COVID-19: Thiamine Efficacy and Safety, In-Vitro Evidence and Pharmacokinetic Profile. Front Pharmacol 2021; 11:598128. [PMID: 33737877 PMCID: PMC7960760 DOI: 10.3389/fphar.2020.598128] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2020] [Accepted: 12/10/2020] [Indexed: 12/19/2022] Open
Abstract
Coronavirus disease identified in 2019 (COVID-19) can be complicated by the Th17 cell-mediated IL-17 proinflammatory response. We tested if thiamine can effectively lower the Th17 response in a clinical study [Proinflammatory state in alcohol use disorder patients termed as disease controls (DC)] and corroborated the results using an in vitro study. We developed an effective dose range and model for key pharmacokinetic measures with the potential of targeting the cytokine storm and neurological symptoms of COVID-19. Three-week 200 mg dose of thiamine was administered to sixteen DC patients. Eight healthy volunteers (HV) were also included in this investigation. A subsequent in vitro study was performed to validate the effectiveness of thiamine [100 mg/day equivalent (0.01 μg/ml)] treatment in lowering the Th17 proinflammatory response in a mouse macrophage cell line (RAW264.7) treated with ethanol. Based on recent publications, we compared the results of the IL-17 response from our clinical and in vitro study to those found in other proinflammatory disease conditions (metabolic conditions, septic shock, viral infections and COVID-19) and effective and safe dose ranges of thiamine. We developed a pharmacokinetic profile for thiamine dose range as a novel intervention strategy in COVID-19. DC group showed significantly elevated proinflammatory cytokines compared to HV. Thiamine-treated DC patients showed significant lowering in IL-17 and increase in the IL-22 levels. In humans, a range of 79-474 mg daily of thiamine was estimated to be effective and safe as an intervention for the COVID-19 cytokine storm. A literature review showed that several neurological symptoms of COVID-19 (∼45.5% of the severe cases) occur in other viral infections and neuroinflammatory states that may also respond to thiamine treatment. Thiamine, a very safe drug even at very high doses, could be repurposed for treating the Th17 mediated IL-17 immune storm, and the subsequent neurological symptoms observed in COVID-19. Further studies using thiamine as an intervention/prevention strategy in COVID-19 patients could identify its precise anti-inflammatory role.
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Affiliation(s)
- Vatsalya Vatsalya
- Department of Medicine, University of Louisville, Louisville, KY, United States
- Robley Rex VA Medical Center, Louisville, KY, United States
| | - Fengyuan Li
- Department of Medicine, University of Louisville, Louisville, KY, United States
- University of Louisville Alcohol Research Center, Louisville, KY, United States
| | - Jane Frimodig
- Department of Medicine, University of Louisville, Louisville, KY, United States
- Robley Rex VA Medical Center, Louisville, KY, United States
| | - Khushboo S. Gala
- Department of Medicine, University of Louisville, Louisville, KY, United States
| | - Shweta Srivastava
- Department of Medicine, University of Louisville, Louisville, KY, United States
- Envirome Institute, University of Louisville, Louisville, KY, United States
| | - Maiying Kong
- Robley Rex VA Medical Center, Louisville, KY, United States
- Department of Bioinformatics and Biostatistics, University of Louisville, Louisville, KY, United States
| | - Vijay A. Ramchandani
- National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, United States
| | - Wenke Feng
- Department of Medicine, University of Louisville, Louisville, KY, United States
- University of Louisville Alcohol Research Center, Louisville, KY, United States
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, United States
- University of Louisville Hepatobiology and Toxicology COBRE, Louisville, KY, United States
| | - Xiang Zhang
- University of Louisville Alcohol Research Center, Louisville, KY, United States
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, United States
- University of Louisville Hepatobiology and Toxicology COBRE, Louisville, KY, United States
- Department of Chemistry, University of Louisville, Louisville, KY, United States
- Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, KY, United States
| | - Craig J. McClain
- Department of Medicine, University of Louisville, Louisville, KY, United States
- Robley Rex VA Medical Center, Louisville, KY, United States
- University of Louisville Alcohol Research Center, Louisville, KY, United States
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, United States
- University of Louisville Hepatobiology and Toxicology COBRE, Louisville, KY, United States
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Salimi S, Yamauchi PS, Thakur R, Weinberg JM, Kircik L, Abdelmaksoud A, Wollina U, Lotti T, Sharma A, Grabbe S, Goldust M. Interleukin 23p19 inhibitors in chronic plaque psoriasis with focus on mirikizumab: A narrative review. Dermatol Ther 2020; 33:e13800. [PMID: 32530083 DOI: 10.1111/dth.13800] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 06/05/2020] [Indexed: 12/29/2022]
Abstract
Psoriasis, a T-cell mediated chronic dermatosis, has a complex etiopathogenesis. There has been extensive research into the aberrant immune response, which leads to the formation of clinical lesions, and the need for developing better and safer drugs has been unrelenting. The past two decades of research has opened up new areas of the immune pathway that can be targeted in order to control the disease. Therefore, we have seen the emergence of biologics which either target T-cell receptors or inhibit Tumor Necrosis Factor-alpha (TNF-α) or inhibit interleukins (IL) like IL-12, IL-17, IL-17 receptor, and more recently IL-23. Drugs specifically targeting the p19 subunit of IL-23 have shown promising results in the management of chronic plaque psoriasis. This has given way to the development of a new class of biologics, that is, the IL-23p19 inhibitors that have a better safety profile as compared to its predecessors. In this review, we shall scrutinize the role of IL-23 and Th17 cell signaling in the evolution of the psoriatic lesions and summarize the clinical experience with IL-23p19 inhibitors especially mirikizumab in the treatment of chronic plaque psoriasis.
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Affiliation(s)
- Sohrab Salimi
- Department of Anesthesiology, School of Medicine, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Paul S Yamauchi
- Dermatology Institute and Skin Care Center, Santa Monica, California, USA.,Division of Dermatology, David Geffen School of Medicine at University of California, Los Angeles, California, USA
| | - Rohini Thakur
- Dermatology, Venereology and Leprology Consultant Dermatology and Cosmetology, Columbia Asia Hospital, Patiala, Punjab, India
| | | | - Leon Kircik
- Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | | | - Uwe Wollina
- Department of Dermatology and Allergology, Städtisches Klinikum Dresden, Academic Teaching Hospital of the Technical University of Dresden, Dresden, Germany
| | - Torello Lotti
- Department of Dermatology, University of Studies Guglielmo Marconi, Rome, Italy
| | - Aseem Sharma
- Dermatology Unit, Skin Saga Centre for Dermatology, Mumbai, India
| | - Stephan Grabbe
- Department of Dermatology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Mohamad Goldust
- Department of Dermatology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.,University of Rome G. Marconi, Rome, Italy.,Department of Dermatology, University Hospital Basel, Basel, Switzerland
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10
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A Nonsystematic Review on Risankizumab: a Novel Drug Recently Approved for Moderate to Severe Psoriasis. ACTA ACUST UNITED AC 2020. [DOI: 10.1007/s42399-020-00356-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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11
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Campione E, Cosio T, Lanna C, Mazzilli S, Ventura A, Dika E, Gaziano R, Dattola A, Candi E, Bianchi L. Predictive role of vitamin A serum concentration in psoriatic patients treated with IL-17 inhibitors to prevent skin and systemic fungal infections. J Pharmacol Sci 2020; 144:52-56. [PMID: 32565006 DOI: 10.1016/j.jphs.2020.06.003] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2020] [Revised: 05/01/2020] [Accepted: 05/11/2020] [Indexed: 12/13/2022] Open
Abstract
The use of biological drugs in psoriasis is replacing traditional therapies due to their specific mechanism and limited side effects. However, the use of Interleukin 17 inhibitors and the modification of its cytokine pathway could favor the risk of fungal infections. All-trans retinoic acid is an active metabolite of vitamin A with anti-inflammatory and immunoregulatory properties through its capacity to stimulate both innate and adaptive immunity and to its effects on proliferation, differentiation and apoptosis in a variety of immune cells. Furthermore, it has been recently discovered that All-trans retinoic acid has a direct fungistatic effect against Candida and Aspergillus Fumigatus. On the basis of these new insights, in the current review, we suggest that the evaluation of serum level of All-trans retinoic acid or vitamin A should be considered as a predictive marker for the development of fungal infections among psoriatic patients treated with Interleukin 17 inhibitors. In clinical practice, vitamin A test could be added in the routine hospital diagnostic management for a better selection of psoriatic patients eligible to Interleukin 17 inhibitors.
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Affiliation(s)
- Elena Campione
- Dermatologic Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy.
| | - Terenzio Cosio
- Dermatologic Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Caterina Lanna
- Dermatologic Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Sara Mazzilli
- Dermatologic Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | | | - Emi Dika
- Dermatology Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna, Italy
| | - Roberta Gaziano
- Microbiology Section, Department of Experimental Medicine and Surgery, University of Rome "Tor Vergata", Rome, Italy
| | - Annunziata Dattola
- Dermatologic Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Eleonora Candi
- Department of Experimental Medicine, University of Rome "Tor Vergata", Rome, Italy
| | - Luca Bianchi
- Dermatologic Unit, Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
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12
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Balogh EA, Bashyam AM, Ghamrawi RI, Feldman SR. Emerging systemic drugs in the treatment of plaque psoriasis. Expert Opin Emerg Drugs 2020; 25:89-100. [PMID: 32192366 DOI: 10.1080/14728214.2020.1745773] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Psoriasis is a common, chronic inflammatory skin condition that affects 2-3% of the US population and represents a large psychosocial burden for patients. Over the last decade, highly effective targeted therapies for psoriasis have been developed - namely, those targeting interleukin (IL)-17 and IL-23. The success of biologic agents targeting IL-17 and IL-23 underscores the importance of the IL-23/T helper (Th)17 cell axis in psoriasis pathogenesis. Oral small molecule drugs - such as Janus kinase (JAK) inhibitors, tyrosine kinase 2 (TYK2) inhibitors, and fumaric acid esters (FAEs) - are also being investigated for the treatment of psoriasis. AREAS COVERED This article reviews systemic biologic and oral small molecule drugs currently undergoing clinical trials for the treatment of plaque psoriasis. EXPERT OPINION Many patients with psoriasis have mild disease, and many with mild disease do not seek medical care for their condition. Many patients with mild disease could be adequately treated with topical treatments and phototherapy; however, adherence and feasibility have often been an issue with these treatment types. There seems to be limited room for development of novel biologics, as the existing ones are extraordinarily safe, effective, and convenient with few injections. Patients would prefer a safe, effective oral treatment; however, JAK inhibitors seem unlikely to fill this role completely.
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Affiliation(s)
- Esther A Balogh
- Center for Dermatology Research, Department of Dermatology, Wake Forest School of Medicine , Winston-Salem, NC, USA
| | - Arjun M Bashyam
- Center for Dermatology Research, Department of Dermatology, Wake Forest School of Medicine , Winston-Salem, NC, USA
| | - Rima I Ghamrawi
- Center for Dermatology Research, Department of Dermatology, Wake Forest School of Medicine , Winston-Salem, NC, USA
| | - Steven R Feldman
- Center for Dermatology Research, Department of Dermatology, Wake Forest School of Medicine , Winston-Salem, NC, USA.,Department of Pathology, Wake Forest School of Medicine , Winston-Salem, NC, USA.,Department of Social Sciences & Health Policy, Wake Forest School of Medicine , Winston-Salem, NC, USA.,Department of Dermatology, University of Southern Denmark , Odense, Denmark
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13
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Asimus S, Palmér R, Albayaty M, Forsman H, Lundin C, Olsson M, Pehrson R, Mo J, Russell M, Carlert S, Close D, Keeling D. Pharmacokinetics, pharmacodynamics and safety of the inverse retinoic acid-related orphan receptor γ agonist AZD0284. Br J Clin Pharmacol 2020; 86:1398-1405. [PMID: 32067249 DOI: 10.1111/bcp.14253] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 02/04/2020] [Indexed: 11/30/2022] Open
Abstract
AIMS Retinoic acid-related orphan receptor γ (RORγ), a master regulator of T-helper 17 (Th17) cell function and differentiation, is an attractive target for treatment of Th17-driven diseases. This first-in-human study aimed to investigate the pharmacokinetics, pharmacodynamics, safety and tolerability of the inverse RORγ agonist AZD0284. METHODS We conducted a phase I, randomized, single-blind, placebo-controlled, two-part, first-in-human study with healthy subjects receiving single (4-238 mg) or multiple (12-100 mg) oral doses of AZD0284 or placebo after overnight fasting. Subjects in the one single dose cohort additionally received a single dose of AZD0284 after a high-calorie meal. AZD0284 plasma concentrations, as well as inhibition of ex vivo-stimulated interleukin (IL)-17A release in whole blood, were frequently measured after both single and multiple dosing. RESULTS Eighty-three men participated in the study. AZD0284 was absorbed rapidly into plasma after oral dosing and exhibited a terminal half-life of 13-16 hours. Both the area under the concentration-time curve (AUC) and maximum concentration (Cmax ) increased subproportionally with increasing dose (95% confidence intervals of slope parameter were 0.71-0.84 and 0.72-0.88 for AUC and Cmax , respectively). Food intake delayed the absorption of AZD0284 but did not affect the overall exposure or half-life. AZD0284 showed dose-dependent reduction of ex vivo-stimulated IL-17A release after both single and multiple doses. No significant safety concerns were identified in the study. CONCLUSIONS AZD0284 was well tolerated, rapidly and dose-dependently absorbed, and reduced stimulated IL-17A release after single and multiple dosing. The results of this study support further clinical development of AZD0284.
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Affiliation(s)
- Sara Asimus
- Clinical Pharmacology & Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca Gaithersburg, MD, USA
| | - Robert Palmér
- Clinical Pharmacology & Quantitative Pharmacology, Clinical Pharmacology & Safety Sciences, R&D, AstraZeneca Gothenburg, Sweden
| | | | - Henrik Forsman
- Clinical Development, Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Christina Lundin
- Clinical Development, Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Marita Olsson
- Early Biostats and Statistical Innovation, Data Science and AI, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Rikard Pehrson
- Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - John Mo
- Patient Safety, Respiratory, Inflammation and Autoimmunity, Chief Medical Office, R&D, AstraZeneca, Gothenburg, Sweden
| | - Muir Russell
- Study Delivery, Early Oncology Clinical, Oncology R&D, AstraZeneca, Cambridge, UK
| | - Sara Carlert
- Early Product Development, Pharmaceutical Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - David Close
- Clinical Development, Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK
| | - David Keeling
- Research and Early Development, Respiratory, Inflammation and Autoimmune, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
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14
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Sawyer LM, Malottki K, Sabry-Grant C, Yasmeen N, Wright E, Sohrt A, Borg E, Warren RB. Assessing the relative efficacy of interleukin-17 and interleukin-23 targeted treatments for moderate-to-severe plaque psoriasis: A systematic review and network meta-analysis of PASI response. PLoS One 2019; 14:e0220868. [PMID: 31412060 PMCID: PMC6693782 DOI: 10.1371/journal.pone.0220868] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Accepted: 07/24/2019] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION New generation biologics, including interleukin (IL)-17 and IL-23 inhibitors, have delivered higher rates of skin clearance than older treatments in head-to-head studies. However, studies comparing these new biologics directly to one another are limited. OBJECTIVES To compare the short-term efficacy of available (or imminently available) biologic and non-biologic systemic therapies for treating patients with moderate-to-severe plaque psoriasis. METHODS A systematic review was undertaken to identify randomised controlled trials evaluating biologic treatments, apremilast and dimethyl fumarate. MEDLINE, MEDLINE In-Process, Embase and the Cochrane Library were searched from the 1st January 2000 to 22nd November 2018. A Bayesian network meta-analysis (NMA) using a random-effects multinomial likelihood model with probit link and meta-regression to adjust for cross-trial variation in placebo responses compared the efficacy of interventions at inducing different levels of Psoriasis Area and Severity Index (PASI) response during the induction period. A range of sensitivity analyses was undertaken. RESULTS Seventy-seven trials (34,816 patients) were included in the NMA. The base-case analysis showed that all active treatments were superior to placebo. IL-17 inhibitors, guselkumab and risankizumab were found to be more efficacious than tildrakizumab, ustekinumab, all TNF inhibitors and non-biologic systemic treatments at inducing all levels of PASI response. In addition, brodalumab, ixekizumab and risankizumab were significantly more efficacious than secukinumab; no significant difference was found in the comparison with guselkumab. The greatest benefit of brodalumab, ixekizumab, guselkumab, and risankizumab was seen for PASI 90 and PASI 100 response. Results were consistent across all analyses. CONCLUSIONS In the NMA brodalumab, ixekizumab, risankizumab and guselkumab showed the highest levels of short-term efficacy. There were differences in efficacy between treatments within the same class. Longer-term analyses are needed to understand differences between these drugs beyond induction in what is a life-long condition.
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Affiliation(s)
| | | | | | | | - Emily Wright
- Symmetron Limited, London, England, United Kingdom
| | | | | | - Richard B. Warren
- Dermatology Centre, Salford Royal NHS Foundation Trust, Manchester NIHR Biomedical Research Centre, The University of Manchester, Manchester, England, United Kingdom
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15
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Tian F, Mauro TM, Li Z. The pathological role of Wnt5a in psoriasis and psoriatic arthritis. J Cell Mol Med 2019; 23:5876-5883. [PMID: 31313518 PMCID: PMC6714168 DOI: 10.1111/jcmm.14531] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 05/30/2019] [Accepted: 06/13/2019] [Indexed: 12/19/2022] Open
Abstract
Psoriasis (PsO) is a chronic inflammatory skin disease with both local and systemic components. PsO‐associated arthritis, known as psoriatic arthritis (PsA), develops in approximately 13%‐25% of PsO patients. Various factors associated with both PsO and PsA indicate that these conditions are part of a single disease. Identification of novel targets for the development of drugs to treat both PsO and PsA is desirable to provide more patient‐friendly treatment regimens. Such targets will likely represent ‘common checkpoints’ of inflammation, for example key components or transduction cascades of the signalling pathways involved. Emerging evidence supports involvement of the non‐canonical Wnt signalling pathways in the development of both PsO and PsA, especially the Wnt5a‐activated signalling cascades. These, together with interlinked factors, are crucial in the interactions among keratinocytes, immune cells and inflammatory factors in PsO, as well as among chondrocytes, osteoblasts and osteoclasts that trigger both subchondral bone remodelling and cartilage catabolism in PsA. This review focuses on the pathological role of Wnt5a signalling and its interaction with other interlinked pathways in both PsO and PsA, and also on the main challenges for future research, particularly with respect to molecules targeting Wnt signalling pathways for the treatment of PsO and PsA.
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Affiliation(s)
- Faming Tian
- Medical Research Center, North China University of Science and Technology, Tangshan, China
| | - Theodora M Mauro
- Dermatology Services, Veterans Affair Medical Center and University of California-San Francisco, San Francisco, CA, USA
| | - Zhengxiao Li
- Department of Dermatology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
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16
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Lunder T, Zorko MS, Kolar NK, Suhodolcan AB, Marovt M, Leskovec NK, Marko PB. Drug survival of biological therapy is showing class effect: updated results from Slovenian National Registry of psoriasis. Int J Dermatol 2019; 58:631-641. [DOI: 10.1111/ijd.14429] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 01/16/2019] [Accepted: 02/18/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Tomaz Lunder
- Department of Dermatovenereology University Medical Centre Ljubljana Ljubljana Slovenia
- Medical Faculty University of Ljubljana Ljubljana Slovenia
| | - Mateja S. Zorko
- Department of Dermatovenereology University Medical Centre Ljubljana Ljubljana Slovenia
- Medical Faculty University of Ljubljana Ljubljana Slovenia
| | - Natasa K. Kolar
- Department of Dermatovenereology Celje General Hospital Celje Slovenia
| | - Aleksandra B. Suhodolcan
- Department of Dermatovenereology University Medical Centre Ljubljana Ljubljana Slovenia
- Medical Faculty University of Ljubljana Ljubljana Slovenia
| | - Maruska Marovt
- Department of Dermatovenereology University Medical Centre Maribor MariborSlovenia
| | - Nada K. Leskovec
- Medical Faculty University of Ljubljana Ljubljana Slovenia
- Remeda, Medical Centre Domzale Slovenia
| | - Pij B. Marko
- Department of Dermatovenereology University Medical Centre Maribor MariborSlovenia
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17
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Abstract
Psoriasis is a chronic, immune-mediated, inflammatory disease that is pathogenically driven by proinflammatory cytokines. This article reviews the immunologic role of interleukin (IL)-17, the major effector cytokine in the pathogenesis of psoriatic disease, along with the rationale for targeting the IL-17 cytokine family (IL-17A, IL-17F, and IL-17 receptor A) in the treatment of psoriasis and psoriatic arthritis. Emerging evidence indicates that major sources of IL-17A in patients with psoriatic disease are mast cells, γδ T cells, αβ T cells, and innate lymphoid cells in lesional skin and synovial fluid. Within the skin and joints, IL-17A acts on cellular targets, including keratinocytes, neutrophils, endothelial cells, fibroblasts, osteoclasts, chondrocytes, and osteoblasts, to stimulate production of various antimicrobial peptides, chemokines, and proinflammatory and proliferative cytokines, which, in turn, promote tissue inflammation and bone remodeling. The critical importance of the IL-23/IL-17A axis to the pathogenesis of psoriatic disease has resulted in many new biologic treatments targeting these cytokines. These biologics dramatically improve skin and joint symptoms in patients with moderate-to-severe psoriasis and psoriatic arthritis.
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Affiliation(s)
- Andrew Blauvelt
- Oregon Medical Research Center, 9495 SW Locust St, Suite G, Portland, OR,, 97223, USA.
| | - Andrea Chiricozzi
- Dermatology Unit, Department of Clinical and Translational Medicine, University of Pisa, Pisa, Italy
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18
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Papp KA, Gooderham M, Jenkins R, Vender R, Szepietowski JC, Wagner T, Hunt B, Souberbielle B. Granulocyte-macrophage colony-stimulating factor (GM-CSF) as a therapeutic target in psoriasis: randomized, controlled investigation using namilumab, a specific human anti-GM-CSF monoclonal antibody. Br J Dermatol 2018; 180:1352-1360. [PMID: 30207587 PMCID: PMC7379964 DOI: 10.1111/bjd.17195] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/06/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND The relevance of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the management of psoriasis has not been studied previously. GM-CSF is important in the initiation and maintenance of chronic inflammatory processes. OBJECTIVES To investigate the clinical use of GM-CSF neutralization by evaluating the efficacy and safety of namilumab (AMG203), a monoclonal antibody GM-CSF inhibitor, in patients with moderate-to-severe plaque psoriasis. METHODS A phase II, multicentre, randomized, double-blind, placebo-controlled, parallel-group, dose-finding, proof-of-concept study (NEPTUNE) was conducted. Four doses of namilumab (20, 50, 80 and 150 mg, via subcutaneous injection) were compared with placebo. Assessment of the primary end point - the proportion of patients achieving ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75 treatment response) - was performed at week 12. Exploratory investigation at the tissue level was conducted in a subset of the overall study population. The trial was registered with the number NCT02129777. RESULTS In total, 122 patients were enrolled and 106 (86·9%) completed the double-blind treatment; 16 (13·1%) prematurely discontinued study medication. Serum concentration-time profiles were as expected for subcutaneous delivery of an IgG1 monoclonal antibody, and exposure increased proportionally with dose elevation. The number of patients showing PASI 75 treatment response at week 12 was low in all groups; no significant difference was recorded in this end point between placebo and any namilumab group. Similar outcomes were recorded for other clinical study end points. Moreover, no significant treatment-related changes from baseline were observed in laboratory investigations of cell types or subpopulations, or cytokines relevant to inflammatory pathways in psoriasis. CONCLUSIONS GM-CSF blockade is not critical for suppression of key inflammatory pathways underlying psoriasis.
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Affiliation(s)
- K A Papp
- K Papp Clinical Research and Probity Medical Research, 135 Union St E, Waterloo, ON, N2J1C4, Canada
| | - M Gooderham
- SKiN Centre for Dermatology, Queen's University and Probity Medical Research, Peterborough, ON, Canada
| | - R Jenkins
- Clinical Science, Takeda International - U.K. Branch, London, U.K
| | - R Vender
- Dermatrials Research Inc, Hamilton, ON, Canada
| | - J C Szepietowski
- Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, Poland
| | - T Wagner
- Modelling and Simulation, Takeda Pharmaceuticals International, Zurich, Switzerland
| | - B Hunt
- Statistics, Takeda International, Deerfield, IL, U.S.A
| | - B Souberbielle
- Clinical Science, Takeda International - U.K. Branch, London, U.K
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19
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Feagan BG, Panés J, Ferrante M, Kaser A, D'Haens GR, Sandborn WJ, Louis E, Neurath MF, Franchimont D, Dewit O, Seidler U, Kim KJ, Selinger C, Padula SJ, Herichova I, Robinson AM, Wallace K, Zhao J, Minocha M, Othman AA, Soaita A, Visvanathan S, Hall DB, Böcher WO. Risankizumab in patients with moderate to severe Crohn's disease: an open-label extension study. Lancet Gastroenterol Hepatol 2018; 3:671-680. [DOI: 10.1016/s2468-1253(18)30233-4] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Revised: 06/22/2018] [Accepted: 06/26/2018] [Indexed: 02/08/2023]
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20
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Abstract
Psoriasis is a chronic skin disorder driven by IL-23 and the downstream T-helper cell 17 (Th17) pathway. Tildrakizumab is a humanized monoclonal antibody selectively targeting the p19 subunit of IL-23, a key cytokine for Th17 cells. Here, we provide an overview of IL-23 in the context of psoriasis pathogenesis and review the results of the Phase I, II and III clinical trials for tildrakizumab in patients with moderate-to-severe chronic plaque psoriasis in order to assess its efficacy, safety and clinical usefulness. In all clinical trials, tildrakizumab demonstrated significant clinical improvement and a favorable safety profile. In Phase III trials, 75% of tildrakizumab-treated patients reached a Psoriasis Area and Severity Index 75 at week 28 demonstrating superior efficacy as compared with etanercept treatment. The tildrakizumab-induced reduction in skin inflammation proves the important pathogenic role of IL-23 in psoriasis and further supports the utility of drugs targeting the IL-23/Th17 pathway. Targeting IL-23p19 with tildrakizumab augments the therapeutic repertoire for patients with moderate-to-severe chronic plaque psoriasis.
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Affiliation(s)
- Christine Bangert
- Department of Dermatology, University of Vienna Medical School, 1090 Vienna, Austria
- Juvenis Medical Center, 1010 Vienna, Austria
| | - Tamara Kopp
- Juvenis Medical Center, 1010 Vienna, Austria
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21
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22
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Sawyer L, Fotheringham I, Wright E, Yasmeen N, Gibbons C, Holmen Møller A. The comparative efficacy of brodalumab in patients with moderate-to-severe psoriasis: a systematic literature review and network meta-analysis. J DERMATOL TREAT 2018; 29:557-568. [PMID: 29323542 DOI: 10.1080/09546634.2018.1427205] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE To evaluate the relative efficacy of brodalumab compared with approved biologic therapies and apremilast for moderate-to-severe psoriasis. METHODS We searched MEDLINE, Embase, and Cochrane for randomized controlled trials reporting induction phase responses. The primary analysis examined the proportion of patients achieving Psoriasis Area Severity Index (PASI) 50, 75, 90, or 100 responses using a random-effects Bayesian multinomial likelihood model with probit link, with and without adjustment for variation in study-level placebo responses. RESULTS A total of 54 studies were included. Based on PASI 100 response, the most efficacious therapies were brodalumab 210 mg every two weeks (Q2W) and ixekizumab. Brodalumab 210 mg Q2W was significantly more efficacious than adalimumab, apremilast, brodalumab 140 mg Q2W, etanercept, infliximab, secukinumab, and ustekinumab. Results were consistent for PASI 50, 75, and 90 outcomes and all sensitivity analyses. CONCLUSIONS Our findings are consistent with pivotal trials which indicate that high levels of complete clearance can be achieved with brodalumab. Based on existing evidence, induction-phase efficacy of brodalumab is similar to ixekizumab and superior to other approved therapies, including anti-TNFs, apremilast, secukinumab, and ustekinumab.
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23
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Yao Z, Hu C, Zhu Y, Xu Z, Randazzo B, Wasfi Y, Chen Y, Sharma A, Zhou H. Population Pharmacokinetic Modeling of Guselkumab, a Human IgG1λ Monoclonal Antibody Targeting IL‐23, in Patients with Moderate to Severe Plaque Psoriasis. J Clin Pharmacol 2018; 58:613-627. [DOI: 10.1002/jcph.1063] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 11/16/2017] [Indexed: 01/13/2023]
Affiliation(s)
- Zhenling Yao
- Global Clinical Pharmacology Janssen Research & Development, LLC Spring House PA USA
| | - Chuanpu Hu
- Global Clinical Pharmacology Janssen Research & Development, LLC Spring House PA USA
| | - Yaowei Zhu
- Global Clinical Pharmacology Janssen Research & Development, LLC Spring House PA USA
| | - Zhenhua Xu
- Global Clinical Pharmacology Janssen Research & Development, LLC Spring House PA USA
| | - Bruce Randazzo
- Immunology Clinical Development Janssen Research & Development, LLC Spring House PA USA
| | - Yasmine Wasfi
- Immunology Clinical Development Janssen Research & Development, LLC Spring House PA USA
| | - Yang Chen
- Global Clinical Pharmacology Janssen Research & Development, LLC Spring House PA USA
| | - Amarnath Sharma
- Global Clinical Pharmacology Janssen Research & Development, LLC Spring House PA USA
| | - Honghui Zhou
- Global Clinical Pharmacology Janssen Research & Development, LLC Spring House PA USA
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24
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Fotiadou C, Lazaridou E, Sotiriou E, Ioannides D. Targeting IL-23 in psoriasis: current perspectives. PSORIASIS-TARGETS AND THERAPY 2018; 8:1-5. [PMID: 29441315 PMCID: PMC5804022 DOI: 10.2147/ptt.s98893] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
The recent advances in the understanding of psoriasis pathogenesis have clarified the pivotal role of interleukin (IL)-23. It is a heterodimeric cytokine consisting of two subunits, the unique p19 and the p40, which are shared with IL-12. The basic role of IL-23 in psoriasis is the activation and maintenance of the T-helper 17 pathway. New research findings indicate that IL-23 is more important than IL-12 in the pathogenesis of psoriasis. Based on that background, the selective targeting of the IL-23p19 subunit emerged as an attractive therapeutic option and led to the development of a new category of biologic agents. Three monoclonal antibodies that selectively inhibit the IL-23p19 subunit, guselkumab, tildrakizumab, and risankizumab, are in the pipeline for the treatment of moderate-to-severe psoriasis. In this article, we review the most recent efficacy and safety data regarding these IL-23p19 inhibitors.
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Affiliation(s)
- Christina Fotiadou
- First Department of Dermatology and Venereology, Aristotle University Medical School, Thessaloniki, Greece
| | - Elizabeth Lazaridou
- First Department of Dermatology and Venereology, Aristotle University Medical School, Thessaloniki, Greece
| | - Eleni Sotiriou
- First Department of Dermatology and Venereology, Aristotle University Medical School, Thessaloniki, Greece
| | - Demetrios Ioannides
- First Department of Dermatology and Venereology, Aristotle University Medical School, Thessaloniki, Greece
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25
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Alsuliman T, Lassoued K, Belghoul M, Debbache K, Choufi B. Durable Resolution of Severe Psoriasis in a Patient Treated with Pentostatin for Hairy Cell Leukemia: A Case Report. Dermatol Ther (Heidelb) 2017; 8:165-169. [PMID: 29196889 PMCID: PMC5825321 DOI: 10.1007/s13555-017-0216-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Indexed: 02/07/2023] Open
Abstract
Introduction Pentostatin (2′-deoxycoformycin) and cladribine (2-chlorodeoxyadenosine) are adenosine analogues widely used to treat lymphoid malignancies, mainly hairy cell leukemia (HCL). Oral or parenteral adenosine analogues have been also used as immunomodulatory agents in multiple sclerosis and in acute graft-versus-host disease. Case Report Here, we report the case of a 43-year-old patient with a history of extensive psoriasis who later developed HCL. Results The patient had achieved complete remission of both psoriasis and HCL after receiving intravenous infusions of pentostatin. It is worth noting that cladribine has already been reported to treat plaque psoriasis lesions in two patients with HCL and in a third patient with gastric marginal zone B cell lymphoma [1]. Conclusion We believe that adenosine analogues constitute a promising therapeutic option for moderate to severe psoriasis, especially for severe and refractory psoriasis, as well as for patients with adjacent lymphoid malignancies.
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Affiliation(s)
- Tamim Alsuliman
- Service d'Hématologie, Centre Hospitalier de Boulogne-Sur-Mer, Boulogne-Sur-Mer, France
- Service d'Hématologie, Centre Hospitalier Régionale Universitaire de Lille, Lille, France
| | - Kaiss Lassoued
- Service d'Hématologie, Centre Hospitalier de Boulogne-Sur-Mer, Boulogne-Sur-Mer, France
- Service de Génétique et d'Immunologie, Hôpital Sud, Centre Hospitalier et Universitaire d'Amiens, Amiens, France
| | | | - Karima Debbache
- Service d'Hématologie, Centre Hospitalier de Boulogne-Sur-Mer, Boulogne-Sur-Mer, France
| | - Bachra Choufi
- Service d'Hématologie, Centre Hospitalier de Boulogne-Sur-Mer, Boulogne-Sur-Mer, France.
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Girolomoni G, Strohal R, Puig L, Bachelez H, Barker J, Boehncke W, Prinz J. The role of IL-23 and the IL-23/T H 17 immune axis in the pathogenesis and treatment of psoriasis. J Eur Acad Dermatol Venereol 2017; 31:1616-1626. [PMID: 28653490 PMCID: PMC5697699 DOI: 10.1111/jdv.14433] [Citation(s) in RCA: 172] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 06/13/2017] [Indexed: 12/11/2022]
Abstract
Psoriasis is a chronic, immune-mediated disease affecting more than 100 million people worldwide and up to 2.2% of the UK population. The aetiology of psoriasis is thought to originate from an interplay of genetic, environmental, infectious and lifestyle factors. The manner in which genetic and environmental factors interact to contribute to the molecular disease mechanisms has remained elusive. However, the interleukin 23 (IL-23)/T-helper 17 (TH 17) immune axis has been identified as a major immune pathway in psoriasis disease pathogenesis. Central to this pathway is the cytokine IL-23, a heterodimer composed of a p40 subunit also found in IL-12 and a p19 subunit exclusive to IL-23. IL-23 is important for maintaining TH 17 responses, and levels of IL-23 are elevated in psoriatic skin compared with non-lesional skin. A number of agents that specifically inhibit IL-23p19 are currently in development for the treatment of moderate-to-severe plaque psoriasis, with recent clinical trials demonstrating efficacy with a good safety and tolerability profile. These data support the role of this cytokine in the pathogenesis of psoriasis. A better understanding of the IL-23/TH 17 immune axis is vital and will promote the development of additional targets for psoriasis and other inflammatory diseases that share similar genetic aetiology and pathogenetic pathways.
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Affiliation(s)
- G. Girolomoni
- Section of DermatologyDepartment of MedicineUniversity of VeronaVeronaItaly
| | - R. Strohal
- Department of Dermatology and VenerologyFederal Academic Teaching Hospital of FeldkirchFeldkirchAustria
| | - L. Puig
- Hospital de la Santa Creu i Sant PauUniversitat Autònoma de BarcelonaBarcelonaSpain
| | - H. Bachelez
- Sorbonne Paris CitéUniversité Paris DiderotParisFrance
- Department of DermatologyHôpital Saint‐LouisAssistance Publique‐Hôpitaux de Paris (AP‐HP)ParisFrance
- UMR INSERM U1163Institut ImagineParisFrance
| | - J. Barker
- St John's Institute of DermatologyKing's College LondonLondonUK
| | - W.H. Boehncke
- Division of DermatologyGeneva University HospitalsDepartment of Pathology and ImmunologyFaculty of MedicineUniversity of GenevaGenevaSwitzerland
| | - J.C. Prinz
- Department of DermatologyUniversity of MunichMunichGermany
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Abstract
Nail psoriasis is often found in patients with plaque psoriasis and can greatly impact quality of life. This is particularly true in more severe cases, as it affects the structure and function of the patient's nail. Treatment for nail psoriasis is often challenging, involving topical medications, injections, and systematic therapies. This article aims to give an overview of the varied clinical presentations of nail psoriasis and the current treatments available for patients with this condition. Risks and efficacies of these treatments will be evaluated to determine the best treatment protocols.
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Affiliation(s)
| | | | - Morgan Rabach
- Mount Sinai Department of Dermatology, New York, New York
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28
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Balato A, Scala E, Balato N, Caiazzo G, Di Caprio R, Monfrecola G, Raimondo A, Lembo S, Ayala F. Biologics that inhibit the Th17 pathway and related cytokines to treat inflammatory disorders. Expert Opin Biol Ther 2017; 17:1363-1374. [PMID: 28791896 DOI: 10.1080/14712598.2017.1363884] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Advances in the understanding of TNF-α and IL-17 synergistic functions have recently led to the concept that patients who do not respond or who respond inadequately to TNF-α inhibitors may have IL-17-driven diseases, opening up the way for a new class of therapeutic development: Th17-inhibitors. Areas covered: In this review, the authors discuss the central role that the IL-23/Th17 axis plays in the pathogenesis of several inflammatory diseases, such as psoriasis, highlighting its position as a relevant therapeutic target. In particular, the authors start by giving a brief historical excursus on biologic agent development up until the success of TNF-α inhibitors, and continue with an overview of IL12/23 pathway inhibition. Next, they describe Th17 cell biology, focusing on the role of IL-17 in host defense and in human immune-inflammatory diseases, discussing the use and side effects of IL-17 inhibitors. Expert opinion: The IL-23/Th17 signaling pathway plays a central role in the pathogenesis of several inflammatory diseases, such as psoriasis. Recent data has demonstrated that biologics neutralizing IL-17 (ixekizumab, secukinumab) or its receptor (brodalumab) are highly effective with a positive safety profile in treating moderate to severe psoriasis, offering new treatment possibilities, especially for patients who do not respond adequately to anti-TNF-α therapies.
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Affiliation(s)
- Anna Balato
- a Department of Advanced Biomedical Sciences , University of Naples Federico II , Naples , Italy
| | - Emanuele Scala
- b Department of Clinical Medicine and Surgery , University of Naples Federico II , Naples , Italy
| | - Nicola Balato
- b Department of Clinical Medicine and Surgery , University of Naples Federico II , Naples , Italy
| | - Giuseppina Caiazzo
- b Department of Clinical Medicine and Surgery , University of Naples Federico II , Naples , Italy
| | - Roberta Di Caprio
- b Department of Clinical Medicine and Surgery , University of Naples Federico II , Naples , Italy
| | - Giuseppe Monfrecola
- b Department of Clinical Medicine and Surgery , University of Naples Federico II , Naples , Italy
| | - Annunziata Raimondo
- b Department of Clinical Medicine and Surgery , University of Naples Federico II , Naples , Italy
| | - Serena Lembo
- c Department of Medicine, Surgery and Dentistry , "Scuola Medica Salernitana" University of Salerno , Salerno , Italy
| | - Fabio Ayala
- b Department of Clinical Medicine and Surgery , University of Naples Federico II , Naples , Italy
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Amin M, Darji K, No D, Wu J. Review of phase III trial data on IL-23 inhibitors tildrakizumab and guselkumab for psoriasis. J Eur Acad Dermatol Venereol 2017; 31:1627-1632. [DOI: 10.1111/jdv.14451] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 06/08/2017] [Indexed: 01/15/2023]
Affiliation(s)
- M. Amin
- School of Medicine; University of California, Riverside; Riverside CA USA
| | - K. Darji
- School of Medicine; Saint Louis University; St. Louis MO USA
| | - D.J. No
- School of Medicine; Loma Linda University; Loma Linda CA USA
| | - J.J. Wu
- Department of Dermatology; Kaiser Permanente Los Angeles Medical Center; Los Angeles CA USA
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30
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Bagchi S, He Y, Zhang H, Cao L, Van Rhijn I, Moody DB, Gudjonsson JE, Wang CR. CD1b-autoreactive T cells contribute to hyperlipidemia-induced skin inflammation in mice. J Clin Invest 2017; 127:2339-2352. [PMID: 28463230 DOI: 10.1172/jci92217] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 03/03/2017] [Indexed: 01/09/2023] Open
Abstract
A large proportion of human T cells are autoreactive to group 1 CD1 proteins, which include CD1a, CD1b, and CD1c. However, the physiological role of the CD1 proteins remains poorly defined. Here, we have generated a double-transgenic mouse model that expresses human CD1b and CD1c molecules (hCD1Tg) as well as a CD1b-autoreactive TCR (HJ1Tg) in the ApoE-deficient background (hCD1Tg HJ1Tg Apoe-/- mice) to determine the role of CD1-autoreactive T cells in hyperlipidemia-associated inflammatory diseases. We found that hCD1Tg HJ1Tg Apoe-/- mice spontaneously developed psoriasiform skin inflammation characterized by T cell and neutrophil infiltration and a Th17-biased cytokine response. Anti-IL-17A treatment ameliorated skin inflammation in vivo. Additionally, phospholipids and cholesterol preferentially accumulated in diseased skin and these autoantigens directly activated CD1b-autoreactive HJ1 T cells. Furthermore, hyperlipidemic serum enhanced IL-6 secretion by CD1b+ DCs and increased IL-17A production by HJ1 T cells. In psoriatic patients, the frequency of CD1b-autoreactive T cells was increased compared with that in healthy controls. Thus, this study has demonstrated the pathogenic role of CD1b-autoreactive T cells under hyperlipidemic conditions in a mouse model of spontaneous skin inflammation. As a large proportion of psoriatic patients are dyslipidemic, this finding is of clinical significance and indicates that self-lipid-reactive T cells might serve as a possible link between hyperlipidemia and psoriasis.
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Affiliation(s)
- Sreya Bagchi
- Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Ying He
- Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Hong Zhang
- Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Liang Cao
- Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
| | - Ildiko Van Rhijn
- Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.,Department of Infectious Diseases and Immunology, School of Veterinary Medicine, Utrecht University, Utrecht, Netherlands
| | - D Branch Moody
- Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | | | - Chyung-Ru Wang
- Department of Microbiology and Immunology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
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31
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Hanley TL, Yiu ZZ. Role of IL-17 in plaque psoriasis: therapeutic potential of ixekizumab. Ther Clin Risk Manag 2017; 13:315-323. [PMID: 28352182 PMCID: PMC5358983 DOI: 10.2147/tcrm.s111107] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Developments in the understanding of the immunopathogenesis of psoriasis have identified interleukin (IL)-17 as the key proinflammatory cytokine in the pathogenesis of plaque psoriasis, with the consequent development of drugs that target this cytokine or associated receptors. Ixekizumab is a subcutaneously administered humanized monoclonal antibody, which acts to neutralize IL-17A. This article reviews the role of IL-17 in the pathogenesis of psoriasis, the biological and pharmacokinetics of ixekizumab and the safety profile and the clinical efficacy of ixekizumab in Phase III clinical trials. Phase III clinical trials of ixekizumab have so far demonstrated excellent early clinical efficacy, with a comparable safety profile to the existing biologic therapies for psoriasis. To further assess its position in the treatment algorithm for psoriasis, a further head to head RCT with secukinumab could be established, alongside comparative effectiveness studies from observational research. In addition, trials are needed to assess its role in those with tumor necrosis factor inhibitors/ustekinumab resistant disease. However, it is clear that the IL-17 antagonists have changed the benchmark for clinical efficacy, and it is likely that ixekizumab along with the other IL-17 antagonists are set to achieve a new standard of care in the treatment of moderate to severe plaque psoriasis.
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Affiliation(s)
| | - Zenas Zn Yiu
- Centre for Dermatology; Centre for Pharmacoepidemiology and Drug Safety, Manchester Academic Health Science Centre, Manchester, UK
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32
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Zweegers J, Groenewoud J, van den Reek J, Otero M, van de Kerkhof P, Driessen R, van Lümig P, Njoo M, Ossenkoppele P, Mommers J, Koetsier M, Arnold W, Andriessen M, Kuijpers A, Berends M, Kievit W, de Jong E. Comparison of the 1- and 5-year effectiveness of adalimumab, etanercept and ustekinumab in patients with psoriasis in daily clinical practice: results from the prospective BioCAPTURE registry. Br J Dermatol 2017; 176:1001-1009. [DOI: 10.1111/bjd.15023] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/20/2016] [Indexed: 01/24/2023]
Affiliation(s)
- J. Zweegers
- Department of Dermatology; Radboud University Medical Center; Nijmegen the Netherlands
| | - J.M.M. Groenewoud
- Radboud University Medical Center; Radboud Institute for Health Sciences; Nijmegen the Netherlands
| | - J.M.P.A. van den Reek
- Department of Dermatology; Radboud University Medical Center; Nijmegen the Netherlands
| | - M.E. Otero
- Department of Dermatology; Radboud University Medical Center; Nijmegen the Netherlands
| | - P.C.M. van de Kerkhof
- Department of Dermatology; Radboud University Medical Center; Nijmegen the Netherlands
| | - R.J.B. Driessen
- Department of Dermatology; Radboud University Medical Center; Nijmegen the Netherlands
| | - P.P.M. van Lümig
- Department of Dermatology; Radboud University Medical Center; Nijmegen the Netherlands
| | - M.D. Njoo
- Department of Dermatology; Ziekenhuisgroep Twente; Almelo/Hengelo the Netherlands
| | - P.M. Ossenkoppele
- Department of Dermatology; Ziekenhuisgroep Twente; Almelo/Hengelo the Netherlands
| | - J.M. Mommers
- Department of Dermatology; St Anna Ziekenhuis; Geldrop the Netherlands
| | - M.I.A. Koetsier
- Department of Dermatology; Gelre Ziekenhuizen; Apeldoorn the Netherlands
| | - W.P. Arnold
- Department of Dermatology; Ziekenhuis Gelderse Vallei; Ede the Netherlands
| | - M.P.M. Andriessen
- Department of Dermatology; Jeroen Bosch Ziekenhuis; Den Bosch the Netherlands
| | - A.L.A. Kuijpers
- Department of Dermatology; Maxima Medisch Centrum; Eindhoven/Veldhoven the Netherlands
| | - M.A.M. Berends
- Department of Dermatology; Slingeland Ziekenhuis; Doetinchem the Netherlands
| | - W. Kievit
- Radboud University Medical Center; Radboud Institute for Health Sciences; Nijmegen the Netherlands
| | - E.M.G.J. de Jong
- Department of Dermatology; Radboud University Medical Center; Nijmegen the Netherlands
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33
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Elewski BE, Puig L, Mordin M, Gilloteau I, Sherif B, Fox T, Gnanasakthy A, Papavassilis C, Strober BE. Psoriasis patients with psoriasis Area and Severity Index (PASI) 90 response achieve greater health-related quality-of-life improvements than those with PASI 75–89 response: results from two phase 3 studies of secukinumab. J DERMATOL TREAT 2017; 28:492-499. [DOI: 10.1080/09546634.2017.1294727] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
| | - Lluís Puig
- Department of Dermatology, Hospital de la Sanat Creu i Sant Pau, Barcelona, Spain
| | | | | | - Bintu Sherif
- RTI Health Solutions, Research Triangle Park, NC, USA
| | - Todd Fox
- Novartis Pharma AG, Basel, Switzerland
| | | | | | - Bruce E. Strober
- University of Connecticut Health Center, Farmington, CT, USA
- Probity Medical Research, Waterloo, Canada
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34
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Abstract
Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent inflammatory nodules mostly located in the armpits and groin. Over the years multiple treatments for HS have been proposed; however, to date a cure is still lacking. In this update we provide an overview of most drug treatments reported on for HS, where possible with their mode of action and side effects. In mild cases, clindamycin lotion or resorcinol cream have proven effective. Tetracyclines are a first-line systemic option in more widespread or severe cases, followed by the combination of clindamycin and rifampicin. However, the recurrence rate is high after discontinuation of clindamycin plus rifampicin combination therapy. Long-term treatment with retinoids, especially acitretin is feasible, although teratogenicity has to be taken into account in females of reproductive age. Multiple anti-inflammatory drugs have been suggested for HS, such as dapsone, fumarates or cyclosporine. However, their effectiveness in HS is based on small case series with varying results. If most common treatments have failed, biologics (e.g., infliximab or adalimumab) are the next step. Although not addressed in this review, surgical interventions are often needed to achieve remission.
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Affiliation(s)
- I E Deckers
- Department of Dermatology, Erasmus University Medical Center, Burg. s' Jacobplein 51, 3015 CA, Rotterdam, The Netherlands.
| | - E P Prens
- Department of Dermatology, Erasmus University Medical Center, Burg. s' Jacobplein 51, 3015 CA, Rotterdam, The Netherlands.
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35
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HLA-Cw6 allele, NFkB1 and NFkBIA polymorphisms play no role in predicting response to etanercept in psoriatic patients. Pharmacogenet Genomics 2016; 26:423-7. [DOI: 10.1097/fpc.0000000000000233] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Burden-Teh E, Thomas KS, Ratib S, Grindlay D, Adaji E, Murphy R. The epidemiology of childhood psoriasis: a scoping review. Br J Dermatol 2016; 174:1242-57. [PMID: 26928555 DOI: 10.1111/bjd.14507] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/29/2016] [Indexed: 12/13/2022]
Abstract
Psoriasis is an inflammatory noncommunicable skin disease that affects both adults and children. At present, the epidemiology and natural history of psoriasis are not widely understood. This scoping review aimed to map the existing literature on the epidemiology of childhood psoriasis, identify research gaps for future studies and provide a comprehensive, clinically useful review. Search strategies were developed for Ovid Medline, Ovid Embase, Google Scholar and hand searching. In total, 131 articles met the inclusion criteria and were mapped; 107 articles were included for data extraction. Over the last 25 years there has been a dramatic increase in the volume of published observational epidemiological studies on childhood psoriasis. The majority were case series or cross-sectional studies, concentrated in Europe, Asia and North America. The prevalence of childhood psoriasis was found to be higher in European countries, older children and girls. Up to 48·8% of children had a family history of psoriasis in a first-degree relative. The most frequent subtype was plaque psoriasis and the most common initial sites of presentation were the scalp, limbs and trunk. Specific genetic differences have been found between child-onset and adult-onset populations. Case-control and cohort studies investigating risk factors for psoriasis onset, comorbidities and long-term health outcomes were extremely limited. The choice of study design and heterogeneity in methodology limit the validity and generalizability of the information, consistency of the results, and comparability of the studies. Well-designed epidemiological studies are needed to provide precise and consistent information about the frequency and clinical presentation, risk factors, associated diseases and long-term outcomes in childhood psoriasis.
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Affiliation(s)
- E Burden-Teh
- Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, U.K
| | - K S Thomas
- Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, U.K
| | - S Ratib
- Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, U.K
| | - D Grindlay
- Centre of Evidence Based Dermatology, University of Nottingham, Nottingham, U.K
| | - E Adaji
- Division of Epidemiology & Public Health, University of Nottingham, Nottingham, U.K
| | - R Murphy
- Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, U.K
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37
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Wakefield D, McCluskey P, Wildner G, Thurau S. Unmet Needs and Future Directions in Inflammatory Eye Disease. Ocul Immunol Inflamm 2016; 25:122-133. [PMID: 27070178 DOI: 10.3109/09273948.2016.1151897] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
PURPOSE To explore the unmet needs in the management of patients with severe inflammatory eye disease (IED), future directions for research and therapy, and to develop and facilitate access and delivery of better medical care to patients with severe IED. METHODS The unmet needs and future directions in inflammatory eye disease were identified and discussed by experts in relevant disciplines at a recent international conference. RESULTS A total of 14 major unmet needs were identified and discussed by experts in the areas of ophthalmology, rheumatology, infectious disease, and internal medicine, at an international conference. The major areas discussed are summarized in this review. CONCLUSIONS Identification of unmet needs in IED is seen as a first step in implementing changes in the way we diagnose and treat patients with these sight-threatening IEDs.
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Affiliation(s)
- Denis Wakefield
- a Department of Medicine , University of New South Wales , Kensington , Sydney , Australia
| | - Peter McCluskey
- b University of Sydney, Ophthalmology, Save Sight Institute , Sydney , Australia
| | - Gerhild Wildner
- c Department of Ophthalmology , University of Munich , Munich , Germany
| | - Stephan Thurau
- c Department of Ophthalmology , University of Munich , Munich , Germany
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38
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Torres T, Raposo I, Selores M. IL-17 Blockade in Psoriasis: Friend or Foe in Cardiovascular Risk? Am J Clin Dermatol 2016; 17:107-12. [PMID: 26596991 DOI: 10.1007/s40257-015-0166-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
Psoriasis is a chronic, immune-mediated inflammatory disorder associated with systemic inflammation and a significantly increased risk of cardiovascular disease. Common pathologic mechanisms are likely involved in the pathogenesis of psoriasis and atherosclerosis, including similar inflammatory cytokine profiles and proinflammatory cell types. The hypothesis that aggressive treatment of skin inflammation may decrease the risk of developing atherosclerosis and consequently cardiovascular disease is currently a focus of major attention. Interleukin (IL)-17 may be an important cytokine linking skin disease to vascular disease/inflammation. However, the role of IL-17 in atherosclerosis is still controversial, as IL-17 may exhibit pro-atherogenic or anti-atherogenic effects depending on the specific tissue, cellular, and immune context. Given the development of several IL-17 inhibitors, the investigation of IL-17 inhibition impact on cardiovascular outcome is extremely important.
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39
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Karabulut S, Afsar ÇU, Karabulut M, Alış H, Kılıc L, Çikot M, Yasasever CT, Aykan NF. Evaluation of Serum Interleukin-17 (IL-17) Levels as a Diagnostic Marker in Pancreatic Adenocarcinoma. J Gastrointest Cancer 2016; 47:47-54. [PMID: 26637231 DOI: 10.1007/s12029-015-9787-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Inflammatory cytokines modulate immune responses in the tumor microenvironment during progression. The role of interleukin (IL-17) in cancer is currently under debate. This study was conducted to investigate the serum levels of IL-17 in patients with pancreatic adenocarcinoma (PA) and the relationship with tumor progression and known prognostic parameters. MATERIAL AND METHODS Thirty-five patients with PA were investigated. Serum samples were obtained on first admission before treatment and follow-up. Both serum IL-17 levels were determined using enzyme-linked immunosorbent assay (ELISA). Age- and sex-matched 35 healthy controls were included in the analysis. RESULTS The median age at diagnosis was 61 years, range 38-84 years; 21 (60%) patients were men. The tumor was located in the head of pancreas in 24 (69%) patients. The most common metastatic site was liver in 20 patients with metastasis (n = 18, 90%). The median follow-up time was 24.0 weeks (range 1.0-191.0 weeks). At the end of the observation period, 12 (34%) patients experienced disease progression and 23 patients (66%) were dead. Forty-four percent of 18 metastatic patients who received palliative chemotherapy (CTx) were CTx-responsive. Median progression-free survival and overall survival of the whole group were 13.7 ± 2.3 weeks [95% confidence interval (CI) = 9-18 weeks] and 48.0 ± 12.8 weeks (95% CI = 23-73 weeks), respectively. The baseline serum IL-17 levels were significantly higher in patients with PA than in the control group (p = 0.001). Moreover, serum IL-17 levels were significantly higher in the patients with large pathologic tumor status and low albumin levels (p = 0.04 and p = 0.03, respectively). However, serum IL-17 assays had no prognostic roles on outcome. CONCLUSION Although serum levels of IL-17 assays were found to be diagnostic value, no predictive and prognostic value was determined in PA patients.
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Affiliation(s)
- Senem Karabulut
- Department of Medical Oncology, Institute of Oncology, Istanbul University, Istanbul, Turkey
| | - Çiğdem Usul Afsar
- Department of Medical Oncology, Istanbul Education and Research Hospital, Istanbul, Turkey.
| | - Mehmet Karabulut
- Clinic of General Surgery, Istanbul Bakırköy Dr. Sadi Konuk Education and Research Hospital, Istanbul, Turkey
| | - Halil Alış
- Clinic of General Surgery, Istanbul Bakırköy Dr. Sadi Konuk Education and Research Hospital, Istanbul, Turkey
| | - Leyla Kılıc
- Department of Medical Oncology, Institute of Oncology, Istanbul University, Istanbul, Turkey
| | - Murat Çikot
- Clinic of General Surgery, Istanbul Bakırköy Dr. Sadi Konuk Education and Research Hospital, Istanbul, Turkey
| | - Ceren Tilgen Yasasever
- Department of Basic Oncology, Institute of Oncology, Istanbul University, Istanbul, Turkey
| | - Nuri Faruk Aykan
- Department of Medical Oncology, Institute of Oncology, Istanbul University, Istanbul, Turkey
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40
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Korman AM, Hill D, Alikhan A, Feldman SR. Oral tofacitinib for the treatment of adults with moderate to severe chronic plaque psoriasis. Expert Rev Clin Pharmacol 2016; 9:525-539. [PMID: 26881913 DOI: 10.1586/17512433.2016.1154785] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
New treatments for psoriasis have been developed based on increasing knowledge of the underlying pathogenesis of the disease. The development of very safe and highly effective biologics has revolutionized the treatment of moderate-to-severe psoriasis. Biologics are not perfect, however, as they are delivered parenterally, immunogenic, and costly. Small molecule agents, with molecular weights of less than 1 kDa, are being developed and hold the advantage of being administered orally. Tofacitinib is an oral Janus kinase inhibitor that has been developed to disrupt the aberrant JAK-STAT pathway that contributes to the pathogenesis of psoriasis. Phase II and Phase III clinical trial results for tofacitinib are encouraging, demonstrating substantial efficacy and satisfactory safety in the treatment of patients with moderate-to-severe chronic plaque psoriasis. An effective oral treatment without the organ toxicities of methotrexate and cyclosporine, tofacitinib is a promising alternative to biologics in the treatment of moderate-to-severe psoriasis.
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Affiliation(s)
- Abraham M Korman
- a Center for Dermatology Research, Department of Dermatology , Wake Forest School of Medicine , Winston-Salem , NC , USA.,d Department of Dermatology , University of Cincinnati College of Medicine , Cincinnati , OH , USA
| | - Dane Hill
- a Center for Dermatology Research, Department of Dermatology , Wake Forest School of Medicine , Winston-Salem , NC , USA
| | - Ali Alikhan
- d Department of Dermatology , University of Cincinnati College of Medicine , Cincinnati , OH , USA
| | - Steven R Feldman
- a Center for Dermatology Research, Department of Dermatology , Wake Forest School of Medicine , Winston-Salem , NC , USA.,b Department of Pathology , Wake Forest School of Medicine , Winston-Salem , NC , USA.,c Department of Public Health Sciences , Wake Forest School of Medicine , Winston-Salem , NC , USA
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