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Wang R, Zhu J, Zhou J, Li J, Wang M, Wu Y, Zhao D, Chen X, Chen X, Wang Y, Zou J. Bioinspired Claw-Engaged Adhesive Microparticles Armed with γGC Alleviate Ulcerative Colitis via Targeted Suppression of Macrophage Ferroptosis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2503903. [PMID: 40298904 DOI: 10.1002/advs.202503903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/02/2025] [Revised: 04/13/2025] [Indexed: 04/30/2025]
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease, characterized by focal iron overload. Herein, we reported that γ-glutamylcysteine (γGC) deletion in UC lesions intensified the disease by depleting intracellular GSH to induce macrophage ferroptosis, leading to macrophage M1 reprogramming and eventually exacerbating inflammation. To counteract this, the advanced microparticles (MPs)-based delivery system is selected to encapsulate γGC. The resulting γGC-MPs displayed the same porous and spiky morphology as their substrate's natural pollens, resulting in improved intestinal adhesion and enhanced lesion contact of γGC-MPs. Our results demonstrated that exogenous γGC supplementation could inhibit macrophage M1 polarization by restraining ferroptosis, as well as suppressing the PI3K/AKT pathway and TNF signaling pathway. Compared with free γGC, γGC-MPs significantly alleviated typical UC symptoms in dextran sulfate sodium (DSS)-induced colitis, evidenced by reduced intestinal inflammation, restored intestinal barrier function, and improved microbiota composition. Consequently, this study addressed critical gaps in understanding the causes of ferroptosis and its impact on macrophage reprogramming in UC, offering a novel synergistic therapeutic strategy for UC.
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Affiliation(s)
- Rong Wang
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu, 210046, China
- Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, Hunan, 410219, China
| | - Jianwei Zhu
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu, 210046, China
- Departments of Diagnostic Radiology Surgery, Chemical and Biomolecular Engineering and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, 119074, Singapore
| | - Jinyi Zhou
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu, 210046, China
| | - Jinyang Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China
| | - Min Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, 210029, China
| | - Yuqi Wu
- Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, Jiangsu, 210046, China
| | - Danshan Zhao
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing, Jiangsu, 210046, China
| | - Xiancheng Chen
- Department of Critical Care Medicine, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu, 210029, China
| | - Xiaoyuan Chen
- Departments of Diagnostic Radiology Surgery, Chemical and Biomolecular Engineering and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, 119074, Singapore
| | - Yuetong Wang
- School of Food Science and Pharmaceutical Engineering, Nanjing Normal University, Nanjing, Jiangsu, 210046, China
| | - Jianhua Zou
- Departments of Diagnostic Radiology Surgery, Chemical and Biomolecular Engineering and Biomedical Engineering, Yong Loo Lin School of Medicine and College of Design and Engineering, National University of Singapore, Singapore, 119074, Singapore
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Lichtenstein GR, Allegretti JR, Loftus EV, Irving PM, Banerjee R, Charabaty A, Kuehbacher T, Bananis E, Woolcott JC, Dalam AB, Lazin K, Keating M, McDonnell A, Danese S. Assessment and Impact of Age on the Safety and Efficacy of Etrasimod in Patients With Ulcerative Colitis: A Post Hoc Analysis of Data From the ELEVATE UC Clinical Program. Inflamm Bowel Dis 2025:izae308. [PMID: 40184206 DOI: 10.1093/ibd/izae308] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Indexed: 04/05/2025]
Abstract
BACKGROUND Patient age can impact the safety and efficacy of ulcerative colitis (UC) treatments. Etrasimod is an oral, once daily (QD), selective sphingosine 1-phosphate1,4,5 receptor modulator for the treatment of moderately to severely active UC. Here, we evaluate the impact of age on etrasimod safety and efficacy in patients with UC in the phase 3 ELEVATE UC clinical program. METHODS Data were pooled from ELEVATE UC 52 and ELEVATE UC 12 in patients receiving etrasimod 2 mg QD or placebo. Proportions and incidence rates (IRs) per 100 patient-years of treatment-emergent adverse events (AEs) were stratified by age (<40, 40-59, and ≥60 years). With the same age stratifications, efficacy was evaluated in patients with baseline Modified Mayo scores of 5-9 and 4-9 for the primary efficacy endpoint (clinical remission) and secondary efficacy endpoints. RESULTS Overall, 787 patients were enrolled (<40 years, n = 420 [53.4%]; 40-59 years, n = 276 [35.1%]; and ≥60 years, n = 91 [11.6%]). Arthralgia, fatigue, and hypertension IRs were higher in older patients, irrespective of treatment. Serious AEs and AEs leading to treatment discontinuation were low and consistent across age groups. Significantly more patients receiving etrasimod 2 mg QD vs placebo achieved efficacy endpoints, regardless of age. CONCLUSIONS The safety profile of etrasimod 2 mg QD in the ELEVATE UC population was consistent across age groups, with no change in the incidence of AEs. Patients receiving etrasimod vs placebo showed significant clinical benefit, regardless of age. CLINICALTRIALS.GOV NCT03945188; NCT03996369.
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Affiliation(s)
- Gary R Lichtenstein
- Division of Gastroenterology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Jessica R Allegretti
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, MA, USA
| | - Edward V Loftus
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Peter M Irving
- IBD Unit, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - Rupa Banerjee
- Department of Gastroenterology, Asian Institute of Gastroenterology, Hyderabad, India
| | - Aline Charabaty
- Division of Gastroenterology and Hepatology, Johns Hopkins School of Medicine, Washington, DC, USA
| | - Tanja Kuehbacher
- Department of Internal Medicine/Gastroenterology, St. Marien- and St. Annastift Hospital, Ludwigshafen am Rhein, Germany
| | | | | | | | | | | | | | - Silvio Danese
- Division of Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital and Vita Salute San Raffaele University, Milan, Italy
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Mariette X, Borchmann S, Aspeslagh S, Szekanecz Z, Charles-Schoeman C, Schreiber S, Choy EH, Peyrin-Biroulet L, Schmalzing M, Tanaka Y, Ten Cate H, Westhovens R, van der Woude CJ, Ekoka Omoruyi EV, Faes M, Masior T, Van Hoek P, Watson C, Rudolph C, Stallmach A. Major adverse cardiovascular, thromboembolic and malignancy events in the filgotinib rheumatoid arthritis and ulcerative colitis clinical development programmes. RMD Open 2025; 11:e005033. [PMID: 40037922 PMCID: PMC11881192 DOI: 10.1136/rmdopen-2024-005033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 01/05/2025] [Indexed: 03/06/2025] Open
Abstract
OBJECTIVES Long-term safety is fundamental for treatment decision-making. This integrated analysis of filgotinib clinical trials in rheumatoid arthritis (RA) and ulcerative colitis (UC) assessed adverse events of interest (AEI): major adverse cardiovascular events (MACE), venous thromboembolism (VTE) and malignancies. METHODS Data were integrated from all phase II and III trials that have investigated filgotinib 100 mg or 200 mg once daily in RA and UC to date. RESULTS Analyses represent >12 500 (RA) and >2800 (UC) patient-years of exposure (PYE) to filgotinib. Incidences of AEI in the integrated analysis population were low. Modest numerical increases in incidence rates occurred in patients aged ≥65 years, including MACE (patients with RA), and malignancies (excluding non-melanoma skin cancer (NMSC)) and NMSC (patients with RA or UC). VTE was rare; in patients with RA aged ≥65 years receiving filgotinib 200 mg, exposure-adjusted incidence rate (95% CI) for VTE was 0.3 (0.1, 0.8)/100 PYE; no VTE events occurred in patients with UC aged ≥65 years. In patients with RA aged ≥65 years, MACE incidence rates were identical between filgotinib 100 mg and 200 mg; rates of malignancies and NMSC were numerically higher with 200 mg compared with 100 mg. CONCLUSIONS Data are consistent with previous overall safety analyses demonstrating low rates of AEI in the overall study population. Numerically increased rates of AEI occurred in patients aged ≥65 years; further data are needed to assess the effect of CV risk factors. Overall, in this analysis, there was no consistent filgotinib dose effect on AEI.
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Affiliation(s)
- Xavier Mariette
- Department of Rheumatology, Université Paris-Saclay, AP-HP-Hôpital Bicêtre, Paris, France
| | - Sven Borchmann
- Department of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Cologne, Germany
| | | | - Zoltan Szekanecz
- Department of Rheumatology, University of Debrecen, Debrecen, Hungary
| | | | - Stefan Schreiber
- Department of Internal Medicine, University Hospital Schleswig Holstein, Kiel, Germany
| | - Ernest Hs Choy
- Section of Rheumatology, Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff University, Cardiff, UK
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, INFINY Institute, FHU-CURE, INSERM NGERE, Nancy University Hospital, Vandoeuvre-Les-Nancy, France
- Groupe Hospitalier privé Ambroise Paré - Hartmann, Neuilly sur Seine, France
- Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Marc Schmalzing
- Department of Internal Medicine II, Rheumatology/Clinical Immunology, University Hospital Würzburg, Würzburg, Germany
| | - Yoshiya Tanaka
- The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Hugo Ten Cate
- Departments of Internal Medicine and Biochemistry and CARIM School for Cardiovascular Diseases, Maastricht University Medical Center, Maastricht, The Netherlands
| | - René Westhovens
- Department of Development and Regeneration, Skeletal Biology and Engineering Research Center, KU Leuven, Leuven, Belgium
| | - C Janneke van der Woude
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands
| | | | | | | | | | | | | | - Andreas Stallmach
- Department of Internal Medicine IV, Jena University Hospital, Jena, Germany
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Puca P, Del Gaudio A, Iaccarino J, Blasi V, Coppola G, Laterza L, Lopetuso LR, Colantuono S, Gasbarrini A, Scaldaferri F, Papa A. Cancer Risk in IBD Patients Treated with JAK Inhibitors: Reassuring Evidence from Trials and Real-World Data. Cancers (Basel) 2025; 17:735. [PMID: 40075582 PMCID: PMC11899451 DOI: 10.3390/cancers17050735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2025] [Revised: 02/16/2025] [Accepted: 02/18/2025] [Indexed: 03/14/2025] Open
Abstract
The advent of Janus kinase (JAK) inhibitors, including tofacitinib, filgotinib, and upadacitinib, has significantly widened the therapeutic options for patients with inflammatory bowel disease (IBD). These agents offer the advantage of oral administration and have demonstrated efficacy in inducing and maintaining remission. However, concerns regarding their safety have emerged, particularly concerning cardiovascular and infectious complications, which appear more pronounced in patients with pre-existing risk factors such as older age, smoking, or comorbidities. While these risks are better understood, the potential association between JAK inhibitors and malignancies remains a subject of ongoing investigation. Current data from randomised controlled trials, pooled and integrated analyses, and real-world studies provide conflicting evidence regarding cancer risk. Notably, studies in patients with rheumatologic diseases treated with JAK inhibitors have contributed additional insights into long-term safety outcomes. Despite the uncertainty surrounding malignancy risks, it is likely that predisposing factors, including older age, smoking history, and long-standing IBD with chronic inflammation, play a more substantial role in cancer development than JAK inhibitor therapy alone. This paper reviews safety data from clinical trials, meta-analyses, and observational studies, focusing on cancer risk in patients treated with JAK inhibitors for IBD. We also review evidence from rheumatology studies, highlighting the need for individualised risk assessment and close monitoring to optimise the safety profile of these medications in clinical practice.
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Affiliation(s)
- Pierluigi Puca
- Department of Medical and Surgical Sciences, Catholic University of the Sacred Heart, 00168 Rome, Italy; (P.P.); (A.D.G.); (J.I.); (V.B.); (L.R.L.); (A.G.); (F.S.)
- IBD Unit, Digestive Diseases Centre (CEMAD), Department of Medical and Surgical Sciences, Policlinico Universitario “A. Gemelli” Foundation, IRCCS, 00168 Rome, Italy; (G.C.); (L.L.); (S.C.)
| | - Angelo Del Gaudio
- Department of Medical and Surgical Sciences, Catholic University of the Sacred Heart, 00168 Rome, Italy; (P.P.); (A.D.G.); (J.I.); (V.B.); (L.R.L.); (A.G.); (F.S.)
| | - Jacopo Iaccarino
- Department of Medical and Surgical Sciences, Catholic University of the Sacred Heart, 00168 Rome, Italy; (P.P.); (A.D.G.); (J.I.); (V.B.); (L.R.L.); (A.G.); (F.S.)
| | - Valentina Blasi
- Department of Medical and Surgical Sciences, Catholic University of the Sacred Heart, 00168 Rome, Italy; (P.P.); (A.D.G.); (J.I.); (V.B.); (L.R.L.); (A.G.); (F.S.)
| | - Gaetano Coppola
- IBD Unit, Digestive Diseases Centre (CEMAD), Department of Medical and Surgical Sciences, Policlinico Universitario “A. Gemelli” Foundation, IRCCS, 00168 Rome, Italy; (G.C.); (L.L.); (S.C.)
| | - Lucrezia Laterza
- IBD Unit, Digestive Diseases Centre (CEMAD), Department of Medical and Surgical Sciences, Policlinico Universitario “A. Gemelli” Foundation, IRCCS, 00168 Rome, Italy; (G.C.); (L.L.); (S.C.)
| | - Loris Riccardo Lopetuso
- Department of Medical and Surgical Sciences, Catholic University of the Sacred Heart, 00168 Rome, Italy; (P.P.); (A.D.G.); (J.I.); (V.B.); (L.R.L.); (A.G.); (F.S.)
- IBD Unit, Digestive Diseases Centre (CEMAD), Department of Medical and Surgical Sciences, Policlinico Universitario “A. Gemelli” Foundation, IRCCS, 00168 Rome, Italy; (G.C.); (L.L.); (S.C.)
| | - Stefania Colantuono
- IBD Unit, Digestive Diseases Centre (CEMAD), Department of Medical and Surgical Sciences, Policlinico Universitario “A. Gemelli” Foundation, IRCCS, 00168 Rome, Italy; (G.C.); (L.L.); (S.C.)
| | - Antonio Gasbarrini
- Department of Medical and Surgical Sciences, Catholic University of the Sacred Heart, 00168 Rome, Italy; (P.P.); (A.D.G.); (J.I.); (V.B.); (L.R.L.); (A.G.); (F.S.)
- IBD Unit, Digestive Diseases Centre (CEMAD), Department of Medical and Surgical Sciences, Policlinico Universitario “A. Gemelli” Foundation, IRCCS, 00168 Rome, Italy; (G.C.); (L.L.); (S.C.)
| | - Franco Scaldaferri
- Department of Medical and Surgical Sciences, Catholic University of the Sacred Heart, 00168 Rome, Italy; (P.P.); (A.D.G.); (J.I.); (V.B.); (L.R.L.); (A.G.); (F.S.)
- IBD Unit, Digestive Diseases Centre (CEMAD), Department of Medical and Surgical Sciences, Policlinico Universitario “A. Gemelli” Foundation, IRCCS, 00168 Rome, Italy; (G.C.); (L.L.); (S.C.)
| | - Alfredo Papa
- Department of Medical and Surgical Sciences, Catholic University of the Sacred Heart, 00168 Rome, Italy; (P.P.); (A.D.G.); (J.I.); (V.B.); (L.R.L.); (A.G.); (F.S.)
- IBD Unit, Digestive Diseases Centre (CEMAD), Department of Medical and Surgical Sciences, Policlinico Universitario “A. Gemelli” Foundation, IRCCS, 00168 Rome, Italy; (G.C.); (L.L.); (S.C.)
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Johnson AM, Loftus EV. An evaluation of risankizumab for the treatment of moderate-to-severe ulcerative colitis. Expert Opin Biol Ther 2024; 24:1317-1327. [PMID: 39530131 DOI: 10.1080/14712598.2024.2428311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 11/07/2024] [Indexed: 11/16/2024]
Abstract
INTRODUCTION Risankizumab (RZB) is a recombinant IgG1 humanized monoclonal antibody which selectively inhibits interleukin (IL)-23 though high-affinity binding of the p19 subunit. RZB was approved for use in Crohn's disease (CD) in 2022 and received regulatory approval for ulcerative colitis (UC) in the United States in June 2024. AREAS COVERED We will examine currently available therapies for UC, provide an overview of the IL-23 pathway, discuss available trial data for RZB in UC, and comment on how RZB may fit into the current UC treatment paradigm and future directions in the field. EXPERT OPINION RZB appears to be an effective agent for inducing and maintaining remission in patients with both treatment-naïve and refractory UC, with a favorable safety profile. The selective blockade of IL-23 has demonstrated potential advantages in efficacy over combined IL-12/23 inhibition for other disease states like CD and psoriasis, although where it will be positioned amidst other clinically available advanced therapies in UC requires further study.
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Affiliation(s)
- Amanda M Johnson
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Edward V Loftus
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
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Fanizzi F, Allocca M, Fiorino G, Zilli A, Furfaro F, Parigi TL, Peyrin-Biroulet L, Danese S, D’Amico F. Raising the bar in ulcerative colitis management. Therap Adv Gastroenterol 2024; 17:17562848241273066. [PMID: 39600566 PMCID: PMC11589388 DOI: 10.1177/17562848241273066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 07/17/2024] [Indexed: 11/29/2024] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by growing incidence and prevalence around the world in the last few decades. The range of available existing treatment and strategies for its management is being implemented. Given the introduction of newly developed molecules and the lack of specific guidelines, drug positioning may represent a tough clinical challenge. UC management is mostly medical, and it has been shifting toward a more personalized approach with the aim to create a tailored strategy depending on the patient's profile. A treat-to target strategy seems to be the best approach to reach disease control as it allows to carry out therapeutic choices based on objective and specific parameters: histological, ultrasonographic, and molecular targets may add to the already used clinical, endoscopic, and biochemical targets. In addition, dual-targeted therapy has emerged as an attractive therapeutic strategy for patients not achieving remission. This review aims to provide an overview of the available strategies to raise the bar in UC.
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Affiliation(s)
- Fabrizio Fanizzi
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milan, Italy
| | - Mariangela Allocca
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milan, Italy
| | - Gionata Fiorino
- Gastroenterology and Digestive Endoscopy, San Camillo-Forlanini Hospital, Rome, Italy
| | - Alessandra Zilli
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milan, Italy
| | - Federica Furfaro
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milan, Italy
| | - Tommaso Lorenzo Parigi
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milan, Italy
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Nancy University Hospital, Vandœuvre-lès-Nancy, France
- INSERM, NGERE, University of Lorraine, Nancy, France
- INFINY Institute, Nancy University Hospital, Vandœuvre-lès-Nancy, France
- FHU-CURE, Nancy University Hospital, Vandœuvre-lès-Nancy, France
- Groupe Hospitalier Privé Ambroise Paré—Hartmann, Paris IBD Center, Neuilly sur Seine, France
- Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, QC, Canada
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milan, Italy
| | - Ferdinando D’Amico
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Via Olgettina 60, Milan 20132, Italy
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Spencer EA, Bergstein S, Dolinger M, Pittman N, Kellar A, Dunkin D, Dubinsky MC. Single-center Experience With Upadacitinib for Adolescents With Refractory Inflammatory Bowel Disease. Inflamm Bowel Dis 2024; 30:2057-2063. [PMID: 38134405 PMCID: PMC12102471 DOI: 10.1093/ibd/izad300] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2023] [Indexed: 12/24/2023]
Abstract
BACKGROUND Upadacitinib (UPA) is a novel selective JAK inhibitor approved for adults with ulcerative colitis (UC) and with positive phase 3 data for Crohn's disease (CD). Pediatric off-label use is common due to delays in pediatric approvals; real-world data on UPA are needed to understand the safety and effectiveness in pediatric IBD. METHODS This is a single-center retrospective case series study of adolescents (12-17 years) with inflammatory bowel disease IBD on UPA. The primary outcome was postinduction steroid-free clinical remission (SF-CR) defined as Pediatric UC Activity Index (PUCAI) or Pediatric CD Activity Index (PCDAI) ≤10. Secondary outcomes include postinduction clinical response (decrease ≥12.5 in PUCAI/PCDAI), postinduction C-reactive protein (CRP) normalization, 6-month SF-CR, and intestinal ultrasound response and remission. Adverse events were recorded through last follow-up. RESULTS Twenty patients (9 CD, 10 UC, 1 IBD-U; 55% female; median age 15 years, 90% ≥2 biologics) were treated with UPA for ≥12 weeks (median 51 [43-63] weeks). Upadacitinib was used as monotherapy in 55% and as combination with ustekinumab and vedolizumab in 35% and 10%, respectively. Week 12 SF-CR was achieved in 75% (15/20) and 80% (16/20) with CRP normalization. About 3/4 (14/19) achieved SF-CR at 6 months. Adverse event occurred in 2 patients (10%): Cytomegalovirus colitis requiring hospitalization and hyperlipidemia requiring no treatment. In the 75% with ultrasound monitoring, response and remission were achieved in 77% and 60%, respectively. CONCLUSION While awaiting pediatric registration trials, our data suggest that UPA is effective in inducing and maintaining SF-CR in adolescents with highly-refractory IBD with an acceptable safety profile.
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Affiliation(s)
- Elizabeth A Spencer
- Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics Mount Sinai, Icahn School of Medicine, 17 E. 102nd Street, Fifth Floor, New York, NY, 10029, USA
| | - Suzannah Bergstein
- Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics Mount Sinai, Icahn School of Medicine, 17 E. 102nd Street, Fifth Floor, New York, NY, 10029, USA
| | - Michael Dolinger
- Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics Mount Sinai, Icahn School of Medicine, 17 E. 102nd Street, Fifth Floor, New York, NY, 10029, USA
| | - Nanci Pittman
- Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics Mount Sinai, Icahn School of Medicine, 17 E. 102nd Street, Fifth Floor, New York, NY, 10029, USA
| | - Amelia Kellar
- Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics Mount Sinai, Icahn School of Medicine, 17 E. 102nd Street, Fifth Floor, New York, NY, 10029, USA
| | - David Dunkin
- Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics Mount Sinai, Icahn School of Medicine, 17 E. 102nd Street, Fifth Floor, New York, NY, 10029, USA
| | - Marla C Dubinsky
- Division of Pediatric Gastroenterology and Nutrition, Department of Pediatrics Mount Sinai, Icahn School of Medicine, 17 E. 102nd Street, Fifth Floor, New York, NY, 10029, USA
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Takeuchi K, Hisamatsu T, Nakase H, Matsuoka K, Keating M, Yuasa H, Oe M, Arai S, Mazur R, Hibi T. Efficacy and Safety of Etrasimod in Patients with Ulcerative Colitis in Japan: Data from the Phase 3 ELEVATE UC 12 and ELEVATE UC 40 JAPAN Trials. Digestion 2024:1-9. [PMID: 39317165 DOI: 10.1159/000541383] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 08/27/2024] [Indexed: 09/26/2024]
Abstract
INTRODUCTION Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). Here, we report the primary analysis of a phase 3 trial evaluating the efficacy and safety of etrasimod in patients from Japan with moderately to severely active UC. METHODS Patients from Japan who completed the 12-week ELEVATE UC 12 induction trial could enroll in the 40-week ELEVATE UC 40 JAPAN maintenance trial for a combined 52-week treatment period. Patients in this Japan cohort continued their baseline assigned treatment (etrasimod 2 mg QD or placebo) from ELEVATE UC 12. Efficacy was assessed at week 12 and week 52. Treatment-emergent adverse events (TEAEs) pooled from both trials were assessed up to 52 weeks of exposure. RESULTS The Japan cohort comprised 32 and 16 patients who received etrasimod and placebo, respectively. A numerically greater proportion of patients who received etrasimod versus placebo achieved clinical remission at week 12 (etrasimod: 14.3%; placebo: 7.1%) and week 52 (etrasimod: 25.0%; placebo: 7.1%); a similar trend was observed for all key secondary efficacy endpoints. TEAEs occurred in 84.4% (27/32) and 62.5% (10/16) of patients who received etrasimod and placebo, respectively. No new safety signals were detected. CONCLUSION In these induction and maintenance trials evaluating etrasimod in patients from Japan with UC, numerically higher proportions of patients who received etrasimod versus placebo achieved efficacy endpoints. Efficacy and safety findings were consistent with those from the global ELEVATE UC trial populations.
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Affiliation(s)
- Ken Takeuchi
- Department of Gastroenterology, IBD Center, Tsujinaka Hospital Kashiwanoha, Chiba, Japan
| | - Tadakazu Hisamatsu
- Department of Gastroenterology and Hepatology, Kyorin University School of Medicine, Tokyo, Japan
| | - Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Katsuyoshi Matsuoka
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University Sakura Medical Center, Chiba, Japan
| | | | | | | | | | | | - Toshifumi Hibi
- Center for Advanced Inflammatory Bowel Disease Research and Treatment, Kitasato University, Kitasato Institute Hospital, Minato City, Japan
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9
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Caballero-Mateos AM, Cañadas-de la Fuente GA. Game changer: How Janus kinase inhibitors are reshaping the landscape of ulcerative colitis management. World J Gastroenterol 2024; 30:3942-3953. [PMID: 39351053 PMCID: PMC11438661 DOI: 10.3748/wjg.v30.i35.3942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2024] [Revised: 08/19/2024] [Accepted: 08/22/2024] [Indexed: 09/13/2024] Open
Abstract
Recent advancements in the treatment landscape of ulcerative colitis (UC) have ushered in a new era of possibilities, particularly with the introduction of Janus kinase (JAK)-signal transducer and activator of transcription inhibitors. These novel agents offer a paradigm shift in UC management by targeting key signaling pathways involved in inflammatory processes. With approved JAK inhibitors (JAKis), such as tofacitinib, filgotinib, and upadacitinib, clinicians now have powerful tools to modulate immune responses and gene expression, potentially revolutionizing the treatment algorithm for UC. Clinical trials have demonstrated the efficacy of JAKis in inducing and maintaining remission, presenting viable options for patients who have failed conventional therapies. Real-world data support the use of JAKis not only as first-line treatments but also in subsequent lines of therapy, particularly in patients with aggressive disease phenotypes or refractory to biologic agents. The rapid onset of action and potency of JAKis have broadened the possibilities in the management strategies of UC, offering timely relief for patients with active disease and facilitating personalized treatment approaches. Despite safety concerns, including cardiovascular risks and infections, ongoing research and post-marketing surveillance will continue to refine our understanding of the risk-benefit profile of JAKis in UC management.
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10
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Hsu CY, Mustafa MA, Moath Omar T, Taher SG, Ubaid M, Gilmanova NS, Nasrat Abdulraheem M, Saadh MJ, Athab AH, Mirzaei R, Karampoor S. Gut instinct: harnessing the power of probiotics to tame pathogenic signaling pathways in ulcerative colitis. Front Med (Lausanne) 2024; 11:1396789. [PMID: 39323474 PMCID: PMC11422783 DOI: 10.3389/fmed.2024.1396789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 08/22/2024] [Indexed: 09/27/2024] Open
Abstract
Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD) marked by persistent inflammation of the mucosal lining of the large intestine, leading to debilitating symptoms and reduced quality of life. Emerging evidence suggests that an imbalance of the gut microbiota plays a crucial role in UC pathogenesis, and various signaling pathways are implicated in the dysregulated immune response. Probiotics are live microorganisms that confer health benefits to the host, have attracted significant attention for their potential to restore gut microbial balance and ameliorate inflammation in UC. Recent studies have elucidated the mechanisms by which probiotics modulate these signaling pathways, often by producing anti-inflammatory molecules and promoting regulatory immune cell function. For example, probiotics can inhibit the nuclear factor-κB (NF-κB) pathway by stabilizing Inhibitor of kappa B alpha (IκBα), dampening the production of proinflammatory cytokines. Similarly, probiotics can modulate the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway, suppressing the activation of STAT1 and STAT3 and thus reducing the inflammatory response. A better understanding of the underlying mechanisms of probiotics in modulating pathogenic signaling pathways in UC will pave the way for developing more effective probiotic-based therapies. In this review, we explore the mechanistic role of probiotics in the attenuation of pathogenic signaling pathways, including NF-κB, JAK/STAT, mitogen-activated protein kinases (MAPKs), Wnt/β-catenin, the nucleotide-binding domain (NOD)-, leucine-rich repeat (LRR)- and pyrin domain-containing protein 3 (NLRP3) inflammasome, Toll-like receptors (TLRs), interleukin-23 (IL-23)/IL-17 signaling pathway in UC.
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Affiliation(s)
- Chou-Yi Hsu
- Department of Pharmacy, Chia Nan University of Pharmacy and Science, Tainan, Taiwan
- Thunderbird School of Global Management, Arizona State University Tempe Campus, Phoenix, AZ, United States
| | - Mohammed Ahmed Mustafa
- Department of Medical Laboratory Technology, Imam Jaafar AL-Sadiq University, Baghdad, Iraq
- Department of Pathological Analyzes, College of Applied Sciences, University of Samarra, Samarra, Iraq
| | - Thabit Moath Omar
- Department of Medical Laboratory Technics, College of Health and Medical Technology, Alnoor University, Mosul, Iraq
| | - Sada Gh Taher
- Department of Pharmacy, National University of Science and Technology, Dhi Qar, Iraq
| | - Mohammed Ubaid
- Department of MTL, Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | - Nataliya S. Gilmanova
- Department of Prosthetic Dentistry, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | | | | | - Aya H. Athab
- Department of Pharmacy, Al-Zahrawi University College, Karbala, Iraq
| | - Rasoul Mirzaei
- Venom and Biotherapeutics Molecules Lab, Medical Biotechnology Department, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
| | - Sajad Karampoor
- Gastrointestinal and Liver Diseases Research Center, Iran University of Medical Sciences, Tehran, Iran
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11
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Tao S, Long X, Gong P, Yu X, Tian L. Phosphoproteomics Reveals Novel Insights into the Pathogenesis and Identifies New Therapeutic Kinase Targets of Ulcerative Colitis. Inflamm Bowel Dis 2024; 30:1367-1378. [PMID: 38085663 DOI: 10.1093/ibd/izad291] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Indexed: 08/02/2024]
Abstract
BACKGROUND Ulcerative colitis (UC) is a chronic recurrent inflammatory disease with unclear etiology. Currently, safe and effective treatment options for UC remain to be developed. Kinases, which catalyze the phosphorylation of substrates, have emerged as promising therapeutic targets for inflammatory diseases. We clarified the kinase activity profile and phosphorylation network in UC and aimed to reveal new pathogenic mechanisms and potential therapeutic targets. METHODS We first performed the phosphoproteomic analysis of rectal tissues from UC patients and healthy individuals. Further bioinformatic analyses revealed the remodeling of key kinases and signaling pathways. Then, we conducted a screening of kinases to identify new potential therapeutic targets through in vivo and in vitro experiments. RESULTS Phosphoproteomics revealed a drastic remodeling of signaling pathways in UC, such as pathways related to tight junction, adhesion junction, and necroptosis. Additionally, the activity of kinases such as CDK2, CLK1 and AURKB were significantly changed. Additional screening of these kinases identified CDK2 as a potential therapeutic target for UC, as inhibiting CDK2 effectively alleviated dextran sulfate sodium-induced colitis in mice. Further research revealed that suppressing CDK2 remarkably inhibited RIPK1, RIPK3, and MLKL phosphorylation, as well as MLKL oligomerization, thereby inhibiting epithelial necroptosis and protecting the intestinal barrier. CONCLUSIONS Our research deepened the understanding of UC pathogenesis through the lens of phosphorylation. Moreover, we identified CDK2 as a new potential therapeutic target for UC, revealing a novel role for CDK2 in necroptosis.
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Affiliation(s)
- Sifan Tao
- Department of Gastroenterology, The Third Xiangya Hospital, The Central South University, Changsha, China
- Key Laboratory of Non-resolving Inflammation and Cancer of the Hunan Province, The Third Xiangya Hospital, The Central South University, Changsha, China
| | - Xiuyan Long
- Department of Gastroenterology, The Third Xiangya Hospital, The Central South University, Changsha, China
| | - Pan Gong
- Department of Gastroenterology, The Third Xiangya Hospital, The Central South University, Changsha, China
| | - Xiaoyu Yu
- Department of Gastroenterology, The Third Xiangya Hospital, The Central South University, Changsha, China
| | - Li Tian
- Department of Gastroenterology, The Third Xiangya Hospital, The Central South University, Changsha, China
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12
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Jairath V, Afif W, Bressler B, Pope JE, Selchen D, Targownik LE, Panaccione R. Practical guidance for managing patients with moderate-to-severe ulcerative colitis using small molecule therapies. J Can Assoc Gastroenterol 2024; 7:282-289. [PMID: 39139217 PMCID: PMC11317630 DOI: 10.1093/jcag/gwae013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/15/2024] Open
Abstract
Ulcerative colitis (UC) is a severe and debilitating illness that affects the quality of life and physical health of many Canadians. Given the dynamic and progressive nature of the disease, advanced therapies are required to support its long-term management. The emergence of small molecule therapies offers novel treatment options that target mechanisms central to the immunopathology of UC. Sphingosine-1-phosphate (S1P) receptor modulators and Janus-activated kinase inhibitors are 2 classes of therapies that target unique pathways to attenuate inflammation and modulate the immune response characteristic of UC. This review aims to provide practical guidance on how these therapeutic options can best be used to optimize treatment management and highlight the emerging role of small molecule therapies as a treatment strategy for UC.
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Affiliation(s)
- Vipul Jairath
- Division of Gastroenterology, Western University, St. Joseph’s Health Care, London, ON, Canada
| | - Waqqas Afif
- Division of Gastroenterology and Hepatology, McGill University, Montreal General Hospital, Montreal, QC H3G 1A4, Canada
| | - Brian Bressler
- Division of Gastroenterology, University of British Columbia, Vancouver, BC V5Z 1M9, Canada
| | - Janet E Pope
- Division of Rheumatology, St Joseph’s Hospital, Western University, London, ON N6A 4V2, Canada
| | - Daniel Selchen
- Division of Neurology, Barlo Multiple Sclerosis Centre, Department of Medicine, St. Michael’s Hospital, University of Toronto, Toronto, ON M5B 1W8, Canada
| | - Laura E Targownik
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, ON M5S 3H2, Canada
- Mount Sinai Hospital IBD Centre, Division of Gastroenterology, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada
| | - Remo Panaccione
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, AB T2N 4Z6, Canada
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13
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Gawron LM, Johnson JB, Flynn AD, Woodcock AL. Family Planning for Patients With Inflammatory Bowel Disease in the Post-Dobbs Era. Gastroenterol Hepatol (N Y) 2024; 20:330-334. [PMID: 39193265 PMCID: PMC11346003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/29/2024]
Abstract
Federal protections for abortion care in the United States ended in June 2022. For people with inflammatory bowel disease (IBD) who are capable of pregnancy, the implications of an unwanted or mistimed conception, particularly in the setting of active disease flares or teratogenic treatment, are precarious and geographically variable. Prioritizing evidence-based and person-centered counseling for preconception health and contraceptive care needs is important during health care visits and not limited to reproductive health providers. Development of multidisciplinary clinics or complex contraception clinics in high-volume IBD centers can support time-sensitive counseling and services for patients. This article reviews reproductive considerations for people with IBD, particularly in the setting of legislative restrictions in the post-Dobbs landscape.
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Affiliation(s)
- Lori M. Gawron
- Division of Family Planning , Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, Utah
| | - Jessica B. Johnson
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Ann D. Flynn
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, Utah
| | - Alexandra L. Woodcock
- Division of Family Planning , Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, Utah
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14
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Fu S, Bao X, Mao Z, Lv Y, Zhu B, Chen Y, Zhou M, Tian S, Zhou F, Ding Z. Tetrastigma hemsleyanum polysaccharide ameliorates cytokine storm syndrome via the IFN-γ-JAK2/STAT pathway. Int J Biol Macromol 2024; 275:133427. [PMID: 38936586 DOI: 10.1016/j.ijbiomac.2024.133427] [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: 01/29/2024] [Revised: 06/20/2024] [Accepted: 06/24/2024] [Indexed: 06/29/2024]
Abstract
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is an disease characterized by pulmonary edema and widespread inflammation, leading to a notably high mortality rate. The dysregulation of both pro-inflammatory and anti-inflammatory systems, results in cytokine storm (CS), is intricately associated with the development of ALI/ARDS. Tetrastigma hemsleyanum polysaccharide (THP) exerts remarkable anti-inflammatory and immunomodulatory effects against the disease, although its precise role in pathogenesis remains unclear. In the present study, an ALI/ARDS model was established using bacterial lipopolysaccharides. THP administration via aerosol inhalation significantly mitigated lung injury, reduced the number of inflammatory cells, and ameliorated glycerophospholipid metabolism. Furthermore, specific CS-related pathways were investigated by examining the synergy between tumor necrosis factor-α and interferon-γ used to establish CS models. The results indicated that THP effectively decreased inflammatory damage and cell death. The RNA sequencing revealed the involvement of the Janus kinase (JAK) 2-signal transducers and activators of transcription (STAT) signaling pathway in exerting the mentioned effects. Additionally, THP inhibited the activation of the JAK-STAT pathway, thereby alleviating the CS both in vivo and in vitro. Overall, THP exhibited marked therapeutic potential against ALI/ARDS and CS, primarily by targeting the IFN-γ-JAK2/STAT signaling pathway.
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Affiliation(s)
- Siyu Fu
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Xiaodan Bao
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Zian Mao
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Yishan Lv
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Bingqi Zhu
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Yuchi Chen
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Mingyuan Zhou
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Shasha Tian
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China
| | - Fangmei Zhou
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
| | - Zhishan Ding
- School of Medical Technology and Information Engineering, Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
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15
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Manrai M, Jha AA, Dawra S, Pachisia AV. Biologics, Small Molecules and More in Inflammatory Bowel Disease: The Present and the Future. FUTURE PHARMACOLOGY 2024; 4:279-316. [DOI: 10.3390/futurepharmacol4010017] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/16/2024]
Abstract
Inflammatory bowel disease (IBD) is a group of heterogeneous chronic inflammatory diseases of the gut presenting with intestinal and extraintestinal manifestations. Most cases fit in predominantly two types, namely, ulcerative colitis and Crohn’s disease. The incidence of IBD has been increasing steadily in the past three decades. Focused research has resulted in many therapeutic options. Biologics (derived from humans or animals) and small molecules have emerged as the cornerstone in the management of IBD and have become widely available. Currently, monoclonal antibodies against tumor necrosis factor-alpha (infliximab, adalimumab, certolizumab, and golimumab), integrins (vedolizumab and natalizumab), and interleukin (IL)-12 and IL-23 antagonists (ustekinumab), along with small molecules (tofacitinib), are approved for use. This article summarizes various aspects of these drugs, like clinical pharmacology, indications for use in IBD, safety in pregnancy and lactation, and the adverse effects profile based on the studies leading to their approval. This review also focuses on the recent advances and future perspectives specific to biologics in IBD.
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Affiliation(s)
- Manish Manrai
- Department of Gastroenterology, Command Hospital, Lucknow Pin 226002, Uttar Pradesh, India
| | - Atul Abhishek Jha
- Department of Gastroenterology, Command Hospital, Lucknow Pin 226002, Uttar Pradesh, India
| | - Saurabh Dawra
- Department of Gastroenterology, Command Hospital, Pune Pin 411040, Maharashtra, India
| | - Aditya Vikram Pachisia
- Department of Gastroenterology, Command Hospital, Bengaluru Pin 560007, Karnataka, India
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16
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Suilik HA, Jaber F, Abuelazm M, Ramadan A, Elzeftawy MA, Elrosasy A, Youssef RA, Abdelazeem B, Hashash JG, Farraye FA, Ghoz H. Sphingosine 1-phosphate (S1P) receptor modulators as an induction and maintenance therapy for ulcerative colitis: a systematic review and meta-analysis of randomized controlled trials. Inflamm Res 2024; 73:183-198. [PMID: 38153524 DOI: 10.1007/s00011-023-01829-6] [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: 09/02/2023] [Revised: 09/02/2023] [Accepted: 11/27/2023] [Indexed: 12/29/2023] Open
Abstract
BACKGROUND AND OBJECTIVE One sphingosine-1-phosphate (S1P) receptor modulator is approved (ozanimod) and another (etrasimod) is under investigation for the induction and maintenance of remission of ulcerative colitis (UC). We aim to evaluate the efficacy and safety of S1P modulators in patients with active UC. METHODS We conducted a systematic review and meta-analysis synthesizing randomized controlled trials (RCTs), which were retrieved by systematically searching: PubMed, Web of Science, SCOPUS, and Cochrane through May 13th, 2023. We used the fixed-effect model to pool dichotomous data using risk ratio (RR) with a 95% confidence interval (CI). RESULTS Five RCTs with a total of 1990 patients were included. S1P receptor modulators were significantly associated with increased clinical response during both the induction (RR 1.71 with 95% CI [1.50, 1.94], P = 0.00001) and maintenance phases (RR 1.89 with 95% CI [1.33, 2.69], P = 0.0004); clinical remission rates during both induction (RR 2.76 with 95% CI [1.88, 4.05], P = 0.00001) and maintenance phases (RR 3.34 with 95% CI [1.41, 7.94], P = 0.006); endoscopic improvement during both induction (RR 2.15 with 95% CI [1.71, 2.70], P = 0.00001) and maintenance phases (RR 2.41 with 95% CI [1.15, 5.05], P = 0.02); and histologic remission during both induction (RR 2.60 with 95% CI [1.89, 3.57] [1.17, 2.10], P = 0.00001) and maintenance phases (RR 2.52 with 95% CI [1.89, 3.37], P = 0.00001). Finally, there was no difference regarding safety outcomes as compared to placebo in both the induction and maintenance phases. CONCLUSION S1P receptor modulators are effective in inducing and maintaining remission in patients with moderate to severe UC.
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Affiliation(s)
| | - Fouad Jaber
- Department of Internal Medicine, University of Missouri-Kansas City, Kansas City, MO, USA.
| | | | - Alaa Ramadan
- Faculty of Medicine, South Valley University, Qena, Egypt
| | | | - Amr Elrosasy
- Faculty of Medicine, Cairo University, Cairo, Egypt
| | | | - Basel Abdelazeem
- West Virginia University, Morgantown, WV, USA
- Michigan State University, East Lansing, MI, USA
| | - Jana G Hashash
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA
| | - Francis A Farraye
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA
| | - Hassan Ghoz
- Division of Gastroenterology and Hepatology, University of Missouri-Kansas City, Kansas City, MO, USA
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17
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Henson JB, King LY. Post-Transplant Management and Complications of Autoimmune Hepatitis, Primary Biliary Cholangitis, and Primary Sclerosing Cholangitis including Disease Recurrence. Clin Liver Dis 2024; 28:193-207. [PMID: 37945160 PMCID: PMC11033708 DOI: 10.1016/j.cld.2023.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2023]
Abstract
Autoimmune liver diseases have unique post-transplant considerations. These recipients are at increased risk of rejection, and recurrent disease may also develop, which can progress to graft loss and increase mortality. Monitoring for and managing these complications is therefore important, though data on associated risk factors and immunosuppression strategies has in most cases been mixed. There are also other disease-specific complications that require management and may impact these decisions, including inflammatory bowel disease in PSC. Further work to better understand the optimal management strategies for these patients post-transplant is needed.
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Affiliation(s)
- Jacqueline B Henson
- Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, DUMC Box 3913, Durham, NC 27710, USA
| | - Lindsay Y King
- Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, DUMC Box 3923, Durham, NC 27710, USA.
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18
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Banerjee R, Sharma V, Patel R, Jena A, Pal P, Raghunathan N, Kumar A, Sood A, Puri AS, Goswami B, Desai D, Mekala D, Ramesh GN, Rao GV, Peddi K, Philip M, Tandon M, Bhatia S, Godbole S, Bhatia S, Ghoshal UC, Dutta U, Midha V, Prasad VGM, Reddy DN. Tofacitinib use in ulcerative colitis: An expert consensus for day-to-day clinical practice. Indian J Gastroenterol 2024; 43:22-35. [PMID: 38347433 DOI: 10.1007/s12664-023-01507-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 12/13/2023] [Indexed: 03/10/2024]
Abstract
Rising number of inflammatory bowel disease (IBD) cases in developing countries necessitate clear guidance for clinicians for the appropriate use of advanced therapies. An expert consensus document was generated to guide the usage of tofacitinib, a Janus kinase inhibitor, in ulcerative colitis. Tofacitinib is a useful agent for the induction and maintenance of remission in ulcerative colitis. It can be used in the setting of biological failure or even steroid-dependent and thiopurine refractory disease. Typically, the induction dose is 10 mg BD orally. Usually, clinical response is evident within eight weeks of therapy. In those with clinical response, the dose can be reduced from 10 mg BD to 5 mg BD. Tofacitinib should be avoided or used cautiously in the elderly, patients with cardiovascular co-morbidity, uncontrolled cardiac risk factors, previous thrombotic episodes and those at high risk for venous thrombosis or previous malignancy. Baseline evaluation should include testing for and management of hepatitis B infection and latent tuberculosis. Where feasible, it is prudent to ensure complete adult vaccination, including Herpes zoster, before starting tofacitinib. The use of tofacitinib may be associated with an increased risk of infections such as herpes zoster and tuberculosis reactivation. Maternal exposure to tofacitinib should be avoided during pre-conception, pregnancy, and lactation. There is emerging evidence of tofacitinib in acute severe colitis, although the exact positioning (first-line with steroids or second-line) is uncertain.
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Affiliation(s)
- Rupa Banerjee
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Mindspace Road, Gachibowli, Hyderabad, 500 032, India.
| | - Vishal Sharma
- Postgraduate Institute of Medical Education and Research, Sector-12, Chandigarh, 160 012, India
| | - Rajendra Patel
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Mindspace Road, Gachibowli, Hyderabad, 500 032, India
| | - Anuraag Jena
- IMS and SUM Hospital, K8, Kalinga Nagar, Bhubaneswar, 751 003, India
| | - Partha Pal
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Mindspace Road, Gachibowli, Hyderabad, 500 032, India
| | - Nalini Raghunathan
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Mindspace Road, Gachibowli, Hyderabad, 500 032, India
| | - Ajay Kumar
- BLK Institute of Digestive Science, BLK-Max Super Speciality Hospital, Pusa Road, New Delhi, 110 005, India
| | - Ajit Sood
- Dayanand Medical College and Hospital, Civil Lines, Tagore Nagar, Ludhiana, 141 001, India
| | - Amarender S Puri
- Medanta Hospital, CH Baktawar Singh Road, Medicity, Islampur Colony, Sector 38, Gurugram, 122 001, India
| | | | - Devendra Desai
- Hinduja Hospital, 8-12, Swatantryaveer Savarkar Road, Mahim West, Mahim, Mumbai, 400 016, India
| | - Dhanush Mekala
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Mindspace Road, Gachibowli, Hyderabad, 500 032, India
| | - G N Ramesh
- Aster Hospital, Kuttisahib Road Cheranelloor, South Chittoor, Kochi, 682 027, India
| | - G V Rao
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Mindspace Road, Gachibowli, Hyderabad, 500 032, India
| | - Kiran Peddi
- Yashoda Hospitals, 6-3-905, Raj Bhavan Road, Matha Nagar, Somajiguda, Hyderabad, 500 082, India
| | - Mathew Philip
- Lisie Institute of Gastroenterology, Cochin, Lisie Hospital Road, North Kaloor, Kaloor, Ernakulam, 682 018, India
| | - Manu Tandon
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Mindspace Road, Gachibowli, Hyderabad, 500 032, India
| | - Shobna Bhatia
- National Institute of Medical Sciences, Kalwad Kalan and Khurd, Jaipur, 303 121, India
| | - Shubhankar Godbole
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Mindspace Road, Gachibowli, Hyderabad, 500 032, India
| | - Sumit Bhatia
- Paras Hospitals, Sec-43, Sushant Lok, Gurugram, 122 002, India
| | - Uday C Ghoshal
- Apollo Institute of Gastrosciences and Liver, Apollo Multispecialty Hospitals, 58, Canal Circular Road, Kadapara, Phool Bagan, Kankurgachi, Kolkata, 700 054, India
| | - Usha Dutta
- Postgraduate Institute of Medical Education and Research, Sector-12, Chandigarh, 160 012, India
| | - Vandana Midha
- Dayanand Medical College and Hospital, Civil Lines, Tagore Nagar, Ludhiana, 141 001, India
| | | | - D Nageshwar Reddy
- Department of Medical Gastroenterology, Asian Institute of Gastroenterology, Mindspace Road, Gachibowli, Hyderabad, 500 032, India
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19
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Lashgari NA, Roudsari NM, Niknejad A, Shamsnia HS, Shayan M, Shalmani LM, Momtaz S, Rezaei N, Abdolghaffari AH. LRRK2; Communicative Role in the Treatment of Parkinson's Disease and Ulcerative Colitis Overlapping. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2024; 23:1177-1188. [PMID: 38279762 DOI: 10.2174/0118715273270874231205050727] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 10/12/2023] [Accepted: 10/23/2023] [Indexed: 01/28/2024]
Abstract
BACKGROUND Involvement of gastrointestinal inflammation in Parkinson's disease (PD) pathogenesis and movement have progressively emerged. Inflammation is involved in the etiology of both PD and inflammatory bowel disease (IBD). Transformations in leucine-rich recurrent kinase 2 (LRRK2) are among the best hereditary supporters of IBD and PD. Elevated levels of LRRK2 have been reported in stimulated colonic tissue from IBD patients and peripheral invulnerable cells from irregular PD patients; thus, it is thought that LRRK2 directs inflammatory cycles. OBJECTIVE Since its revelation, LRRK2 has been seriously linked in neurons, albeit various lines of proof affirmed that LRRK2 is profoundly communicated in invulnerable cells. Subsequently, LRRK2 might sit at a junction by which stomach inflammation and higher LRRK2 levels in IBD might be a biomarker of expanded risk for inconsistent PD or potentially may address a manageable helpful objective in incendiary sicknesses that increment the risk of PD. Here, we discuss how PD and IBD share covering aggregates, especially regarding LRRK2 and present inhibitors, which could be a helpful objective in ongoing treatments. METHOD English data were obtained from Google Scholar, PubMed, Scopus, and Cochrane library studies published between 1990-December 2022. RESULT Inhibitors of the LRRK2 pathway can be considered as the novel treatment approaches for IBD and PD treatment. CONCLUSION Common mediators and pathways are involved in the pathophysiology of IBD and PD, which are majorly correlated with inflammatory situations. Such diseases could be used for further clinical investigations.
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Affiliation(s)
- Naser-Aldin Lashgari
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Nazanin Momeni Roudsari
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amirhossein Niknejad
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Hedieh Sadat Shamsnia
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Maryam Shayan
- Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Leila Mohaghegh Shalmani
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Saeideh Momtaz
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran
- Toxicology and Diseases Group (TDG), Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), and Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Nima Rezaei
- Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Hossein Abdolghaffari
- Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
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20
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Hilley P, Con D, Choy MC, Srinivasan A, De Cruz P. Upadacitinib in end stage renal disease: A case of acute severe ulcerative colitis. JGH Open 2023; 7:1012-1015. [PMID: 38162859 PMCID: PMC10757473 DOI: 10.1002/jgh3.13015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/10/2023] [Accepted: 11/17/2023] [Indexed: 01/03/2024]
Abstract
Recent data, indicating that inflammatory bowel disease (IBD) may be a risk factor for future chronic kidney disease, highlight the need to study the safety and clinical effectiveness of advanced IBD therapies in patients with end stage renal disease (ESRD), defined as an eGFR <15 mL/min/1.73m2. Upadacitinib, a selective oral Janus kinase (JAK) 1 inhibitor, has demonstrated efficacy in the management of moderate to severe ulcerative colitis. There is also emerging data indicating that JAK inhibition may be clinically effective in the setting of steroid-refractory acute severe ulcerative colitis (ASUC). There is, however, a lack of "real-world" data documenting the use of JAK inhibitors in patients with ESRD. Here, we report the use of upadacitinib in a patient with ESRD for the management of steroid-refractory ASUC, demonstrating, for the first time, the safe and clinically effective use of upadacitinib in this population.
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Affiliation(s)
- Patrick Hilley
- Department of GastroenterologyAustin HealthHeidelbergVictoriaAustralia
| | - Danny Con
- Department of GastroenterologyAustin HealthHeidelbergVictoriaAustralia
| | - Matthew C. Choy
- Department of GastroenterologyAustin HealthHeidelbergVictoriaAustralia
- Austin Academic CentreUniversity of MelbourneParkvilleVictoriaAustralia
| | - Ashish Srinivasan
- Department of GastroenterologyAustin HealthHeidelbergVictoriaAustralia
- Austin Academic CentreUniversity of MelbourneParkvilleVictoriaAustralia
| | - Peter De Cruz
- Department of GastroenterologyAustin HealthHeidelbergVictoriaAustralia
- Austin Academic CentreUniversity of MelbourneParkvilleVictoriaAustralia
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21
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Schreiber S, Rogler G, Watanabe M, Vermeire S, Maaser C, Danese S, Faes M, Van Hoek P, Hsieh J, Moerch U, Zhou Y, de Haas A, Rudolph C, Oortwijn A, Loftus EV. Integrated safety analysis of filgotinib for ulcerative colitis: Results from SELECTION and SELECTIONLTE. Aliment Pharmacol Ther 2023; 58:874-887. [PMID: 37718932 DOI: 10.1111/apt.17674] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 06/04/2023] [Accepted: 07/16/2023] [Indexed: 09/19/2023]
Abstract
BACKGROUND Filgotinib 200 mg (FIL200) is an approved treatment for adults with moderately to severely active ulcerative colitis (UC). AIM To report integrated safety data from the phase 2b/3 SELECTION study (NCT02914522) and its ongoing long-term extension study SELECTIONLTE (NCT02914535). METHODS Safety outcomes were analysed in adults with moderately to severely active UC who received FIL200, filgotinib 100 mg (FIL100) or placebo once daily throughout the 11-week SELECTION induction study, the 47-week SELECTION maintenance study (if applicable) and SELECTIONLTE (if applicable). Exposure-adjusted incidence rates (EAIRs) per 100 censored patient-years of exposure with 95% confidence intervals were reported for treatment-emergent adverse events (AEs). Certain AE data were presented in subgroups, including age and prior biologic exposure status. RESULTS This interim analysis included 1348 patients representing 3326.2 patient-years of exposure. Baseline characteristics of patients entering SELECTION were similar across treatment groups. EAIRs for serious infection, thromboembolic events and major adverse cardiovascular events (MACE) were consistently low across treatment groups. Most patients with MACE had cardiovascular risk factors. The EAIR for herpes zoster was numerically higher for FIL200 than for placebo. Infection incidences were numerically higher in biologic-experienced than biologic-naive patients. Higher incidences of certain AEs in patients 65 years of age or older were as expected. Four deaths occurred, including three cardiovascular deaths, none of which was considered related to filgotinib. CONCLUSION FIL200 and FIL100 were well tolerated with no unexpected safety signals in patients with moderately to severely active UC, regardless of previous biologic exposure or age. CLINICALTRIALS GOV IDENTIFIERS (NCT NUMBERS) NCT02914522, NCT02914535.
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Affiliation(s)
- Stefan Schreiber
- Department Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany
| | - Gerhard Rogler
- University Hospital of Zurich, University of Zurich, Zurich, Switzerland
| | - Mamoru Watanabe
- Advanced Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
| | - Séverine Vermeire
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Christian Maaser
- Outpatients Department of Gastroenterology, Department of Geriatrics, Hospital Lüneburg, Lüneburg, Germany
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele, Milan, Italy
- Vita-Salute San Raffaele University, Milan, Italy
| | | | | | - Jeremy Hsieh
- Gilead Sciences, Inc., Foster City, California, USA
| | | | - Yan Zhou
- Gilead Sciences, Inc., Foster City, California, USA
| | | | | | | | - Edward V Loftus
- Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
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22
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He S, Xia J, Jia H, Dai Q, Chen C, Zhou Y, Wang XB. Peficitinib ameliorates 5-fluorouracil-induced intestinal damage by inhibiting aging, inflammatory factors and oxidative stress. Int Immunopharmacol 2023; 123:110753. [PMID: 37572505 DOI: 10.1016/j.intimp.2023.110753] [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: 02/20/2023] [Revised: 07/30/2023] [Accepted: 07/31/2023] [Indexed: 08/14/2023]
Abstract
5-Fluorouracil (5-FU) is a conventional and effective drug for colorectal cancer patients, and it is an important part of combined chemotherapy and adjuvant chemotherapy. Chemotherapy intestinal mucositis (CIM) is a severe side effect caused by 5-FU that, induces cancer treatment failure and affects patients' quality of life. The mechanism of 5-FU-induced CIM is related to normal cell senescence induced by 5-FU. Peficitinib, a Janus Kinase (JAK) inhibitor, treats inflammatory disorders, including rheumatoid arthritis, psoriasis, and inflammatory bowel disease. However, the therapeutic role and underlying mechanism of peficitinib in CIM remain unclear. The main objective of our research was to investigate the effects of peficitinib on 5-FU-induced senescence and intestinal damage in human umbilical vein endothelial (HUVEC) cells, human intestinal epithelial (HIEC) cells and BABL/C mice. The results showed that 5-FU caused intestinal damage by inducing aging and increasing inflammation and oxidative stress. Peficitinib alleviated aging by reducing senescence-beta-galactosidase (SA-β-gal) activity and the protein levels of aging indicators (p53, p21, p16). Moreover, peficitinib reversed the changes in senescence-associated secretory phenotype (SASP) expression caused by 5-FU. Besides, 5-FU induced release of inflammatory factors and oxidative stress indicators was reversed by peficitinib. Additionally, the combination of peficitinib and 5-FU reinforced the anticancer curative intent of 5-FU in two colorectal cancer cell lines (HCT116 cells and SW620 cells). In conclusion, peficitinib alleviates mucositis by alleviating aging, reducing inflammatory accumulation and oxidative stress and enhancing the antitumor activity of 5-FU.
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Affiliation(s)
- Siyue He
- School of Basic Medicine, Dali University, Dali, Yunnan Province 671000, China; Key Laboratory of University Cell Biology Yunnan Province, Dali, Yunnan Province 671000, China
| | - Jing Xia
- School of Basic Medicine, Dali University, Dali, Yunnan Province 671000, China; Key Laboratory of University Cell Biology Yunnan Province, Dali, Yunnan Province 671000, China
| | - Huijie Jia
- School of Basic Medicine, Dali University, Dali, Yunnan Province 671000, China; Key Laboratory of University Cell Biology Yunnan Province, Dali, Yunnan Province 671000, China
| | - Qianlong Dai
- School of Basic Medicine, Dali University, Dali, Yunnan Province 671000, China; Key Laboratory of University Cell Biology Yunnan Province, Dali, Yunnan Province 671000, China
| | - Cui Chen
- School of Basic Medicine, Dali University, Dali, Yunnan Province 671000, China; Qujing Medical College, Qujing, Yunnan Province 655011, China
| | - Yue Zhou
- School of Basic Medicine, Dali University, Dali, Yunnan Province 671000, China.
| | - Xiao Bo Wang
- School of Basic Medicine, Dali University, Dali, Yunnan Province 671000, China; Key Laboratory of University Cell Biology Yunnan Province, Dali, Yunnan Province 671000, China.
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23
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Yao Z, Jiang F, Luo H, Zhou J, Shi W, Xu S, Zhang Y, Dai F, Li X, Liu Z, Wang X. Causal Effects of Blood Lipid Traits on Inflammatory Bowel Diseases: A Mendelian Randomization Study. Metabolites 2023; 13:730. [PMID: 37367888 DOI: 10.3390/metabo13060730] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 05/28/2023] [Accepted: 06/06/2023] [Indexed: 06/28/2023] Open
Abstract
Inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC), have become a global health problem with a rapid growth of incidence in newly industrialized countries. Observational studies have recognized associations between blood lipid traits and IBDs, but the causality still remains unclear. To determine the causal effects of blood lipid traits, including triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) on IBDs, two-sample Mendelian randomization (MR) analyses were conducted using the summary-level genome-wide association study (GWAS) statistics of blood lipid traits and IBDs. Our univariable MR using multiplicative random-effect inverse-variance weight (IVW) method identified TC (OR: 0.674; 95% CI: 0.554, 0.820; p < 0.00625) and LDL-C (OR: 0.685; 95% CI: 0.546, 0.858; p < 0.00625) as protective factors of UC. The result of our multivariable MR analysis further provided suggestive evidence of the protective effect of TC on UC risk (OR: 0.147; 95% CI: 0.025, 0.883; p < 0.05). Finally, our MR-BMA analysis prioritized TG (MIP: 0.336; θ^MACE: -0.025; PP: 0.31; θ^λ: -0.072) and HDL-C (MIP: 0.254; θ^MACE: -0.011; PP: 0.232; θ^λ: -0.04) for CD and TC (MIP: 0.721; θ^MACE: -0.257; PP: 0.648; θ^λ: -0.356) and LDL-C (MIP: 0.31; θ^MACE: -0.095; PP: 0.256; θ^λ: -0.344) for UC as the top-ranked protective factors. In conclusion, the causal effect of TC for UC prevention was robust across all of our MR approaches, which provide the first evidence that genetically determined TC is causally associated with reduced risk of UC. The finding of this study provides important insights into the metabolic regulation of IBDs and potential metabolites targeting strategies for IBDs intervention.
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Affiliation(s)
- Ziqin Yao
- Department of Blood Transfusion, Sir Run Run Shaw Hospital, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Feiyu Jiang
- Department of Blood Transfusion, Sir Run Run Shaw Hospital, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Hongbin Luo
- Department of Blood Transfusion, Sir Run Run Shaw Hospital, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Jiahui Zhou
- Department of Blood Transfusion, Sir Run Run Shaw Hospital, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Wanting Shi
- Department of Blood Transfusion, Sir Run Run Shaw Hospital, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Shoufang Xu
- Department of Blood Transfusion, Sir Run Run Shaw Hospital, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Yingying Zhang
- Department of Blood Transfusion, Sir Run Run Shaw Hospital, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Feng Dai
- Department of Blood Transfusion, Sir Run Run Shaw Hospital, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Xinran Li
- Department of Blood Transfusion, Sir Run Run Shaw Hospital, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Zhiwei Liu
- Department of Blood Transfusion, Sir Run Run Shaw Hospital, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Xinhui Wang
- Department of Blood Transfusion, Sir Run Run Shaw Hospital, School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China
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McCormack MD, Wahedna NA, Aldulaimi D, Hawker P. Emerging role of dual biologic therapy for the treatment of inflammatory bowel disease. World J Clin Cases 2023; 11:2621-2630. [PMID: 37214562 PMCID: PMC10198105 DOI: 10.12998/wjcc.v11.i12.2621] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 02/07/2023] [Accepted: 03/24/2023] [Indexed: 04/25/2023] Open
Abstract
Biologic agents have now been used in the management of inflammatory bowel disease (IBD) for many years where experience, expertise and confidence in their use has developed over time. In the United Kingdom, there are well established guidelines and recommendations for both single agent biologic treatments, and with combination therapy of a biologic agent with a small molecule agent in maintenance therapy. In recent times, there has been increasing interest and experience using dual biologic therapy (DBT) in IBD, primarily in difficult to treat and refractory cases with high disease burden. However, published data on use, experience and safety profiles is limited and large-scale studies remain low in number in this developing area. We therefore aim to present a summary and review of the available published data in this area to help us better understand the emerging role of DBT in IBD.
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Affiliation(s)
- Matthew D McCormack
- Department of Gastroenterology, South Warwickshire NHS Foundation Trust, Warwick Hospital, Warwick CV34 5BW, United Kingdom
| | - Natasha A Wahedna
- Department of Gastroenterology, South Warwickshire NHS Foundation Trust, Warwick Hospital, Warwick CV34 5BW, United Kingdom
| | - David Aldulaimi
- Department of Gastroenterology, South Warwickshire NHS Foundation Trust, Warwick Hospital, Warwick CV34 5BW, United Kingdom
| | - Peter Hawker
- Department of Gastroenterology, South Warwickshire NHS Foundation Trust, Warwick Hospital, Warwick CV34 5BW, United Kingdom
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25
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Borcherding DC, Amin NV, He K, Zhang X, Lyu Y, Dehner C, Bhatia H, Gothra A, Daud L, Ruminski P, Pratilas CA, Pollard K, Sundby T, Widemann BC, Hirbe AC. MEK Inhibition Synergizes with TYK2 Inhibitors in NF1-Associated Malignant Peripheral Nerve Sheath Tumors. Clin Cancer Res 2023; 29:1592-1604. [PMID: 36799629 PMCID: PMC10102849 DOI: 10.1158/1078-0432.ccr-22-3722] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/23/2023] [Accepted: 02/15/2023] [Indexed: 02/18/2023]
Abstract
PURPOSE Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas with limited treatment options and poor survival rates. About half of MPNST cases are associated with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Overexpression of TYK2 occurs in the majority of MPNST, implicating TYK2 as a therapeutic target. EXPERIMENTAL DESIGN The effects of pharmacologic TYK2 inhibition on MPNST cell proliferation and survival were examined using IncuCyte live cell assays in vitro, and downstream actions were analyzed using RNA-sequencing (RNA-seq), qPCR arrays, and validation of protein changes with the WES automated Western system. Inhibition of TYK2 alone and in combination with MEK inhibition was evaluated in vivo using both murine and human MPNST cell lines, as well as MPNST PDX. RESULTS Pharmacologic inhibition of TYK2 dose-dependently decreased proliferation and induced apoptosis over time. RNA-seq pathway analysis on TYK2 inhibitor-treated MPNST demonstrated decreased expression of cell cycle, mitotic, and glycolysis pathways. TYK2 inhibition resulted in upregulation of the MEK/ERK pathway gene expression, by both RNA-seq and qPCR array, as well as increased pERK1/2 levels by the WES Western system. The compensatory response was tested with dual treatment with TYK2 and MEK inhibitors, which synergistically decreased proliferation and increased apoptosis in vitro. Finally, combination therapy was shown to inhibit growth of MPNST in multiple in vivo models. CONCLUSIONS These data provide the preclinical rationale for the development of a phase I clinical trial of deucravacitinib and mirdametinib in NF1-assosciated MPNST.
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Affiliation(s)
- Dana C. Borcherding
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Neha V. Amin
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Kevin He
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Xiaochun Zhang
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Yang Lyu
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Carina Dehner
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri
| | - Himanshi Bhatia
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Angad Gothra
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Layla Daud
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Peter Ruminski
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Christine A. Pratilas
- Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland
| | - Kai Pollard
- Division of Pediatric Oncology, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland
| | - Taylor Sundby
- Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Brigitte C. Widemann
- Pediatric Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland
| | - Angela C. Hirbe
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri
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26
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Sandborn WJ, Vermeire S, Peyrin-Biroulet L, Dubinsky MC, Panes J, Yarur A, Ritter T, Baert F, Schreiber S, Sloan S, Cataldi F, Shan K, Rabbat CJ, Chiorean M, Wolf DC, Sands BE, D'Haens G, Danese S, Goetsch M, Feagan BG. Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies. Lancet 2023; 401:1159-1171. [PMID: 36871574 DOI: 10.1016/s0140-6736(23)00061-2] [Citation(s) in RCA: 163] [Impact Index Per Article: 81.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/19/2022] [Accepted: 12/23/2022] [Indexed: 03/06/2023]
Abstract
BACKGROUND Etrasimod, a once-daily, oral, sphingosine 1-phosphate (S1P) receptor modulator that selectively activates S1P receptor subtypes 1, 4, and 5, with no detectable activity on S1P2,3, is in development for the treatment of immune-mediated diseases, including ulcerative colitis. In these two phase 3 trials, we aimed to evaluate the safety and efficacy of etrasimod in adult patients with moderately to severely active ulcerative colitis. METHODS In two independent randomised, multicentre, double-blind, placebo-controlled, phase 3 trials, ELEVATE UC 52 and ELEVATE UC 12, adults with active moderate-to-severe ulcerative colitis and an inadequate or loss of response or intolerance to at least one approved ulcerative colitis therapy were randomly assigned (2:1) to once-daily oral etrasimod 2 mg or placebo. Patients in ELEVATE UC 52 were enrolled from 315 centres in 40 countries. Patients in ELEVATE UC 12 were enrolled from 407 centres in 37 countries. Randomisation was stratified by previous exposure to biologicals or Janus kinase inhibitor therapy (yes vs no), baseline corticosteroid use (yes vs no), and baseline disease activity (modified Mayo score [MMS]; 4-6 vs 7-9). ELEVATE UC 52 comprised a 12-week induction period followed by a 40-week maintenance period with a treat-through design. ELEVATE UC 12 independently assessed induction at week 12. The primary efficacy endpoints were the proportion of patients with clinical remission at weeks 12 and 52 in ELEVATE UC 52 and week 12 in ELEVATE UC 12. Safety was evaluated in both trials. ELEVATE UC 52 and ELEVATE UC 12 were registered with ClinicalTrials.gov, NCT03945188 and NCT03996369, respectively. FINDINGS Patients in ELEVATE UC 52 were enrolled between June 13, 2019, and Jan 28, 2021. Patients in ELEVATE UC 12 were enrolled between Sept 15, 2020, and Aug 12, 2021. ELEVATE UC 52 and ELEVATE UC 12 screened 821 patients and 606 patients, respectively, with 433 and 354 subsequently undergoing random assignment. The full analysis set of ELEVATE UC 52 comprised 289 patients assigned to etrasimod and 144 to placebo. In ELEVATE UC 12, 238 patients were assigned to etrasimod and 116 to placebo. In ELEVATE UC 52, a significantly greater proportion of patients in the etrasimod group achieved clinical remission compared with patients in the placebo group at completion of the 12-week induction period (74 [27%] of 274 patients vs ten [7%] of 135 patients; p<0·0001) and at week 52 (88 [32%] of 274 patients vs nine [7%] of 135 patients; p<0·0001). In ELEVATE UC 12, 55 (25%) of 222 patients in the etrasimod group had clinical remission compared with 17 (15%) of 112 patients in the placebo group at the end of the 12-week induction period (p=0·026). Adverse events were reported in 206 (71%) of 289 patients in the etrasimod group and 81 (56%) of 144 patients in the placebo group in ELEVATE UC 52 and 112 (47%) of 238 patients in the etrasimod group and 54 (47%) of 116 patients in the placebo group in ELEVATE UC 12. No deaths or malignancies were reported. INTERPRETATION Etrasimod was effective and well tolerated as an induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Etrasimod is a treatment option with a unique combination of attributes that might address the persistent unmet needs of patients with ulcerative colitis. FUNDING Arena Pharmaceuticals.
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Affiliation(s)
- William J Sandborn
- Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA.
| | - Séverine Vermeire
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, University of Lorraine, Inserm, NGERE, F-54000 Nancy, France; Groupe Hospitalier Privé Ambroise Paré-Hartmann, Paris IBD Center, Nully-sur-Seine, France
| | - Marla C Dubinsky
- Department of Gastroenterology, Feinstein IBD Center, Mount Sinai, New York, NY, USA
| | - Julian Panes
- Department of Gastroenterology, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Andres Yarur
- Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Timothy Ritter
- Department of Research and Education, GI Alliance Research, Southlake, TX, USA
| | - Filip Baert
- Department of Gastroenterology, AZ Delta, Roeselare, Belgium
| | - Stefan Schreiber
- University Hospital Schleswig-Holstein, Department Internal Medicine I, Kiel University, Kiel, Germany
| | - Sheldon Sloan
- Arena Pharmaceuticals, San Diego, CA, USA; a wholly-owned subsidiary of Pfizer Inc, New York, NY, USA
| | - Fabio Cataldi
- Arena Pharmaceuticals, San Diego, CA, USA; a wholly-owned subsidiary of Pfizer Inc, New York, NY, USA
| | - Kevin Shan
- Arena Pharmaceuticals, San Diego, CA, USA; a wholly-owned subsidiary of Pfizer Inc, New York, NY, USA
| | - Christopher J Rabbat
- Arena Pharmaceuticals, San Diego, CA, USA; a wholly-owned subsidiary of Pfizer Inc, New York, NY, USA
| | - Michael Chiorean
- Division of Gastroenterology and Hepatology, IBD Center, Swedish Medical Center, Seattle, WA, USA
| | | | - Bruce E Sands
- Dr Henry D Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Geert D'Haens
- Inflammatory Bowel Disease Centre, University of Amsterdam, Amsterdam, Netherlands
| | - Silvio Danese
- Department of Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milan, Italy
| | - Martina Goetsch
- Arena Pharmaceuticals Development GmbH, Zug, Switzerland; a wholly-owned subsidiary of Pfizer Inc, New York, NY, USA
| | - Brian G Feagan
- Department of Medicine, University of Western Ontario/Alimentiv Inc, London, ON, Canada
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Herrera-deGuise C, Serra-Ruiz X, Lastiri E, Borruel N. JAK inhibitors: A new dawn for oral therapies in inflammatory bowel diseases. Front Med (Lausanne) 2023; 10:1089099. [PMID: 36936239 PMCID: PMC10017532 DOI: 10.3389/fmed.2023.1089099] [Citation(s) in RCA: 37] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 02/09/2023] [Indexed: 03/06/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic immune-mediated condition of the gastrointestinal tract that requires chronic treatment and strict surveillance. Development of new monoclonal antibodies targeting one or a few single cytokines, including anti-tumor necrosis factor agents, anti-IL 12/23 inhibitors, and anti-α4β7 integrin inhibitors, have dominated the pharmacological armamentarium in IBD in the last 20 years. Still, many patients experience incomplete or loss of response or develop serious adverse events and drug discontinuation. Janus kinase (JAK) is key to modulating the signal transduction pathway of several proinflammatory cytokines directly involved in gastrointestinal inflammation and, thus, probably IBD pathogenesis. Targeting the JAK-STAT pathway offers excellent potential for the treatment of IBD. The European Medical Agency has approved three JAK inhibitors for treating adults with moderate to severe Ulcerative Colitis when other treatments, including biological agents, have failed or no longer work or if the patient cannot take them. Although there are currently no approved JAK inhibitors for Crohn's disease, upadacitinib and filgotinib have shown increased remission rates in these patients. Other JAK inhibitors, including gut-selective molecules, are currently being studied IBD. This review will discuss the JAK-STAT pathway, its implication in the pathogenesis of IBD, and the most recent evidence from clinical trials regarding the use of JAK inhibitors and their safety in IBD patients.
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Affiliation(s)
| | | | | | - Natalia Borruel
- Unitat d’Atenció Crohn-Colitis, Digestive System Research Unit, Hospital Universitari Vall d’Hebrón, Barcelona, Spain
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Sadeghi S, Goodarzi A. Various Application of Tofacitinib and Ruxolitinib (Janus Kinase Inhibitors) in Dermatology and Rheumatology: A Review of Current Evidence and Future Perspective. Dermatol Pract Concept 2022; 12:e2022178. [PMID: 36534552 PMCID: PMC9681403 DOI: 10.5826/dpc.1204a178] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/01/2022] [Indexed: 08/11/2023] Open
Abstract
INTRODUCTION Janus kinase inhibitors (JAKi) are anti-inflammatory medications suppressing Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway by inhibiting various cytokines receptors on the membrane of cells. Mutations and polymorphisms on JAK and STAT proteins can cause dysregulation in the balance of immune system, and ultimately result in autoimmune disorders. OBJECTIVES To record and summarize the overall efficacy and safety of JAKi in various autoimmune conditions such as alopecia areata (AA), psoriasis vulgaris (PV), psoriatic arthritis (PsA), atopic dermatitis (AD), vitiligo, hidradenitis suppurative (HS), lichen planus (LP), and pyoderma gangrenosum (PG). METHODS A thorough review of articles was performed across PubMed and Google Scholar on meta-analyses, systematic reviews, clinical trials and case studies evaluating the treatment of autoimmune disorders such as AA, PV, PsA, AD, vitiligo, LP, HS, and PG with JAKi. Duplicated data and animal experiments or in vitro/ex vivo studies were excluded. RESULTS All the reviewed articles reported beneficial effects of tofacitinib and ruxolitinib application in the treatment of disorders mentioned above with the autoimmune predisposition. CONCLUSIONS Tofacitinib and ruxolitinib showed potential efficacy in treating several autoimmune disorders. Based on records in the reviewed studies, both medications had acceptable safety profiles; however, physicians are recommended to outweigh the risks and benefits of such treatments for each specific condition.
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Affiliation(s)
- Sara Sadeghi
- Rasool Akram Medical Complex Clinical Research Development Center (RCRDC), Iran University of Medical Sciences, Tehran, Iran
| | - Azadeh Goodarzi
- Rasool Akram Medical Complex Clinical Research Development Center (RCRDC), Iran University of Medical Sciences, Tehran, Iran
- Department of Dermatology, Faculty of Dermatology, Rasool Akram Medical Complex Clinical Research Development Center (RCRDC), School of Medicine, Iran University of Medical Sciences, Tehran, Iran
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29
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Castiblanco LL, García de Yébenes MJ, Martín Martín JM, Carmona L. Safety and efficacy in the nursing care of people with rheumatic diseases on janus kinase inhibitor therapy. Rheumatol Int 2022; 42:2125-2133. [PMID: 35982184 DOI: 10.1007/s00296-022-05185-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Accepted: 08/06/2022] [Indexed: 11/29/2022]
Abstract
Nurses's support of patients needs an evidence base as much as that of specialists management. However, some more practical aspects need specific questions that are not addressed in medical societies' recommendations. Our objective was to investigate the effect of Janus kinase inhibitors (jakinibs) on efficacy, safety, infections, cardiovascular risk, vaccination, pregnancy and lactation, interactions, surgery, and switch in adult patients with rheumatic diseases. We used the methodology for rapid reviews. Medline was searched for systematic reviews of randomised clinical trials and longitudinal observational studies reporting on the target aspects, without limits, yielding 540 titles, of which 70 articles were selected for detailed reading after the screening of title and abstract. In the case of no systematic review being published on a specific question, we resorted to the information provided by primary studies. The efficacy and safety profiles are similar to that of TNF-inhibitors to which they are compared in most studies; however, there is an increased risk of herpes zoster infections with jakinibs. The evidence on pregnancy, surgery and switches between jakinibs is very limited, although, so far, there are no major issues to inform patients about or to implement specific measures. In general, evidence to support nursing management in patients being treated with jakinibs is of moderate quality and scarce, ought to the recent incursion of jakinibs as a treatment.
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Affiliation(s)
| | | | | | - Loreto Carmona
- Institute of Musculoskeletal Health (Inmusc), Calle de Méndez Álvaro, 20, 28045, Madrid, Spain.
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Mishra S, Jena A, Kakadiya R, Sharma V, Ahuja V. Positioning of tofacitinib in treatment of ulcerative colitis: a global perspective. Expert Rev Gastroenterol Hepatol 2022; 16:737-752. [PMID: 35875997 DOI: 10.1080/17474124.2022.2106216] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2022] [Accepted: 07/22/2022] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Tofacitinib has emerged as a useful drug for the treatment of ulcerative colitis (UC). AREAS COVERED There is an unmet need for cost-effective, non-immunogenic drugs with a safe adverse effect profile to treat patients with ulcerative colitis. In the present review, we evaluate the available literature to inform the appropriate positioning of tofacitinib in the current drug landscape and identify subsets where its use should be done with caution. EXPERT OPINION Tofacitinib is helpful in the treatment of patients where the standard conventional or biological therapies have failed or were not tolerated. With lower costs of the generic drug than the biologicals (or biosimilars), it could be an important therapy in low- to middle-income countries. The risk of infections, especially Herpes Zoster and tuberculosis, needs to be addressed before initiation. Tofacitinib should be avoided in patients with venous thromboembolism and cardiovascular disease risk factors. Due to limited evidence, the use is not recommended in pregnancy, while it should be used with caution in elderly citizens. Future trials should look into the head-to-head comparison of tofacitinib with biologicals. The role of tofacitinib in acute severe colitis needs evaluation with comparative trials with current standards of care.
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Affiliation(s)
- Shubhra Mishra
- Department of Gastroenterology, Asian Institute of Gastroenterology Hospitals, Hyderabad, India
| | - Anuraag Jena
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Rinkalben Kakadiya
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Vishal Sharma
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Vineet Ahuja
- Department of Gastroenterology, All India Institute of Medical Education and Research, New Delhi, India
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Mori Y, Iwamoto F, Kuno T, Kobayashi S, Yoshida T, Yamaguchi T, Takano S, Kondo T, Kirito K, Enomoto N. Trisomy 8-positive Polycythemia Vera Complicated with Intestinal Behçet's-like Disease: A New Perspective for a Clinical Approach. Intern Med 2022; 61:1713-1719. [PMID: 34744109 PMCID: PMC9259299 DOI: 10.2169/internalmedicine.8395-21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Behçet's disease (BD) is a multisystem inflammatory disease of unknown origin. It rarely but occasionally occurs together with myelodysplastic syndrome and primary myelofibrosis. Trisomy 8 is one of the most common cytogenetic abnormalities in myeloid neoplasms; however, the association of BD with polycythemia vera (PV) and trisomy 8 has not been reported. A 70-year-old woman, diagnosed with PV and treated with hydroxyurea, had bloody stool due to multiple ulcers in the ileocecal region. Considering the lack of a response to treatment and other features, we suspected complication with intestinal Behçet's-like disease. Our case suggests relationships among BD, trisomy 8, and PV.
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Affiliation(s)
- Yuki Mori
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Japan
| | - Fumihiko Iwamoto
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Japan
| | - Toru Kuno
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Japan
| | - Shoji Kobayashi
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Japan
| | - Takashi Yoshida
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Japan
| | - Tatsuya Yamaguchi
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Japan
| | - Shinichi Takano
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Japan
| | - Tetsuo Kondo
- Department of Pathology, Faculty of Medicine, University of Yamanashi, Japan
| | - Keita Kirito
- Department of Hematology and Oncology, University of Yamanashi, Japan
| | - Nobuyuki Enomoto
- First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Japan
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Aghamohammad S, Sepehr A, Miri ST, Najafi S, Pourshafie MR, Rohani M. Anti-inflammatory and immunomodulatory effects of Lactobacillus spp. as a preservative and therapeutic agent for IBD control. Immun Inflamm Dis 2022; 10:e635. [PMID: 35634951 PMCID: PMC9119005 DOI: 10.1002/iid3.635] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Revised: 04/27/2022] [Accepted: 04/29/2022] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Probiotics have a beneficial effect on inflammatory responses and immune regulation, via Janus kinase/signal transduction and activator of transcription (JAK/STAT) and NF-κB signaling pathways. To evaluate the precise effects of Lactobacillus spp. as a protective and therapeutic agent, we aimed to investigate the efficacy of Lactobacillus spp. in modulating JAK/STAT and nuclear factor kappa B (NF-κB) inflammatory signaling pathways. METHODS A quantitative real-time polymerase chain reaction (qPCR) assay was used to analyze the expression of JAK/STAT and inflammatory genes (TIR-associated Protein [TIRAP], Interleukin 1 Receptor Associated Kinase[IRAK4], Nuclear factor-kappa B Essential Modulator [NEMO], and receptor interacting protein [RIP]) followed by treatment of the HT-29 cell line with sonicated pathogens before, after, and simultaneously with Lactobacillus spp. A cytokine assay was also used to evaluate interleukin (IL)-6 and IL-1β production after treatment with Lactobacillus spp. RESULTS Lactobacillus spp. downregulated JAK and TIRAP, IRAK4, NEMO, and RIP genes in the NF-κB pathway compared to sonicate-treated cells. The expression of STAT genes was different after treatment with probiotics. The production of IL-6 and IL-1β decreased after probiotic treatment. CONCLUSIONS Our Lactobacillus spp. cocktail showed anti-inflammatory effects on HT-29 cells by modulating JAK/STAT and NF-κB signaling pathways in all three treatment variants. Therefore, Lactobacillus spp. as a dietary supplement can both prevent and reduce inflammation-related diseases such as inflammatory bowel disease.
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Affiliation(s)
| | - Amin Sepehr
- Department of BacteriologyPasteur Institute of IranTehranIran
| | - Seyedeh Tina Miri
- Department of Biology, Science and Research BranchIslamic Azad UniversityTehranIran
| | - Saeideh Najafi
- Department of Biology, Science and Research BranchIslamic Azad UniversityTehranIran
| | | | - Mahdi Rohani
- Department of BacteriologyPasteur Institute of IranTehranIran
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Xu Z, Chu M. Advances in Immunosuppressive Agents Based on Signal Pathway. Front Pharmacol 2022; 13:917162. [PMID: 35694243 PMCID: PMC9178660 DOI: 10.3389/fphar.2022.917162] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Accepted: 05/02/2022] [Indexed: 12/13/2022] Open
Abstract
Immune abnormality involves in various diseases, such as infection, allergic diseases, autoimmune diseases, as well as transplantation. Several signal pathways have been demonstrated to play a central role in the immune response, including JAK/STAT, NF-κB, PI3K/AKT-mTOR, MAPK, and Keap1/Nrf2/ARE pathway, in which multiple targets have been used to develop immunosuppressive agents. In recent years, varieties of immunosuppressive agents have been approved for clinical use, such as the JAK inhibitor tofacitinib and the mTOR inhibitor everolimus, which have shown good therapeutic effects. Additionally, many immunosuppressive agents are still in clinical trials or preclinical studies. In this review, we classified the immunosuppressive agents according to the immunopharmacological mechanisms, and summarized the phase of immunosuppressive agents.
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Affiliation(s)
- Zhiqing Xu
- Department of Immunology, National Health Commission (NHC) Key Laboratory of Medical Immunology (Peking University), School of Basic Medical Sciences, Peking University, Beijing, China
- Department of Pharmacology, Jilin University, Changchun, China
| | - Ming Chu
- Department of Immunology, National Health Commission (NHC) Key Laboratory of Medical Immunology (Peking University), School of Basic Medical Sciences, Peking University, Beijing, China
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34
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Spiewak TA, Patel A. User's guide to JAK inhibitors in inflammatory bowel disease. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2022; 3:100096. [PMID: 35300073 PMCID: PMC8920857 DOI: 10.1016/j.crphar.2022.100096] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 01/01/2022] [Accepted: 02/28/2022] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD), such as ulcerative colitis (UC) and Crohn's disease (CD), are remitting and relapsing disorders of the gastrointestinal tract, highlighted by the dysregulation of pro- and anti-inflammatory mediators, which lead to mucosal damage. These conditions cause a significant burden worldwide as primary and secondary treatment failure rates remain high even with our current therapeutic options. This emphasizes the need for continued advancement in treatment efficacy with improved safety profiles. Novel disease-targeting therapeutics have been developed, most recently being the Janus kinase inhibitors (JAKi). JAKi serve as a promising new class of non-immunogenic small molecule inhibitors that modulate inflammatory pathways by blocking the critical role that Janus kinase (JAK) proteins play in mediating the innate and adaptive immune responses. Tofacitinib has been shown to be therapeutically efficacious, to have a tolerable safety profile, and to be available for adult patients with moderate-to-severe UC. This review was designed to serve as an overview and as practical guidance for medical practitioners. Author recommendations and appraisals of the quality of evidence throughout this article are based solely on personal opinion and are not the outcome of a formal methodology followed by a consensus group.
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Affiliation(s)
- Ted A. Spiewak
- Division of Gastroenterology & Hepatology, Brooke Army Medical Center, USA
| | - Anish Patel
- Division of Gastroenterology & Hepatology, Brooke Army Medical Center, USA
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35
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Selective Forms of Therapy in the Treatment of Inflammatory Bowel Diseases. J Clin Med 2022; 11:jcm11040994. [PMID: 35207271 PMCID: PMC8879972 DOI: 10.3390/jcm11040994] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 02/05/2022] [Accepted: 02/08/2022] [Indexed: 12/17/2022] Open
Abstract
Selective interference with the functioning of the immune system consisting of the selective blockade of pro-inflammatory factors is a modern, promising, and developing strategy for the treatment of diseases resulting from dysregulation of the immune system, including inflammatory bowel disease. Inhibition of the TNF alpha pathway, group 12/23 cytokines, and lymphocyte migration is used in the treatment of severe or moderate ulcerative colitis and Crohn’s disease. Intracellular signal transduction by influencing the phosphorylation of SAT (signal transducer and activator of transcription) proteins remains in clinical trials.
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36
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Hardwick RN, Brassil P, Badagnani I, Perkins K, Obedencio GP, Kim AS, Conner MW, Bourdet DL, Harstad EB. OUP accepted manuscript. Toxicol Sci 2022; 186:323-337. [PMID: 35134999 PMCID: PMC8963331 DOI: 10.1093/toxsci/kfac002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Affiliation(s)
| | - Patrick Brassil
- Drug Metabolism and Pharmacokinetics, Theravance Biopharma US, Inc., South San Francisco, California 94080, USA
| | - Ilaria Badagnani
- Drug Metabolism and Pharmacokinetics, Theravance Biopharma US, Inc., South San Francisco, California 94080, USA
| | - Kimberly Perkins
- Translational Safety Sciences, Theravance Biopharma US, Inc., South San Francisco, California 94080, USA
| | - Glenmar P Obedencio
- Drug Metabolism and Pharmacokinetics, Theravance Biopharma US, Inc., South San Francisco, California 94080, USA
| | | | | | - David L Bourdet
- Drug Metabolism and Pharmacokinetics, Theravance Biopharma US, Inc., South San Francisco, California 94080, USA
| | - Eric B Harstad
- To whom correspondence should be addressed at Translational Safety Sciences, Theravance Biopharma US, Inc., 901 Gateway Boulevard, South San Francisco, CA 94080, USA. E-mail:
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Gaspar R, Branco CC, Macedo G. Liver manifestations and complications in inflammatory bowel disease: A review. World J Hepatol 2021; 13:1956-1967. [PMID: 35070000 PMCID: PMC8727205 DOI: 10.4254/wjh.v13.i12.1956] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 05/27/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatobiliary manifestations are common in inflammatory bowel disease (IBD), with 30% of patients presenting abnormal liver tests and 5% developing chronic liver disease. They range from asymptomatic elevated liver tests to life-threatening disease and usually follow an independent course from IBD. The pathogenesis of liver manifestations or complications and IBD can be closely related by sharing a common auto-immune background (in primary sclerosing cholangitis, IgG4-related cholangitis, and autoimmune hepatitis), intestinal inflammation (in portal vein thrombosis and granulomatous hepatitis), metabolic impairment (in non-alcoholic fatty liver disease or cholelithiasis), or drug toxicity (in drug induced liver injury or hepatitis B virus infection reactivation). Their evaluation should prompt a full diagnostic workup to identify and readily treat all complications, improving management and outcome.
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Affiliation(s)
- Rui Gaspar
- Department of Gastroenterology and Hepatology, Centro Hospitalar de São João, Porto 4200, Portugal
| | - Catarina Castelo Branco
- Internal Medicine Department, Centro Hospitalar e Universitário do Porto, Porto 4200, Portugal
| | - Guilherme Macedo
- Department of Gastroenterology and Hepatology, Centro Hospitalar de São João, Porto 4200, Portugal
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Zöllkau J, Hagenbeck C, Hecher K, Pecks U, Schlembach D, Simon A, Schlösser R, Schleußner E. [Recommendations for SARS-CoV-2/COVID-19 during Pregnancy, Birth and Childbed - Update November 2021 (Long Version)]. Z Geburtshilfe Neonatol 2021; 226:e1-e35. [PMID: 34918334 DOI: 10.1055/a-1688-9398] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Since the onset of the SARS-CoV-2 pandemic, the German Society of Gynecology and Obstetrics and the Society for Peri-/Neonatal Medicine have published and repeatedly updated recommendations for the management of SARS-CoV-2 positive pregnancies and neonates. As a continuation of existing recommendations, the current update addresses key issues related to the prenatal, perinatal, and postnatal care of pregnant women, women who have given birth, women who have recently given birth, women who are breastfeeding with SARS-CoV-2 and COVID-19, and their unborn or newborn infants, based on publications through September 2021. Recommendations and opinions were carefully derived from currently available scientific data and subsequently adopted by expert consensus. This guideline - here available in the long version - is intended to be an aid to clinical decision making. Interpretation and therapeutic responsibility remain with the supervising local medical team, whose decisions should be supported by these recommendations. Adjustments may be necessary due to the rapid dynamics of new evidence. The recommendations are supported by the endorsement of the professional societies: German Society for Perinatal Medicine (DGPM), German Society of Gynecology and Obstetrics (DGGG), German Society for Prenatal and Obstetric Medicine (DGPGM), German Society for Pediatric Infectiology (DGPI), Society for Neonatology and Pediatric Intensive Care Medicine (GNPI).
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Affiliation(s)
- Janine Zöllkau
- Klinik für Geburtsmedizin, Universitätsklinikum Jena, Deutschland
| | - Carsten Hagenbeck
- Klinik für Frauenheilkunde und Geburtshilfe, Universität Düsseldorf, Deutschland
| | - Kurt Hecher
- Klinik für Geburtshilfe und Pränatalmedizin, Universitätsklinikum Hamburg-Eppendorf, Deutschland
| | - Ulrich Pecks
- Klinik für Gynäkologie und Geburtshilfe, Campus Kiel, Universitätsklinikum Schleswig-Holstein, Deutschland
| | - Dietmar Schlembach
- Klinik für Geburtsmedizin, Vivantes Klinikum Neukölln, Berlin, Deutschland
| | - Arne Simon
- Klinik für Pädiatrische Onkologie und Hämatologie, Universitätsklinikum des Saarlandes, Homburg/Saar, Deutschland
| | - Rolf Schlösser
- Schwerpunkt Neonatologie, Klinik für Kinder- und Jugendmedizin, Universitätsklinikum Frankfurt, Deutschland
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D’Amico F, Magro F, Peyrin-Biroulet L, Danese S. Positioning Filgotinib in the Treatment Algorithm of Moderate to Severe Ulcerative Colitis. J Crohns Colitis 2021; 16:835-844. [PMID: 34791103 PMCID: PMC9228886 DOI: 10.1093/ecco-jcc/jjab206] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 10/19/2021] [Accepted: 11/12/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Filgotinib is a small molecule that selectively inhibits Janus kinase [JAK] type 1. It is already approved for the treatment of rheumatoid arthritis and is being evaluated for the management of patients with moderate to severe ulcerative colitis [UC]. The purpose of this review is to provide an overview of the currently available data on filgotinib and to define how to position this new drug in the treatment algorithm of patients with UC. METHODS The Pubmed, Embase and Scopus databases were searched up to June 25, 2021 in order to identify studies reporting efficacy and safety data of filgotinib in patients with UC. RESULTS Data from a phase III study enrolling UC patients with moderate to severe disease show that filgotinib is effective with a reassuring safety profile. Filgotinib treatment is not associated with a greater risk of thrombosis and herpes zoster infections compared to other JAK inhibitors. However, animal studies reported impaired spermatogenesis and histopathological effects on male reproductive organs, making it necessary to deepen this aspect in dedicated human studies. CONCLUSIONS Filgotinib is an effective and safe drug for treatment of both biologic-naive and biologic-experienced patients with moderate to severe UC and may soon be available.
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Affiliation(s)
- Ferdinando D’Amico
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy,Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milan, Italy
| | - Fernando Magro
- Department of Gastroenterology, Centro Hospitalar São João, Porto, Portugal
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology and Inserm NGERE U1256, University Hospital of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France
| | - Silvio Danese
- Corresponding author: Prof. Silvio Danese, MD, PhD, Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Via Olgettina 60, Milan, Italy. Tel: (+39) 0226432069; Fax: (+39) 0282242591,
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Borcherding DC, He K, Amin NV, Hirbe AC. TYK2 in Cancer Metastases: Genomic and Proteomic Discovery. Cancers (Basel) 2021; 13:4171. [PMID: 34439323 PMCID: PMC8393599 DOI: 10.3390/cancers13164171] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/07/2021] [Accepted: 08/12/2021] [Indexed: 12/12/2022] Open
Abstract
Advances in genomic analysis and proteomic tools have rapidly expanded identification of biomarkers and molecular targets important to cancer development and metastasis. On an individual basis, personalized medicine approaches allow better characterization of tumors and patient prognosis, leading to more targeted treatments by detection of specific gene mutations, overexpression, or activity. Genomic and proteomic screens by our lab and others have revealed tyrosine kinase 2 (TYK2) as an oncogene promoting progression and metastases of many types of carcinomas, sarcomas, and hematologic cancers. TYK2 is a Janus kinase (JAK) that acts as an intermediary between cytokine receptors and STAT transcription factors. TYK2 signals to stimulate proliferation and metastasis while inhibiting apoptosis of cancer cells. This review focuses on the growing evidence from genomic and proteomic screens, as well as molecular studies that link TYK2 to cancer prevalence, prognosis, and metastasis. In addition, pharmacological inhibition of TYK2 is currently used clinically for autoimmune diseases, and now provides promising treatment modalities as effective therapeutic agents against multiple types of cancer.
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Affiliation(s)
- Dana C. Borcherding
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; (D.C.B.); (K.H.); (N.V.A.)
| | - Kevin He
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; (D.C.B.); (K.H.); (N.V.A.)
| | - Neha V. Amin
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; (D.C.B.); (K.H.); (N.V.A.)
| | - Angela C. Hirbe
- Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA; (D.C.B.); (K.H.); (N.V.A.)
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO 63110, USA
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Gonciarz M, Pawlak-Buś K, Leszczyński P, Owczarek W. TYK2 as a therapeutic target in the treatment of autoimmune and inflammatory diseases. Immunotherapy 2021; 13:1135-1150. [PMID: 34235974 DOI: 10.2217/imt-2021-0096] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
JAKs are intracellular protein tyrosine kinases that, through activation of STATs, are responsible for signal transduction pathways that regulate cellular responses to numerous cytokines, growth factors and hormones in many different cells. JAK-STAT signaling plays a key role in regulating immune function, and cytokines - such as IL-23, IL-12 and type I interferons - are central to the pathogenesis of autoimmune diseases, including psoriasis, inflammatory bowel disease and systemic lupus erythematosus. Here the authors review the evidence for targeting TYK2 as a more specific approach to treating these conditions. TYK2 inhibitors are clinically effective in autoimmune and inflammatory diseases and may avoid some of the complications reported with nonselective JAK inhibitors.
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Affiliation(s)
- Maciej Gonciarz
- Department of Gastroenterology & Internal Medicine, Military Institute of Medicine, Warsaw, Poland
| | - Katarzyna Pawlak-Buś
- Department of Rheumatology, Rehabilitation & Internal Medicine, University of Medical Sciences, Poznan, Poland
| | - Piotr Leszczyński
- Department of Rheumatology, Rehabilitation & Internal Medicine, University of Medical Sciences, Poznan, Poland
| | - Witold Owczarek
- Department of Dermatology, Military Institute of Medicine, Warsaw, Poland
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Zhang W, Michalowski CB, Beloqui A. Oral Delivery of Biologics in Inflammatory Bowel Disease Treatment. Front Bioeng Biotechnol 2021; 9:675194. [PMID: 34150733 PMCID: PMC8209478 DOI: 10.3389/fbioe.2021.675194] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 04/19/2021] [Indexed: 12/11/2022] Open
Abstract
Inflammatory bowel disease (IBD) has been posed as a great worldwide health threat. Having an onset during early adulthood, IBD is a chronic inflammatory disease characterized by remission and relapse. Due to its enigmatic etiology, no cure has been developed at the moment. Conventionally, steroids, 5-aminosalicylic acid, and immunosuppressants have been applied clinically to relieve patients’ syndrome which, unfavorably, causes severe adverse drug reactions including diarrhea, anemia, and glaucoma. Insufficient therapeutic effects also loom, and surgical resection is mandatory in half of the patients within 10 years after diagnosis. Biologics demonstrated unique and differentiative therapeutic mechanism which can alleviate the inflammation more effectively. However, their application in IBD has been hindered considering their stability and toxicity. Scientists have brought up with the concept of nanomedicine to achieve the targeted drug delivery of biologics for IBD. Here, we provide an overview of biologics for IBD treatment and we review existing formulation strategies for different biological categories including antibodies, gene therapy, and peptides. This review highlights the current trends in oral delivery of biologics with an emphasis on the important role of nanomedicine in the development of reliable methods for biologic delivery in IBD treatment.
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Affiliation(s)
- Wunan Zhang
- Advanced Drug Delivery and Biomaterials, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
| | - Cecilia Bohns Michalowski
- Advanced Drug Delivery and Biomaterials, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
| | - Ana Beloqui
- Advanced Drug Delivery and Biomaterials, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium
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Gisbert JP, Chaparro M. Safety of New Biologics (Vedolizumab and Ustekinumab) and Small Molecules (Tofacitinib) During Pregnancy: A Review. Drugs 2021; 80:1085-1100. [PMID: 32562207 DOI: 10.1007/s40265-020-01346-4] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Two new biological drugs (vedolizumab and ustekinumab) and one small molecule (tofacitinib) have been recently approved for the treatment of inflammatory bowel disease. Therefore, we must be familiar with the safety of these "new" drugs during pregnancy and breastfeeding. In the present article, we critically review available data on the safety of new biologics (vedolizumab and ustekinumab) and small molecules (tofacitinib) during pregnancy and breastfeeding, with special focus on women with inflammatory bowel disease. Bibliographical searches (MEDLINE) up to April 2020 were performed. The timing and mechanisms of placental transfer of vedolizumab and ustekinumab are expected to be similar to anti-TNF agents. Animal studies show no evidence of adverse effects on pre- or post-natal development after administration of vedolizumab and ustekinumab. Just a few studies including patients treated with vedolizumab or ustekinumab during pregnancy have been published, reporting uneventful pregnancies in most cases. The clinical programme of both drugs and post-marketing studies showed no new safety concerns. Due to the expected safety of vedolizumab and ustekinumab during pregnancy, it may be recommended to plan the final pregnancy dose approximately 8 or 12 weeks, respectively, before the estimated date of delivery. Live vaccines should be avoided for up to a year in children exposed in utero to vedolizumab or ustekinumab unless drug elimination has been documented. Miniscule amounts of vedolizumab and ustekinumab are transferred to breast milk, so breastfeeding is probably safe. There is no evidence of adverse effect of vedolizumab or ustekinumab paternal exposure. Regarding tofacitinib, it is reasonable to assume that this molecule crosses the placenta from the beginning of pregnancy. In animal studies, tofacitinib was feticidal and teratogenic in rats and rabbits, although at exposures many times greater than the standard human dose. Reported outcomes of pregnancy cases identified from tofacitinib randomised controlled trials, post-approval and non-interventional studies, and spontaneous adverse-event reporting appear similar to those observed in the general population. Nevertheless, at present, the use of tofacitinib during pregnancy should be avoided. Although no human studies have reported outcomes of breastfeeding with small molecules such as tofacitinib, this drug is present in lactating rat milk so, at present, breastfeeding should be avoided. Pregnancy among patients with paternal exposure to tofacitinib appears to be safe. In summary, we can conclude that new biologic agents (vedolizumab and ustekinumab) and small molecules (tofacitinib) should be used during pregnancy only if the benefits to the mother outweigh the risks to the mother and unborn child.
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Affiliation(s)
- Javier P Gisbert
- Gastroenterology Unit, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Diego de León, 62, 28006, Madrid, Spain.
| | - María Chaparro
- Gastroenterology Unit, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Diego de León, 62, 28006, Madrid, Spain
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Affiliation(s)
- Bram Verstockt
- Imelda GI Clinical Research Center, Imelda General Hospital, Bonheiden, Belgium
- Department of Gastroenterology and Hepatology, KU Leuven, University Hospitals Leuven, Leuven, Belgium
- Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
| | - Lieven Pouillon
- Imelda GI Clinical Research Center, Imelda General Hospital, Bonheiden, Belgium
| | - Peter Bossuyt
- Imelda GI Clinical Research Center, Imelda General Hospital, Bonheiden, Belgium
- Department of Gastroenterology and Hepatology, KU Leuven, University Hospitals Leuven, Leuven, Belgium
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De Lima-Karagiannis A, Juillerat P, Sebastian S, Pedersen N, Bar-Gil Shitrit A, van der Woude CJ. Management of Pregnant Inflammatory Bowel Disease Patients During the COVID-19 Pandemic. J Crohns Colitis 2020; 14:S807-S814. [PMID: 33085970 PMCID: PMC7665400 DOI: 10.1093/ecco-jcc/jjaa125] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
UNLABELLED The rapid emergence of the novel coronavirus [SARS-CoV2] and the coronavirus disease 2019 [COVID-19] has caused significant global morbidity and mortality. This is particularly concerning for vulnerable groups such as pregnant women with inflammatory bowel disease [IBD]. Care for pregnant IBD patients in itself is a complex issue because of the delicate balance between controlling maternal IBD as well as promoting the health of the unborn child. This often requires continued immunosuppressive maintenance medication or the introduction of new IBD medication during pregnancy. The current global COVID-19 pandemic creates an additional challenge in the management of pregnant IBD patients. In this paper we aimed to answer relevant questions that can be encountered in daily clinical practice when caring for pregnant women with IBD during the current COVID-19 pandemic. PODCAST This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.
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Affiliation(s)
- A De Lima-Karagiannis
- Erasmus University Medical Center, Department of Gastroenterology and Hepatology, the Netherlands
| | - P Juillerat
- Gastroenterology, Clinic for Visceral Surgery and Medicine, Bern University Hospital, Bern, Switzerland
| | - S Sebastian
- IBD Unit, Hull University Teaching Hospital NHS Trust, Hull, UK
| | - N Pedersen
- Slagelse Hospital, University of Copenhagen, Department of Gastroenterology, Denmark
| | - A Bar-Gil Shitrit
- IBD MOM unit, Digestive Diseases Institute, Shaare Zedek Medical Center affiliated with the Hebrew University School of Medicine, Jerusalem, Israel
| | - C J van der Woude
- Erasmus University Medical Center, Department of Gastroenterology and Hepatology, the Netherlands
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Abstract
Previously, the natural history of Crohn's disease and ulcerative colitis included significant morbidity due to limited treatment options that were not without serious side effects. Early treatment options included corticosteroids as well as mesalamine, thiopurines, and methotrexate. In 1998, monoclonal antibodies to a key inflammatory cytokine, TNFα, became available. Over the next 22 years, the field of gastroenterology has seen multiple new treatments emerging for inflammatory bowel disease (IBD) that target different aspects of the inflammatory cascade, significantly changing the therapeutic landscape. Additional monoclonal antibodies are available that target the integrins, which are adhesion proteins that traffic inflammatory leukocytes. Small molecule inhibitors block the inflammatory signals of several cytokines. New therapies that modulate lymphocyte escape from lymphoid tissue are promising. Lastly, stem cell technology has emerged as a platform to successfully treat perianal fistulizing disease. Our aim is to summarize the currently available therapies for IBD beyond steroids, mesalamine, and immune modulators. We highlight the most important clinical trials that have brought these treatments to clinical practice, and we discuss the ongoing clinical trials of novel therapies that have a high probability of eventual regulatory approval.
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D'Amico F, Peyrin-Biroulet L, Danese S. JAK or GUT Selectivity: Tipping the Balance for Efficacy and Safety in Ulcerative Colitis. J Crohns Colitis 2020; 14:1185-1187. [PMID: 32579170 DOI: 10.1093/ecco-jcc/jjaa074] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Ferdinando D'Amico
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,Department of Gastroenterology and Inserm NGERE U1256, University Hospital of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology and Inserm NGERE U1256, University Hospital of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France
| | - Silvio Danese
- Department of Biomedical Sciences, Humanitas University, Milan, Italy.,Department of Gastroenterology, Humanitas Clinical and Research Center, IRCCS, Milan, Italy
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Lambin T, Faye AS, Colombel JF. Inflammatory Bowel Disease Therapy and Venous Thromboembolism. CURRENT TREATMENT OPTIONS IN GASTROENTEROLOGY 2020; 18:462-475. [PMID: 37063454 PMCID: PMC10100457 DOI: 10.1007/s11938-020-00304-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Purpose of review To explore the relationship between IBD (inflammatory bowel diseases) therapy and VTE (venous thromboembolism) risk, as well as the safety, barriers, and utility of VTE prophylaxis. Recent findings In 2019, the Food and Drug Administration (FDA) issued a black box warning concerning the use of tofacitinib among ulcerative colitis (UC) patients with a post hoc analysis revealing that all patients had additional risk factors for VTE. Additionally, although IBD patients experiencing a disease flare often present with hematochezia, these patients are less likely to receive VTE prophylaxis, despite data showing that pharmacologic prophylaxis has not been associated with clinically significant signs of bleeding. Summary Among IBD patients, corticosteroid use has been associated with an increased risk of VTE, whereas anti-TNF therapy does not appear to increase this risk. High-dose tofacitinib has also been shown to increase the likelihood of VTE in patients with additional risk factors. In order to prevent future VTE events, pharmacologic thromboprophylaxis should be emphasized, particularly in hospitalized IBD patients, with recent data suggesting that a select population at risk may benefit from continued prophylaxis.
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Affiliation(s)
- Thomas Lambin
- Gastroenterology Department, CHU de Lille – Hôpital Claude Huriez, Université de Lille, Rue Michel Polonovski, 59037, Lille, France
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Adam S. Faye
- Department of Medicine, New York-Presbyterian Columbia University Medical Center, New York, NY, USA
| | - Jean-Frédéric Colombel
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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Abstract
INTRODUCTION Janus kinases inhibitors (JAKi) are new small molecules recently introduced in the armamentarium of treatments for Inflammatory Bowel Disease (IBD). Janus Kinases (JAK) are tyrosine kinases that act by linkage with different intracellular receptors, regulating cytokines gene transcription implicated in the inflammatory burden seen in IBD patients. AREAS COVERED A comprehensive literature search was performed to retrieve studies on JAKi and IBD to discuss the latest developments and how the selectivity of these drugs is changing the natural course of IBD. EXPERT OPINION Available data on efficacy and safety of JAKi in IBD are highly encouraging and because of their selectivity, these drugs might become among the foremost options in the treatment algorithm.
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Affiliation(s)
- Giulia Roda
- IBD Unit, Humanitas Clinical and Research Center - IRCCS - , Milan, Italy
| | - Arianna Dal Buono
- IBD Unit, Humanitas Clinical and Research Center - IRCCS - , Milan, Italy
| | - Marjorie Argollo
- Gastroenterology, Universidade Federal De São Paulo , São Paulo, Brazil
| | - Silvio Danese
- IBD Unit, Humanitas Clinical and Research Center - IRCCS - , Milan, Italy.,Department of Biomedical Sciences, Humanitas University , Milan, Italy
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Magro F, Estevinho MM. Is tofacitinib a game-changing drug for ulcerative colitis? United European Gastroenterol J 2020; 8:755-763. [PMID: 32552501 PMCID: PMC7435001 DOI: 10.1177/2050640620935732] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Accepted: 05/26/2020] [Indexed: 12/26/2022] Open
Abstract
The increasing knowledge on ulcerative colitis' pathophysiology has contributed to the expansion of the therapeutic arsenal for this condition. However, to date, 25-40% of patients with ulcerative colitis remain primary or secondary non-responders to therapy, and up to 10% need to eventually undergo a colectomy. Janus kinase inhibitors block cytokine signalling involved in the pathogenesis of several inflammatory conditions. Tofacitinib is the first drug of this class approved for moderate-to-severely active ulcerative colitis in patients for whom disease worsened and those who did not improve with conventional therapy (aminosalicylates, corticosteroids and immunosuppressants) or monoclonal antibodies. We aimed to review the main aspects and concerns related to the current use of tofacitinib and to explore its future application.
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Affiliation(s)
- Fernando Magro
- Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal
- Department of Gastroenterology, São João Hospital Center, Porto, Portugal
- MedInUP, Center for Drug Discovery and Innovative Medicines, Porto, Portugal
- Clinical Pharmacology Unit, São João Hospital University Center, Porto, Portugal
| | - Maria Manuela Estevinho
- Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Porto, Portugal
- Department of Gastroenterology, Vila Nova de Gaia/Espinho Hospital Center, Vila Nova de Gaia, Portugal
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