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Pickett JR, Wu Y, Ta HT. VCAM-1 as a common biomarker in inflammatory bowel disease and colorectal cancer: unveiling the dual anti-inflammatory and anti-cancer capacities of anti-VCAM-1 therapies. Cancer Metastasis Rev 2025; 44:40. [PMID: 40095109 PMCID: PMC11913972 DOI: 10.1007/s10555-025-10258-2] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Accepted: 03/04/2025] [Indexed: 03/19/2025]
Abstract
Vascular cell adhesion molecule (VCAM)-1 has garnered significant research attention due to its potential as a disease biomarker and drug target across several inflammatory pathologies-including atherosclerosis, asthma, rheumatoid arthritis, and inflammatory bowel disease (IBD). The VCAM-1 protein has also been noted for its functional involvement in cancer metastasis and drug resistance to conventional chemotherapeutics. Although the anti-inflammatory and anti-cancer facets of VCAM-1 antagonisation have been examined separately, there is yet to be a review that explicitly addresses the functional interrelationship between these mechanisms. Furthermore, the pleiotropic mechanisms of anti-VCAM-1 therapies may present a useful paradigm for designing drug candidates with synergistic anti-inflammatory and anti-tumorigenic effects. The pathological overlap between inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CRC) serves as the quintessential disease model to observe this therapeutic duality. This review thereby details the adhesive mechanisms of VCAM-1 in colorectal disease-specifically, driving immune cell infiltration during IBD and tumour cell metastasis in CRC-and posits the potential of this receptor as a common drug target for both diseases. To explore this hypothesis, the current progress of novel VCAM-1-directed drug candidates in experimental models of IBD and CRC is also discussed.
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Affiliation(s)
- Jessica R Pickett
- School of Environment and Science, Griffith University, Nathan Campus, Brisbane, 4111, QLD, Australia
| | - Yuao Wu
- School of Environment and Science, Griffith University, Nathan Campus, Brisbane, 4111, QLD, Australia
| | - Hang Thu Ta
- School of Environment and Science, Griffith University, Nathan Campus, Brisbane, 4111, QLD, Australia.
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Kaur P, Karuppuchamy T, Chilukuri A, Kim M, Urrete J, Shen Z, Saxon L, Lundborg LR, Mikulski Z, Jedlicka P, Rivera-Nieves J. S1P Lyase Inhibition Increased Intestinal S1P, Disrupted the Intestinal Barrier and Aggravated DSS-Induced Colitis. Inflamm Bowel Dis 2025:izaf030. [PMID: 39960746 DOI: 10.1093/ibd/izaf030] [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: 12/19/2024] [Indexed: 04/02/2025]
Abstract
BACKGROUND Sphingosine-1-phospate (S1P) receptor agonists (eg, ozanimod) desensitize migrating lymphocytes by irreversibly binding to S1P receptors (S1PR) and triggering their proteasomal degradation. Desensitized lymphocytes cannot sense S1P, therefore, halting lymphocyte recirculation. The S1P lyase (SPL) irreversibly degrades S1P and its inhibition disrupts the S1P gradient. We previously found that systemic SPL inhibitors induce central immunosuppression. Here, we examined whether SPL inhibition may attenuate colitis without systemic immunotoxicity. METHODS We first analyzed SPL expression and localization in mice using qRT-PCR and immunohistochemistry. SPL inhibitors 4-deoxypyridoxine hydrochloride (DOP) and 2-acetyl-4-(tetrahydroxybutyl) imidazole (THI) were used to inhibit SPL systemically, whereas a conditional intestinal epithelial cell (IEC)-specific SPL-deficient mouse was used to evaluate the effects of IEC-specific SPL inhibition on survival, disease activity, histological severity of dextran sulfate sodium-induced colitis, S1P levels, and intestinal permeability. RESULTS Sgpl1 mRNA transcripts and protein were ubiquitously expressed in gastrointestinal (GI) tract leukocytes and IEC. Systemic SPL inhibitors did not induce colitis by themselves but depleted CD4+ and CD8+ T cells from blood. However, contrary to its therapeutic effects on ileitis, systemic inhibition reduced survival, accelerated weight loss, worsened histopathological inflammation indices, and tissue damage. We then examined the effects of IEC-specific inhibition on peripheral cell counts and severity of colitis. We found that while it spared peripheral immunity, it similarly hastened colitis. Finally, we examined whether colitis acceleration was due to epithelial barrier compromise after disruption of the S1P gradient. We found that not only systemic but also IEC-specific SPL inhibition increased local S1P levels and led to IEC barrier compromise. CONCLUSION Homeostatic intestinal S1P levels are critical for the regulation of IEC barrier function. Further studies using adaptive immunity-based inflammatory bowel diseases (IBD) models are required to assess the translational value of IEC-specific SPL inhibition as a therapeutic target for human IBD.
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Affiliation(s)
- Prabhdeep Kaur
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
| | - Thangaraj Karuppuchamy
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA 92161, USA
| | - Amruth Chilukuri
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
| | - Margaret Kim
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA 92161, USA
| | - Josef Urrete
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
| | - Zining Shen
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
| | - Leo Saxon
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA 92161, USA
| | - Luke R Lundborg
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA 92161, USA
| | - Zbigniew Mikulski
- Histology and Microscopy Core, La Jolla Institute for Immunology, La Jolla, CA, USA
| | - Paul Jedlicka
- Department of Pathology, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Jesús Rivera-Nieves
- Division of Gastroenterology, Department of Medicine, University of California San Diego, La Jolla, CA 92093-0063, USA
- Gastroenterology Section, San Diego VA Medical Center, La Jolla Village Drive, San Diego, CA 92161, USA
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3
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Vieujean S, Jairath V, Peyrin-Biroulet L, Dubinsky M, Iacucci M, Magro F, Danese S. Understanding the therapeutic toolkit for inflammatory bowel disease. Nat Rev Gastroenterol Hepatol 2025:10.1038/s41575-024-01035-7. [PMID: 39891014 DOI: 10.1038/s41575-024-01035-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/19/2024] [Indexed: 02/03/2025]
Abstract
Inflammatory bowel disease (IBD), encompassing ulcerative colitis and Crohn's disease, is a group of chronic, immune-mediated disorders of the gastrointestinal tract that present substantial clinical challenges owing to their complex pathophysiology and tendency to relapse. A treat-to-target approach is recommended, involving iterative treatment adjustments to achieve clinical response, reduce inflammatory markers and achieve long-term goals such as mucosal healing. Lifelong medication is often necessary to manage the disease, maintain remission and prevent complications. The therapeutic landscape for IBD has evolved substantially; however, a ceiling on therapeutic efficacy remains and surgery is sometimes required (owing to uncontrolled disease activity or complications). Effective IBD management involves comprehensive care, including medication adherence and a collaborative clinician-patient relationship. This Review discusses current therapeutic options for IBD, detailing mechanisms of action, efficacy, safety profiles and guidelines for use of each drug class. We also explore emerging therapies and the role of surgery. Additionally, the importance of a multidisciplinary team and personalized care in managing IBD is emphasized, advocating for patient empowerment and involvement in treatment decisions. By synthesizing current knowledge and emerging trends, this Review aims to equip healthcare professionals with a thorough understanding of therapeutic options for IBD, enhancing informed, evidence-based decisions in clinical practice.
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Affiliation(s)
- Sophie Vieujean
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
- Department of Gastroenterology, INFINY Institute, CHRU Nancy, Vandœuvre-lès-Nancy, France
| | - Vipul Jairath
- Division of Gastroenterology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, INFINY Institute, CHRU Nancy, Vandœuvre-lès-Nancy, France
- Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Marla Dubinsky
- Department of Paediatrics, Susan and Leonard Feinstein IBD Center, Icahn School of Medicine, Mount Sinai, New York, NY, USA
| | - Marietta Iacucci
- APC Microbiome Ireland, College of Medicine and Health, University College of Cork, Cork, Ireland
| | - Fernando Magro
- CINTESIS@RISE, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milano, Italy.
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Mansouri P, Mansouri P, Behmard E, Najafipour S, Kouhpayeh A, Farjadfar A. Novel targets for mucosal healing in inflammatory bowel disease therapy. Int Immunopharmacol 2025; 144:113544. [PMID: 39571265 DOI: 10.1016/j.intimp.2024.113544] [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: 06/01/2024] [Revised: 10/13/2024] [Accepted: 10/28/2024] [Indexed: 12/15/2024]
Abstract
Inflammatory bowel disease (IBD) is a chronic condition affecting the gastrointestinal tract, primarily manifesting as ulcerative colitis (UC) or Crohn's disease (CD). Both inflammation and disruption of the intestinal epithelial barrier are key factors in IBD pathogenesis. Substantial evidence has revealed a significant association between aberrant immune responses and impairment of the intestinal epithelial barrier in IBD pathogenesis. The components of the intestinal epithelium, particularly goblet cells and Paneth cells, are crucial to gut homeostasis, as they secrete mucin, antimicrobial peptides (AMPs), and cytokines. Furthermore, impairment of epithelial integrity, which is regulated by tight junctions, is a hallmark of IBD pathology. While common treatments for IBD, such as anti-inflammatory drugs, target various signaling pathways with varying efficacies, therapeutic approaches focused on mucosal and epithelial barrier healing have been largely neglected. Moreover, high costs, side effects, and insufficient or inconsistent therapeutic outcomes remain major drawbacks of conventional anti-IBD drugs. Recent studies on epithelial barrier regeneration and permeability reduction have introduced promising therapeutic targets, including farnesoid X receptor (FXR), urokinase-type plasminogen activator (uPA)-urokinase-type plasminogen activator receptor (uPAR) interaction, fecal microbiota transplantation (FMT), and insulin receptor (INSR). Notably, the simultaneous targeting of intestinal inflammation and promotion of epithelial barrier healing shows promise for efficient IBD treatment. Future research should explore targeted therapies and combination treatments, including natural remedies, microbiota colonization, stem cell approaches, and computer-aided drug design. It is also crucial to focus on accurate prognosis and developing a thorough understanding of IBD development mechanisms.
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Affiliation(s)
- Pardis Mansouri
- Student Research Committee, Fasa University of Medical Sciences, Fasa, Iran; Department of Medical Biotechnology, Fasa University of Medical Sciences, Fasa, Iran
| | - Pegah Mansouri
- Student Research Committee, Fasa University of Medical Sciences, Fasa, Iran; Department of Medical Biotechnology, Fasa University of Medical Sciences, Fasa, Iran
| | - Esmaeil Behmard
- School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran; Zarrin Avaye Kowsar Salamat (ZAX Company), Fasa, Iran
| | - Sohrab Najafipour
- School of Advanced Technologies in Medicine, Fasa University of Medical Sciences, Fasa, Iran; Zarrin Avaye Kowsar Salamat (ZAX Company), Fasa, Iran
| | - Amin Kouhpayeh
- Department of Pharmacology, Faculty of Medicine, Fasa University of Medical Sciences, Fasa, Iran; Zarrin Avaye Kowsar Salamat (ZAX Company), Fasa, Iran.
| | - Akbar Farjadfar
- Department of Medical Biotechnology, Fasa University of Medical Sciences, Fasa, Iran; Zarrin Avaye Kowsar Salamat (ZAX Company), Fasa, Iran.
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Xia X, Huang Z, Xu C, Fu H, Wang S, Tian J, Rui K. Regulation of intestinal tissue‑resident memory T cells: a potential target for inflammatory bowel disease. Cell Commun Signal 2024; 22:610. [PMID: 39695803 DOI: 10.1186/s12964-024-01984-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Accepted: 12/05/2024] [Indexed: 12/20/2024] Open
Abstract
Tissue-resident memory T (TRM) cells are populations which settle down in non-lymphoid tissues instead of returning to secondary lymph organs after the antigen presentation. These cells can provide rapid on-site immune protection as well as long-term tissue damage. It is reported that TRM cells from small intestine and colon exhibited distinctive patterns of cytokine and granzyme expression along with substantial transcriptional and functional heterogeneity. In this review, we focus on the reason why they lodge in intestinal tract, their developmental plasticity of going back to to circulation, as well as their regulators associated with retention, maintenance, exhaustion and metabolism. We also elaborate their role in the inflammatory bowel disease (IBD) and discuss the potential therapeutic strategies targeting TRM cells.
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Affiliation(s)
- Xin Xia
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Zhanjun Huang
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China
| | - Chengcheng Xu
- Department of Nuclear Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Hailong Fu
- Center for Clinical Laboratory, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Shengjun Wang
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Jie Tian
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
- Department of Immunology, Jiangsu Key Laboratory of Laboratory Medicine, School of Medicine, Jiangsu University, Zhenjiang, China.
| | - Ke Rui
- Department of Laboratory Medicine, Affiliated Hospital of Jiangsu University, Zhenjiang, China.
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Din S, Segal J, Blackwell J, Gros B, Black CJ, Ford AC. Harms with placebo in trials of biological therapies and small molecules as induction therapy in inflammatory bowel disease: a systematic review and meta-analysis. Lancet Gastroenterol Hepatol 2024; 9:1020-1029. [PMID: 39307145 DOI: 10.1016/s2468-1253(24)00264-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 07/30/2024] [Accepted: 07/30/2024] [Indexed: 10/14/2024]
Abstract
BACKGROUND Randomised placebo-controlled trials are the gold standard to assess novel drugs in ulcerative colitis and Crohn's disease. However, there might be risks associated with receiving placebo. We aimed to examine the harms associated with receiving placebo in trials of licensed biologics and small molecules for the induction of remission in ulcerative colitis and luminal Crohn's disease in a meta-analysis. METHODS We performed a systematic review and meta-analysis. We searched MEDLINE, Embase, Embase Classic, and the Cochrane Central Register of Controlled Trials from database inception to May 30, 2024, for randomised placebo-controlled trials of licensed biologics and small molecules for induction of remission in adults (≥18 years) with moderately to severely active ulcerative colitis or luminal Crohn's disease reporting data on adverse events over a minimum treatment period of 4 weeks. There were no prespecified study exclusion criteria. We extracted summary data and pooled data using a random-effects model for any treatment-emergent adverse event, any drug-related adverse event, infection, worsening of inflammatory bowel disease (IBD) activity, withdrawal due to adverse events, serious adverse events, serious infection, serious worsening of IBD activity, or venous thromboembolic events (VTEs), reporting relative risks (RRs) with 95% CIs. The protocol for this meta-analysis was registered with PROSPERO (CRD42024527341). FINDINGS The search identified 10 826 citations, of which 47 trials including 20 987 patients (14 267 [68·0%] receiving active drug and 6720 [32·0%] receiving placebo) were eligible. The risk of any treatment-emergent adverse event was no different with active drug than with placebo (7660/14 267 [53·7%] patients on active drug vs 3758/6720 [55·9%] on placebo; RR 0·97, 95% CI 0·94-1·00; I2 =36%). However, the risks of worsening of IBD activity (563/13 473 [4·2%] vs 530/6252 [8·5%]; 0·48, 0·40-0·59; I2 =54%), withdrawal due to adverse event (401/13 363 [3·0%] vs 299/6267 [4·8%]; 0·62, 0·48-0·79; I2 =46%), serious adverse event (682/14 267 [4·8%] vs 483/6720 [7·2%]; 0·69, 0·59-0·80; I2 =30%), serious infection (140/14 194 [1·0%] vs 91/6647 [1·4%]; 0·67, 0·50-0·89; I2 =0%), serious worsening of IBD activity (187/11 271 [1·7%] vs 189/5056 [3·7%]; 0·45, 0·34-0·60; I2 =27%), or VTEs (13/7542 [0·2%] vs 12/2981 [0·4%]; 0·45, 0·21-0·94; I2 =0%) were all significantly lower with active drug than placebo. Numbers needed to treat with active drug to avoid these potentially serious adverse events ranged from 23 for worsening of IBD activity to 452 for VTEs. 27 randomised controlled trials were judged as low risk of bias across all domains. INTERPRETATION Patients with moderately to severely active IBD receiving placebo are more likely to experience significant worsening of IBD activity and some serious adverse events, which might relate to a reduction in risk of these events with active drug. Patients should be counselled about these potential harms, and alternative trial designs to mitigate these harms should be considered. FUNDING None.
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Affiliation(s)
- Shahida Din
- Edinburgh Inflammatory Bowel Diseases Unit, Western General Hospital, Edinburgh, UK; Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Jonathan Segal
- Department of Gastroenterology, Royal Melbourne Hospital, Melbourne, VIC, Australia; Department of Medicine, The University of Melbourne, Melbourne, VIC, Australia
| | - Jonathan Blackwell
- Edinburgh Inflammatory Bowel Diseases Unit, Western General Hospital, Edinburgh, UK
| | - Beatriz Gros
- Department of Gastroenterology, Reina Sofía University Hospital, Cordoba, Spain; Maimonides Biomedical Research Institute of Cordoba, University of Cordoba, Cordoba, Spain
| | - Christopher J Black
- Leeds Gastroenterology Institute, St James's University Hospital, Leeds, UK; Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
| | - Alexander C Ford
- Leeds Gastroenterology Institute, St James's University Hospital, Leeds, UK; Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
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7
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Ignacio A, Cipelli M, Takiishi T, Favero Aguiar C, Fernandes Terra F, Ghirotto B, Martins Silva E, Castoldi A, Magalhães YT, Antonio T, Nunes Padovani B, Ioshie Hiyane M, Andrade-Oliveira V, Forti FL, Olsen Saraiva Camara N. Lack of mTORC2 signaling in CD11c+ myeloid cells inhibits their migration and ameliorates experimental colitis. J Leukoc Biol 2024; 116:779-792. [PMID: 38652699 DOI: 10.1093/jleuko/qiae084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 01/30/2024] [Accepted: 03/05/2024] [Indexed: 04/25/2024] Open
Abstract
The mammalian target of rapamycin (mTOR) pathway plays a key role in determining immune cells function through modulation of their metabolic status. By specific deletion of Rictor in CD11c+ myeloid cells (referred to here as CD11cRicΔ/Δ), we investigated the role of mTOR complex 2 (mTORC2) signaling in dendritic cells (DCs) function in mice. We showed that upon dextran sulfate sodium-induced colitis, the lack of mTORC2 signaling CD11c+ cells diminishes the colitis score and abrogates DC migration to the mesenteric lymph nodes, thereby diminishing the infiltration of T helper 17 cells in the lamina propria and subsequent inflammation. These findings corroborate with the abrogation of cytoskeleton organization and the decreased activation of Rac1 and Cdc42 GTPases observed in CD11c+-mTORC2-deficient cells. Meta-analysis on colonic samples from ulcerative colitis patients revealed increased gene expression of proinflammatory cytokines, which coincided with augmented expression of the mTOR pathway, a positive correlation between the DC marker ITGAX and interleukin-6, the expression of RICTOR, and CDC42. Together, this work proposes that targeting mTORC2 on DCs offers a key to hamper inflammatory responses, and this way, ameliorates the progression and severity of intestinal inflammatory diseases.
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Affiliation(s)
- Aline Ignacio
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Marcella Cipelli
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Tatiane Takiishi
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Cristhiane Favero Aguiar
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Fernanda Fernandes Terra
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Bruno Ghirotto
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Eloisa Martins Silva
- Center for Natural and Human Sciences, Federal University of ABC. Alameda da Universidade (UFABC) 09606045, São Bernardo do Campo, SP, Brazil
| | - Angela Castoldi
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Yuli Thamires Magalhães
- Laboratory of Signaling in Biomolecular Systems, Department of Biochemistry, Institute of Chemistry, University of São Paulo. Av. Prof. Lineu Prestes, 748 05508900, São Paulo, Brazil
| | - Tiago Antonio
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Barbara Nunes Padovani
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Meire Ioshie Hiyane
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Vinicius Andrade-Oliveira
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
| | - Fabio Luis Forti
- Laboratory of Signaling in Biomolecular Systems, Department of Biochemistry, Institute of Chemistry, University of São Paulo. Av. Prof. Lineu Prestes, 748 05508900, São Paulo, Brazil
| | - Niels Olsen Saraiva Camara
- Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences, University of São Paulo. Av. Prof. Lineu Prestes 1730, ICB IV, 05508000 São Paulo, Brazil
- Laboratory of Renal Physiology, Department of Medicine, Federal University of São Paulo (UNIFESP). Rua Botucatu 740, 04023-062, São Paulo, Brazil
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Rohekar S, Boyd T, Lambert RG, Beaton M, Chande N, Gregor J, Lennox H, Mcintosh K, Ponich T, Rahman A, Sharma T, Sey M, Tauqir M, Jairath V. Initiation of vedolizumab did not provoke new-onset spondylarthritis in patients with inflammatory bowel disease: A prospective 24-week study with imaging assessments. United European Gastroenterol J 2024; 12:859-869. [PMID: 38965810 PMCID: PMC11497674 DOI: 10.1002/ueg2.12621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 05/31/2024] [Indexed: 07/06/2024] Open
Abstract
BACKGROUND A temporal relationship between vedolizumab and new-onset spondyloarthritis (SpA) has been suggested. AIMS We evaluated the relationship between vedolizumab initiation and development of new-onset SpA in patients with inflammatory bowel disease (IBD) through serial clinical evaluation and magnetic resonance imaging (MRI). METHODS A single-centre prospective observational study of 24 patients with IBD. Patients were eligible if they had active ulcerative colitis or Crohn's disease (CD), were initiating vedolizumab, had no prior history of arthritis or SpA and were suitable for serial MRI. A rheumatologist performed clinical evaluation prior to the first dose and 8 and 24 weeks. Axial MRI was evaluated by a blinded central reader and performed at baseline 8 and 24 weeks. RESULTS Nine tumor necrosis factor (TNF) inhibitor-naïve patients (4 male; mean age 53.2 years; 6 UC; 3 CD) and eight TNF inhibitor-experienced patients (7 male; mean age 48 years; 3 UC; 5 CD) completed all assessments. No patients developed new features of axial arthritis or features of peripheral SpA (inflammatory oligoarthritis, enthesitis, dactylitis, or psoriasis (nail, body, or scalp)). Both groups demonstrated a good intestinal response. CONCLUSION Vedolizumab initiation did not induce new features of axial or peripheral SpA after 24 weeks of treatment in TNF inhibitor-experienced or TNF inhibitor-naive patients with IBD.
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Affiliation(s)
- Sherry Rohekar
- Department of MedicineDivision of RheumatologySchulich School of Medicine & DentistryWestern UniversityLondonOntarioCanada
- Lawson Health Research InstituteLondonOntarioCanada
| | - Tristan Boyd
- Department of MedicineDivision of RheumatologySchulich School of Medicine & DentistryWestern UniversityLondonOntarioCanada
- Lawson Health Research InstituteLondonOntarioCanada
| | - Robert G. Lambert
- Department of Radiology and Diagnostic ImagingUniversity of AlbertaEdmontonAlbertaCanada
| | - Melanie Beaton
- Department of MedicineDivision of GastroenterologyWestern UniversityLondonOntarioCanada
| | - Nilesh Chande
- Southwestern Ontario Inflammatory Bowel Disease ClinicLondonOntarioCanada
| | - Jamie Gregor
- Department of MedicineDivision of GastroenterologyWestern UniversityLondonOntarioCanada
| | | | - Keith Mcintosh
- Department of MedicineDivision of GastroenterologyWestern UniversityLondonOntarioCanada
| | - Terry Ponich
- Department of MedicineDivision of GastroenterologyWestern UniversityLondonOntarioCanada
| | - Adam Rahman
- Department of MedicineDivision of GastroenterologyWestern UniversityLondonOntarioCanada
| | | | - Michael Sey
- Lawson Health Research InstituteLondonOntarioCanada
- Department of MedicineDivision of GastroenterologyWestern UniversityLondonOntarioCanada
| | - Maria Tauqir
- Schulich School of Medicine & DentistryWestern UniversityLondonOntarioCanada
| | - Vipul Jairath
- Lawson Health Research InstituteLondonOntarioCanada
- Department of MedicineDivision of GastroenterologyWestern UniversityLondonOntarioCanada
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9
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Kim KO, Lee SH. [Old and New Biologics and Small Molecules in Inflammatory Bowel Disease: Anti Integrins]. THE KOREAN JOURNAL OF GASTROENTEROLOGY = TAEHAN SOHWAGI HAKHOE CHI 2024; 84:43-50. [PMID: 39176460 DOI: 10.4166/kjg.2024.070] [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: 07/06/2024] [Revised: 08/04/2024] [Accepted: 08/12/2024] [Indexed: 08/24/2024]
Abstract
Recently, novel biologics or small molecular drugs have been introduced for overcoming the unmet needs associated with anti-tumor necrosis factor α agents for inflammtory bowel disease (IBD) treatment. Among these novel drugs, anti integrin agents block leukocyte trafficking to the intestine by blocking the interaction between integrin and cell adhesion molecules. Vedolizumab (anti-α4β7) is most widely used anti-integrin approved in both ulcerative colitis and Crohn's disease .It has been shown to be effective in both induction and maintenance therapy with a favorable safety profile due to gut selectivity. Several models incorporating clinical, genetic, immune and gut microbial markers to predict response to vedolizumab in IBD have been developed. Etrolizumab (anti-β7) blocks leukocyte trafficking via α4β7 and cell adhesion via αEβ7 integrins. In addition, the introduction of subcutaneous vedolizumab showed similar efficacy and safety with improved patients' convenience. Other investigational anti-integrin therapies include abrilumab (anti-α4β7 IgG2), PN-943 (orally administered and gut-restricted α4β7 antagonist peptide), AJM300 (orally active small molecule inhibitor of α4), and ontamalimab (anti-MAdCAM-1 IgG).
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Affiliation(s)
- Kyeong Ok Kim
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Si Hyung Lee
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
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10
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Mokmued K, Obeng G, Kawamoto E, Caidengbate S, Leangpanich S, Akama Y, Gaowa A, Shimaoka M, Park EJ. miR-200c-3p regulates α4 integrin-mediated T cell adhesion and migration. Exp Cell Res 2024; 440:114146. [PMID: 38936759 DOI: 10.1016/j.yexcr.2024.114146] [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: 03/29/2024] [Revised: 06/01/2024] [Accepted: 06/22/2024] [Indexed: 06/29/2024]
Abstract
A microRNA miR-200c-3p is a regulator of epithelial-mesenchymal transition to control adhesion and migration of epithelial and mesenchymal cells. However, little is known about whether miR-200c-3p affects lymphocyte adhesion and migration mediated by integrins. Using TK-1 (a T lymphoblast cell) as a model of T cell, here we show that repressed expression of miR-200c-3p upregulated α4 integrin-mediated adhesion to and migration across mucosal addressin cell adhesion molecule-1 (MAdCAM-1). Conversely, overexpression of miR-200c-3p downregulated α4 integrin-mediated adhesion and migration. Unlike in epithelial cells, miR-200c-3p did not target talin, a conformation activator of integrin, but, targeted E26-transformation-specific sequence 1 (ETS1), a transcriptional activator of α4 integrin, in T cells. Treatment of the miR-200c-3p-low-expressing TK-1 cells that possessed elevated α4 integrin with ETS1 small interfering RNA (siRNA) resulted in the reversion of the α4 integrin expression, supporting that ETS1 is a target of miR-200c-3p. A potential proinflammatory immune-modulator retinoic acid (RA) treatment of TK-1 cells elicited a significant reduction of miR-200c-3p and simultaneously a marked increase in ETS1 and α4 integrin expression. An anti-inflammatory cytokine TGF-β1 treatment elevated miR-200c-3p, thereby downregulating ETS1 and α4 integrin expression. These results suggest that miR-200c-3p is an important regulator of α4 integrin expression and functions and may be controlled by RA and TGF-β1 in an opposite way. Overexpression of miR-200c-3p could be a novel therapeutic option for treatment of gut inflammation through suppressing α4 integrin-mediated T cell migration.
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Affiliation(s)
- Khwanchanok Mokmued
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan
| | - Gideon Obeng
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan
| | - Eiji Kawamoto
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; Department of Emergency and Disaster Medicine, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan
| | - Siqingaowa Caidengbate
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan
| | - Supasuta Leangpanich
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan
| | - Yuichi Akama
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan; Department of Emergency and Disaster Medicine, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan
| | - Arong Gaowa
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan
| | - Motomu Shimaoka
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan
| | - Eun Jeong Park
- Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.
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11
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Levar T, Johnston M, Ding NS, Behrenbruch C. Update for surgeons on novel induction treatments for acute severe inflammatory bowel disease associated colitis. ANZ J Surg 2024; 94:795-803. [PMID: 38450582 DOI: 10.1111/ans.18924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 02/14/2024] [Accepted: 02/19/2024] [Indexed: 03/08/2024]
Abstract
BACKGROUND The landscape of biologic agents for the treatment of inflammatory bowel disease (IBD) associated colitis is rapidly evolving, requiring surgeons to be up-to-date as part of multi-disciplinary, evidence-based care. An update on novel therapies used to induce remission in IBD-associated colitis is presented. METHODS A systematic search through Ovid MEDLINE and CENTRAL using a combination of MeSH terms and Boolean operators was conducted. RESULTS One thousand and twenty articles from which 38 articles were selected for inclusion in this review. Novel agents were trialled as 4th or 5th line treatment following conventional treatment failure. Rates of serious adverse effects were low. Janus kinase (JAK) inhibitors (upadacitinib and tofacitinib) were efficacious in inducing remission in ulcerative colitis, and IL-23p19 inhibitors (mirikizumab, guselkumab, and risankizumab) in Crohn's colitis. Evidence was limited for other drug classes. CONCLUSION JAK-inhibitors and IL-23p19 inhibitors were found to be the most effective agents for inducting remission following failure of standard of care treatment. A significant proportion of patients did not respond, highlighting the inherent challenge in optimizing treatment for moderate to severe IBD-associated colitis. More robust study designs and comparator trials are required.
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Affiliation(s)
- Timothy Levar
- Department of General Surgery (Colorectal), St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia
- Department of Medical Education, The University of Melbourne, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia
| | - Michael Johnston
- Department of Medical Education, The University of Melbourne, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia
- Department of Medicine, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia
| | - Nik S Ding
- Department of Medical Education, The University of Melbourne, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia
- Department of Medicine, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia
| | - Corina Behrenbruch
- Department of General Surgery (Colorectal), St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia
- Department of Medical Education, The University of Melbourne, St Vincent's Hospital Melbourne, Melbourne, Victoria, Australia
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12
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Rindi LV, Zaçe D, Braccialarghe N, Massa B, Barchi V, Iannazzo R, Fato I, De Maria F, Kontogiannis D, Malagnino V, Sarmati L, Iannetta M. Drug-Induced Progressive Multifocal Leukoencephalopathy (PML): A Systematic Review and Meta-Analysis. Drug Saf 2024; 47:333-354. [PMID: 38321317 DOI: 10.1007/s40264-023-01383-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/15/2023] [Indexed: 02/08/2024]
Abstract
INTRODUCTION Progressive multifocal leukoencephalopathy (PML) was first described among patients affected by hematological or solid tumors. Following the human immunodeficiency virus (HIV) epidemic, people living with HIV have represented most cases for more than a decade. With the diffusion of highly active antiretroviral therapy, this group progressively decreased in favor of patients undergoing treatment with targeted therapy/immunomodulators. In this systematic review and meta-analysis, the objective was to assess which drugs are most frequently related to PML development, and report the incidence of drug-induced PML through a meta-analytic approach. METHODS The electronic databases MEDLINE, EMBASE, ClinicalTrials.gov, Web of Science and the Canadian Agency for Drugs and Technologies in Health Database (CADTH) were searched up to May 10, 2022. Articles that reported the risk of PML development after treatment with immunomodulatory drugs, including patients of both sexes under the age of 80 years, affected by any pathology except HIV, primary immunodeficiencies or malignancies, were included in the review. The incidence of drug-induced PML was calculated based on PML cases and total number of patients observed per 100 persons and the observation time. Random-effect metanalyses were conducted for each drug reporting pooled incidence with 95% confidence intervals (CI) and median (interquartile range [IQR]) of the observation time. Heterogeneity was measured by I2 statistics. Publication bias was examined through funnel plots and Egger's test. RESULTS A total of 103 studies were included in the systematic review. In our analysis, we found no includible study reporting cases of PML during the course of treatment with ocrelizumab, vedolizumab, abrilumab, ontamalimab, teriflunomide, daclizumab, inebilizumab, basiliximab, tacrolimus, belimumab, infliximab, firategrast, disulone, azathioprine or danazole. Dalfampridine, glatiramer acetate, dimethyl fumarate and fingolimod show a relatively safe profile, although some cases of PML have been reported. The meta-analysis showed an incidence of PML cases among patients undergoing rituximab treatment for multiple sclerosis (MS) of 0.01 cases/100 persons (95% CI - 0.08 to 0.09; I2 = 20.4%; p = 0.25) for a median observation period of 23.5 months (IQR 22.1-42.1). Treatment of MS with natalizumab carried a PML risk of 0.33 cases/100 persons (95% CI 0.29-0.37; I2 = 50%; p = 0.003) for a median observation period of 44.1 months (IQR 28.4-60) and a mean number of doses of 36.3 (standard deviation [SD] ± 20.7). When comparing data about patients treated with standard interval dosing (SID) and extended interval dosing (EID), the latter appears to carry a smaller risk of PML, that is, 0.08 cases/100 persons (95% CI 0.0-0.15) for EID versus 0.3 cases/100 persons (95% CI 0.25-0.34) for SID. CONCLUSIONS A higher risk of drug-related PML in patients whose immune system is not additionally depressed by means of neoplasms, HIV or concomitant medications is found in the neurological field. This risk is higher in MS treatment, and specifically during long-term natalizumab therapy. While this drug is still routinely prescribed in this field, considering the efficacy in reducing MS relapses, in other areas it could play a smaller role, and be gradually replaced by other safer and more recently approved agents.
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Affiliation(s)
- Lorenzo Vittorio Rindi
- Department of Systems Medicine, Tor Vergata University, Via Montpellier, 1, 00133, Rome, Italy
| | - Drieda Zaçe
- Department of Systems Medicine, Tor Vergata University, Via Montpellier, 1, 00133, Rome, Italy
| | - Neva Braccialarghe
- Department of Systems Medicine, Tor Vergata University, Via Montpellier, 1, 00133, Rome, Italy
| | - Barbara Massa
- Department of Systems Medicine, Tor Vergata University, Via Montpellier, 1, 00133, Rome, Italy
| | - Virginia Barchi
- Department of Systems Medicine, Tor Vergata University, Via Montpellier, 1, 00133, Rome, Italy
| | - Roberta Iannazzo
- Department of Systems Medicine, Tor Vergata University, Via Montpellier, 1, 00133, Rome, Italy
| | - Ilenia Fato
- Department of Systems Medicine, Tor Vergata University, Via Montpellier, 1, 00133, Rome, Italy
| | - Francesco De Maria
- Department of Systems Medicine, Tor Vergata University, Via Montpellier, 1, 00133, Rome, Italy
| | - Dimitra Kontogiannis
- Department of Systems Medicine, Tor Vergata University, Via Montpellier, 1, 00133, Rome, Italy
| | - Vincenzo Malagnino
- Department of Systems Medicine, Tor Vergata University, Via Montpellier, 1, 00133, Rome, Italy
- Infectious Disease Clinic, Policlinico Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy
| | - Loredana Sarmati
- Department of Systems Medicine, Tor Vergata University, Via Montpellier, 1, 00133, Rome, Italy
- Infectious Disease Clinic, Policlinico Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy
| | - Marco Iannetta
- Department of Systems Medicine, Tor Vergata University, Via Montpellier, 1, 00133, Rome, Italy.
- Infectious Disease Clinic, Policlinico Tor Vergata, Viale Oxford, 81, 00133, Rome, Italy.
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Kelly AJ, Long A. Targeting T-cell integrins in autoimmune and inflammatory diseases. Clin Exp Immunol 2024; 215:15-26. [PMID: 37556361 PMCID: PMC10776250 DOI: 10.1093/cei/uxad093] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 07/28/2023] [Accepted: 08/08/2023] [Indexed: 08/11/2023] Open
Abstract
The recruitment of T cells to tissues and their retention there are essential processes in the pathogenesis of many autoimmune and inflammatory diseases. The mechanisms regulating these processes have become better understood over the past three decades and are now recognized to involve temporally and spatially specific interactions between cell-adhesion molecules. These include integrins, which are heterodimeric molecules that mediate in-to-out and out-to-in signalling in T cells, other leukocytes, and most other cells of the body. Integrin signalling contributes to T-cell circulation through peripheral lymph nodes, immunological synapse stability and function, extravasation at the sites of inflammation, and T-cell retention at these sites. Greater understanding of the contribution of integrin signalling to the role of T cells in autoimmune and inflammatory diseases has focused much attention on the development of therapeutics that target T-cell integrins. This literature review describes the structure, activation, and function of integrins with respect to T cells, then discusses the use of integrin-targeting therapeutics in inflammatory bowel disease, multiple sclerosis, and psoriasis. Efficacy and safety data from clinical trials and post-marketing surveillance are presented for currently approved therapeutics, therapeutics that have been withdrawn from the market, and novel therapeutics currently in clinical trials. This literature review will inform the reader of the current means of targeting T-cell integrins in autoimmune and inflammatory diseases, as well as recent developments in the field.
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Affiliation(s)
- Aidan J Kelly
- Trinity Translational Medicine Institute, Trinity College Dublin, Trinity Centre for Health Sciences, St James's Hospital, Dublin D08 NHY1, Ireland
| | - Aideen Long
- Trinity Translational Medicine Institute, Trinity College Dublin, Trinity Centre for Health Sciences, St James's Hospital, Dublin D08 NHY1, Ireland
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14
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Vebr M, Pomahačová R, Sýkora J, Schwarz J. A Narrative Review of Cytokine Networks: Pathophysiological and Therapeutic Implications for Inflammatory Bowel Disease Pathogenesis. Biomedicines 2023; 11:3229. [PMID: 38137450 PMCID: PMC10740682 DOI: 10.3390/biomedicines11123229] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 10/11/2023] [Accepted: 11/22/2023] [Indexed: 12/24/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a lifelong inflammatory immune mediated disorder, encompassing Crohn's disease (CD) and ulcerative colitis (UC); however, the cause and specific pathogenesis of IBD is yet incompletely understood. Multiple cytokines produced by different immune cell types results in complex functional networks that constitute a highly regulated messaging network of signaling pathways. Applying biological mechanisms underlying IBD at the single omic level, technologies and genetic engineering enable the quantification of the pattern of released cytokines and new insights into the cytokine landscape of IBD. We focus on the existing literature dealing with the biology of pro- or anti-inflammatory cytokines and interactions that facilitate cell-based modulation of the immune system for IBD inflammation. We summarize the main roles of substantial cytokines in IBD related to homeostatic tissue functions and the remodeling of cytokine networks in IBD, which may be specifically valuable for successful cytokine-targeted therapies via marketed products. Cytokines and their receptors are validated targets for multiple therapeutic areas, we review the current strategies for therapeutic intervention and developing cytokine-targeted therapies. New biologics have shown efficacy in the last few decades for the management of IBD; unfortunately, many patients are nonresponsive or develop therapy resistance over time, creating a need for novel therapeutics. Thus, the treatment options for IBD beyond the immune-modifying anti-TNF agents or combination therapies are expanding rapidly. Further studies are needed to fully understand the immune response, networks of cytokines, and the direct pathogenetic relevance regarding individually tailored, safe and efficient targeted-biotherapeutics.
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Affiliation(s)
- Marek Vebr
- Departments of Pediatrics, Faculty Hospital, Faculty of Medicine in Pilsen, Charles University of Prague, 323 00 Pilsen, Czech Republic; (R.P.); (J.S.); (J.S.)
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15
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Chen K, Gu X, Yang S, Tao R, Fan M, Bao W, Wang X. Research progress on intestinal tissue-resident memory T cells in inflammatory bowel disease. Scand J Immunol 2023; 98:e13332. [PMID: 38441381 DOI: 10.1111/sji.13332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 09/18/2023] [Accepted: 09/21/2023] [Indexed: 03/07/2024]
Abstract
Tissue-resident memory T (TRM) cells are a recently discovered subpopulation of memory T cells that reside in non-lymphoid tissues such as the intestine and skin and do not enter the bloodstream. The intestine encounters numerous pathogens daily. Intestinal mucosal immunity requires a balance between immune responses to pathogens and tolerance to food antigens and symbiotic microbiota. Therefore, intestinal TRM cells exhibit unique characteristics. In healthy intestines, TRM cells induce necessary inflammation to strengthen the intestinal barrier and inhibit bacterial translocation. During intestinal infections, TRM cells rapidly eliminate pathogens by proliferating, releasing cytokines, and recruiting other immune cells. Moreover, certain TRM cell subsets may have regulatory functions. The involvement of TRM cells in inflammatory bowel disease (IBD) is increasingly recognized as a critical factor. In IBD, the number of pro-inflammatory TRM cells increases, whereas the number of regulatory subgroups decreases. Additionally, the classic markers, CD69 and CD103, are not ideal for intestinal TRM cells. Here, we review the phenotype, development, maintenance, and function of intestinal TRM cells, as well as the latest findings in the context of IBD. Further understanding of the function of intestinal TRM cells and distinguishing their subgroups is crucial for developing therapeutic strategies to target these cells.
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Affiliation(s)
- Ke Chen
- Nanjing Medical University, Nanjing, China
| | - Xin Gu
- Nanjing Medical University, Nanjing, China
| | | | - Rui Tao
- Nanjing Medical University, Nanjing, China
| | | | | | - Xiaoyun Wang
- Wuxi Second Hospital Affiliated to Nanjing Medical University, Wuxi, China
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16
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Zhao R, Ding Z, Gupta P, Gozalo L, Bruette R, Johnson VM, Maughn K, Liu Y, Kachroo S. Evaluation of Treatment Patterns and Maintenance Dose Titration Among Patients With Crohn's Disease Initiating Biologics With 3 Years of Follow-Up. JOURNAL OF HEALTH ECONOMICS AND OUTCOMES RESEARCH 2023; 10:111-120. [PMID: 38025989 PMCID: PMC10664831 DOI: 10.36469/001c.88947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 10/09/2023] [Indexed: 12/01/2023]
Abstract
Background: There is limited real-world evidence on treatment patterns of patients with Crohn's disease (CD) initiating biologics with an extensive follow-up period. This study describes persistence and dose titration among CD patients with 3 years of follow-up. Methods: This retrospective observational study was conducted using the STATinMED RWD Insights all-payer medical and pharmacy data. Adult patients with at least 1 CD medical claim and at least 1 medical/pharmacy claim for a biologic (adalimumab [ADA], certolizumab pegol (CZP), infliximab [IFX] and its biosimilar products [IFX-BS], ustekinumab [UST], and vedolizumab [VDZ]) between September 2016 and October 2018 were identified. Commercially insured patients with continuous capture for at least 12 months before and at least 36 months after biologics initiation were selected. Confirmed CD patients were included in the final cohort. Baseline patient characteristics and treatment patterns over the 3-year follow-up period were evaluated. Results were summarized using means and SD or counts and percentages. Results: A total of 2309 confirmed patients with CD were identified (847 [36.7%] IFX, 534 [23.1%] ADA, 486 [21.1%] VDZ, 394 [17.1%] UST, 85 [3.7%] CZP, and 72 [3.1%] IFX-BS). CZP and IFX-BS were excluded due to small sample sizes. Approximately half of CD patients were between ages 35 and 54. Patients on UST had a higher Charlson Comorbidity Index score. Common comorbidities (>10%) included anemia, anxiety, depression, and hypertension. Persistence over 3 years' follow-up was highest for UST (61.4%) patients, followed by VDZ (58.0% ), ADA (52.1% , and IFX (48.1%). The discontinuation rate without switch or restart was highest for ADA (37.3%), followed by UST (30.7%), IFX (28.1%), and VDZ (25.3%). Over the 3 years of follow-up, the dose titration rate was highest for IFX (76.5%) and lowest for UST (50.8%). In particular, UST had the lowest dose escalation rate (35.5%) and highest dose-reduction rate (16.5%). Conclusions: Patients with CD on UST had the highest persistence and lowest dose escalation across different biologic users over the 3-year follow-up period, possibly suggesting a better clinical response of UST. Future studies with longer follow-up adjusting for confounders are needed to better understand treatment patterns among biologics users.
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Affiliation(s)
- Ruizhi Zhao
- Janssen Scientific Affairs, LLC, Horsham, Pennsylvania
| | - Zhijie Ding
- Janssen Scientific Affairs, LLC, Horsham, Pennsylvania
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17
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Hanzel J, Solitano V, Zou L, Zou G, Peyrin-Biroulet L, Danese S, Singh S, Ma C, Wils P, Jairath V. A Comparison of Treatment Effect Sizes in Matched Phase 2 and Phase 3 Trials of Advanced Therapeutics in Inflammatory Bowel Disease: Systematic Review and Meta-Analysis. Clin Transl Gastroenterol 2023; 14:e00629. [PMID: 37578211 PMCID: PMC10684248 DOI: 10.14309/ctg.0000000000000629] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 08/02/2023] [Indexed: 08/15/2023] Open
Abstract
INTRODUCTION Phase 2 trials are fundamental to the rational and efficient design of phase 3 trials. We aimed to determine the relationship of treatment effect size estimates from phase 2 and phase 3 clinical trials on advanced therapeutics in inflammatory bowel disease. METHODS MEDLINE, EMBASE, CENTRAL, and the Cochrane library were searched from inception to December 19, 2022, to identify paired phase 2 and 3 placebo-controlled induction studies of advanced therapeutics for Crohn's disease (CD) and ulcerative colitis (UC). Treatment effect sizes were expressed as a risk ratio (RR) between the active arm and placebo arm. For the same therapeutics, RRs from phase 2 trials were divided by the RR from phase 3 trial to quantify the relationship of effect sizes between phases. RESULTS Twenty-two studies (9 phase 2 trials, 13 phase 3 trials) were included for CD and 30 studies (12 phase 2 trials, 18 phase 3 trials) for UC. In UC (pooled RR 0.72; 95% confidence interval: 0.58-0.86; RR <1 indicates smaller treatment effect sizes in phase 2 trials), but not CD (pooled RR 1.01; 95% confidence interval: 0.84-1.18), phase 2 trials systematically underestimated treatment effect sizes for the primary endpoint compared with phase 3 trials. The underestimation was observed for clinical, but not endoscopic, endpoints in UC. DISCUSSION Treatment effect sizes for the primary and clinical endpoints were similar across clinical trial phases in CD, but not UC, where only endoscopic endpoints were comparable. This will help inform clinical development plans and future trial design.
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Affiliation(s)
- Jurij Hanzel
- Department of Gastroenterology and Hepatology, University Medical Center Ljubljana, Ljubljana, Slovenia
- Alimentiv Inc, London, Ontario, Canada
| | - Virginia Solitano
- Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
| | - Lily Zou
- Department of Statistics and Actuarial Sciences, University of Waterloo, Waterloo, Ontario, Canada
| | - G.Y. Zou
- Alimentiv Inc, London, Ontario, Canada
- Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
- Robarts Research Institute, Western University, London, Ontario, Canada
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology and Inserm NGERE U1256, University Hospital of Nancy, University of Lorraine, Nancy, France
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita‐Salute San Raffaele, Milan, Italy
| | - Siddharth Singh
- Division of Gastroenterology, University of California, San Diego, La Jolla, California, USA
| | - Christopher Ma
- Alimentiv Inc, London, Ontario, Canada
- Division of Gastroenterology & Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Community Health Sciences, University of Calgary, Calgary, Alberta, Canada
| | - Pauline Wils
- Department of Gastroenterology, Claude Huriez Hospital, University of Lille 2, Lille, France
- Inserm, CHU Lille, U1286 Infinite, Institute for Translational Research in Inflammation, University of Lille, Lille, France
| | - Vipul Jairath
- Alimentiv Inc, London, Ontario, Canada
- Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada
- Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
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Wils P, Jairath V, Sands BE, Magro F, Reinisch W, Rubin D, Danese S, Baumann C, Peyrin‐Biroulet L. Comparison of treatment effect between phase 2 and phase 3 trials in patients with inflammatory bowel disease. United European Gastroenterol J 2023; 11:797-806. [PMID: 37670487 PMCID: PMC10576605 DOI: 10.1002/ueg2.12455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Accepted: 07/27/2023] [Indexed: 09/07/2023] Open
Abstract
BACKGROUND AND AIMS The accumulation of multiple randomized controlled trials in the field of inflammatory bowel diseases provides an opportunity to compare treatment effects between phase 2 and 3 trials. We aimed to determine whether treatment effects observed in phase 3 investigating biologics and small molecule drugs differed from those in their preceding phase 2 trial. METHODS We first performed a review of phase 2 and phase 3 trials enrolling ulcerative colitis (UC) or Crohn's disease (CD) patients. We compared the percent overall success for key endpoints between phases (several phase 3 could be matched to a single phase 2 trial). Then, we compared the percent overall success in the matched phase 2 and 3 trials (ratio 1:1), and performed sensitivity analysis. RESULTS We identified 14 phase 2 (8 CD; 6 UC) and 24 phase 3 (13 CD; 11 UC) trials. In CD, the different analyses suggest that the percentage of overall success of clinical remission and clinical response was significantly higher in phase 2 than in phase 3 trials. In UC, the analyses suggest collectively that the percent of treatment effect seemed similar for clinical remission, clinical response and histologic outcomes between phases but with a lower percentage of overall success in phase 2 than in phase 3 trials for endoscopic endpoints. CONCLUSIONS In UC, we observed a similar percentage of treatment effect for clinical and histologic outcomes between phase 2 and 3 trials but not for endoscopic outcomes. Whereas in CD, we showed a failure to reproduce similar results between phases. These results may help sponsors in the design of future drug development programs.
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Affiliation(s)
- Pauline Wils
- Department of GastroenterologyClaude Huriez HospitalUniversity of Lille 2LilleFrance
- InsermCHU LilleU1286‐ INFINITE‐ Institute for Translational Research in InflammationUniversity of LilleLilleFrance
| | - Vipul Jairath
- Division of GastroenterologyDepartment of MedicineWestern UniversityLondonOntarioCanada
| | - Bruce E. Sands
- The Dr Henry J Janowitz Division of GastroenterologyIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Fernando Magro
- Department of GastroenterologyCentro Hospitalar São JoãoPortoPortugal
| | - Walter Reinisch
- Division Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - David Rubin
- Inflammatory Bowel Disease CenterUniversity of Chicago MedicineChicagoIllinoisUSA
| | - Silvio Danese
- Gastroenterology and EndoscopyIRCCS Ospedale San Raffaele and Vita‐Salute San Raffaele UniversityMilanItaly
| | - Cédric Baumann
- Unit of Methodology, Data Management and StatisticNancy University HospitalNancyFrance
| | - Laurent Peyrin‐Biroulet
- Department of GastroenterologyCHRU‐NancyUniversity of LorraineNancyFrance
- InsermNGEREUniversity of LorraineNancyFrance
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19
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Quann K, Sacirbegovic F, Shlomchik WD. Natalizumab for GVHD: too little or too late? Blood Adv 2023; 7:5187-5188. [PMID: 37698891 PMCID: PMC10505719 DOI: 10.1182/bloodadvances.2023010486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/13/2023] Open
Affiliation(s)
- Kevin Quann
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Faruk Sacirbegovic
- Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA
- Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA
| | - Warren D Shlomchik
- Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA
- Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA
- Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA
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20
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Al Malki MM, London K, Baez J, Akahoshi Y, Hogan WJ, Etra A, Choe H, Hexner E, Langston A, Abhyankar S, Ponce DM, DeFilipp Z, Kitko CL, Adekola K, Reshef R, Ayuk F, Capellini A, Chanswangphuwana C, Eder M, Eng G, Gandhi I, Grupp S, Gleich S, Holler E, Javorniczky NR, Kasikis S, Kowalyk S, Morales G, Özbek U, Rösler W, Spyrou N, Yanik G, Young R, Chen YB, Nakamura R, Ferrara JLM, Levine JE. Phase 2 study of natalizumab plus standard corticosteroid treatment for high-risk acute graft-versus-host disease. Blood Adv 2023; 7:5189-5198. [PMID: 37235690 PMCID: PMC10505783 DOI: 10.1182/bloodadvances.2023009853] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 04/05/2023] [Accepted: 04/10/2023] [Indexed: 05/28/2023] Open
Abstract
Graft-versus-host disease (GVHD) of the gastrointestinal (GI) tract is the main cause of nonrelapse mortality (NRM) after allogeneic hematopoietic cell transplantation. Ann Arbor (AA) scores derived from serum biomarkers at onset of GVHD quantify GI crypt damage; AA2/3 scores correlate with resistance to treatment and higher NRM. We conducted a multicenter, phase 2 study using natalizumab, a humanized monoclonal antibody that blocks T-cell trafficking to the GI tract through the α4 subunit of α4β7 integrin, combined with corticosteroids as primary treatment for patients with new onset AA2/3 GVHD. Seventy-five patients who were evaluable were enrolled and treated; 81% received natalizumab within 2 days of starting corticosteroids. Therapy was well tolerated with no treatment emergent adverse events in >10% of patients. Outcomes for patients treated with natalizumab plus corticosteroids were compared with 150 well-matched controls from the MAGIC database whose primary treatment was corticosteroids alone. There were no significant differences in overall or complete response between patients treated with natalizumab plus corticosteroids and those treated with corticosteroids alone (60% vs 58%; P = .67% and 48% vs 48%; P = 1.0, respectively) including relevant subgroups. There were also no significant differences in NRM or overall survival at 12 months in patients treated with natalizumab plus corticosteroids compared with controls treated with corticosteroids alone (38% vs 39%; P = .80% and 46% vs 54%; P = .48, respectively). In this multicenter biomarker-based phase 2 study, natalizumab combined with corticosteroids failed to improve outcome of patients with newly diagnosed high-risk GVHD. This trial was registered at www.clinicaltrials.gov as # NCT02133924.
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Affiliation(s)
- Monzr M. Al Malki
- Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA
| | - Kaitlyn London
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Janna Baez
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Yu Akahoshi
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | | | - Aaron Etra
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Hannah Choe
- Division of Hematology, James Cancer Center, The Ohio State University, Columbus, OH
| | - Elizabeth Hexner
- Blood and Marrow Transplantation Program, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA
| | | | - Sunil Abhyankar
- Division of Hematologic Malignancies and Cellular Therapeutics, University of Kansas Medical Center, Kansas City, KS
| | - Doris M. Ponce
- Division of Hematology/Oncology, Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering, New York, NY
| | - Zachariah DeFilipp
- Hematopoietic Cell Transplant and Cellular Therapy Program, Massachusetts General Hospital, Boston, MA
| | - Carrie L. Kitko
- Pediatric Stem Cell Transplant Program, Vanderbilt University Medical Center, Nashville, TN
| | - Kehinde Adekola
- Division of Hematology/Oncology, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL
| | - Ran Reshef
- Blood and Marrow Transplantation, Columbia University Medical Center, New York, NY
| | - Francis Ayuk
- Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Alexandra Capellini
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Chantiya Chanswangphuwana
- Department of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand
| | - Matthias Eder
- Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany
| | - Gilbert Eng
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Isha Gandhi
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Stephan Grupp
- Division of Oncology, The Children’s Hospital of Philadelphia, Philadelphia, PA
| | - Sigrun Gleich
- Department of Hematology and Oncology, Internal Medicine III, University of Regensburg, Regensburg, Germany
| | - Ernst Holler
- Department of Hematology and Oncology, Internal Medicine III, University of Regensburg, Regensburg, Germany
| | - Nora Rebeka Javorniczky
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, Albert Ludwigs University, Freiburg, Germany
| | - Stelios Kasikis
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Steven Kowalyk
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - George Morales
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Umut Özbek
- Department of Population Health Science and Policy, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Wolf Rösler
- Department of Internal Medicine 5, University Hospital Erlangen, Erlangen, Germany
| | - Nikolaos Spyrou
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Gregory Yanik
- Blood and Marrow Transplant Program, Michigan Medicine, Ann Arbor, MI
| | - Rachel Young
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Yi-Bin Chen
- Hematopoietic Cell Transplant and Cellular Therapy Program, Massachusetts General Hospital, Boston, MA
| | - Ryotaro Nakamura
- Hematology/Hematopoietic Cell Transplantation, City of Hope National Medical Center, Duarte, CA
| | - James L. M. Ferrara
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - John E. Levine
- The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
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21
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Imbrizi M, Magro F, Coy CSR. Pharmacological Therapy in Inflammatory Bowel Diseases: A Narrative Review of the Past 90 Years. Pharmaceuticals (Basel) 2023; 16:1272. [PMID: 37765080 PMCID: PMC10537095 DOI: 10.3390/ph16091272] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 08/23/2023] [Accepted: 09/04/2023] [Indexed: 09/29/2023] Open
Abstract
Inflammatory Bowel Diseases had their first peak in incidence in countries in North America, Europe, and Oceania and are currently experiencing a new acceleration in incidence, especially in Latin America and Asia. Despite technological advances, 90 years after the development of the first molecule for the treatment of IBD, we still do not have drugs that promote disease remission in a generalized way. We carried out a narrative review on therapeutic advances in the treatment of IBD, the mechanisms of action, and the challenges facing the therapeutic goals in the treatment of IBD. Salicylates are still used in the treatment of Ulcerative Colitis. Corticosteroids have an indication restricted to the period of therapeutic induction due to frequent adverse events, while technologies with less systemic action have been developed. Most immunomodulators showed a late onset of action, requiring a differentiated initial strategy to control the disease. New therapeutic perspectives emerged with biological therapy, initially with anti-TNF, followed by anti-integrins and anti-interleukins. Despite the different mechanisms of action, there are similarities between the general rates of effectiveness. These similar results were also evidenced in JAK inhibitors and S1p modulators, the last therapeutic classes approved for the treatment of IBD.
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Affiliation(s)
- Marcello Imbrizi
- Department of Surgery, Faculty of Medical Sciences, University of Campinas, Cidade Universitária Zeferino Vaz-Barão Geraldo, Campinas 13083-970, SP, Brazil
| | - Fernando Magro
- Unit of Pharmacology and Therapeutics, Department of Biomedicine, Faculty of Medicine, University of Porto, 4200-450 Porto, Portugal
| | - Claudio Saddy Rodrigues Coy
- Department of Surgery, Faculty of Medical Sciences, University of Campinas, Cidade Universitária Zeferino Vaz-Barão Geraldo, Campinas 13083-970, SP, Brazil
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22
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Sarangi SC, Pattnaik SS, Sinha S, R G. An update on efficacy and safety comparison of biologics in treatment of inflammatory bowel disease targeting TNF-α, interleukins, leukocyte trafficking, Janus-kinase, and sphingosine-1-phosphate receptor. Expert Rev Gastroenterol Hepatol 2023; 17:837-861. [PMID: 36469630 DOI: 10.1080/17474124.2022.2155136] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 11/30/2022] [Indexed: 12/08/2022]
Abstract
INTRODUCTION Along with the rising prevalence of inflammatory bowel disease (IBD) [Crohn's disease (CD) and ulcerative colitis (UC)], biological therapies need an update/insight. AREA COVERED This review included randomized controlled trials (RCTs) from PubMed database (2000-October 2022) of approved biologics and small molecules with primary outcome analysis on efficacy (clinical response/remission/mucosal healing) and/or adverse events (AEs). Considered for this review under biologics classes are TNF-α inhibitors, leukocyte trafficking inhibitors, and anti IL-12/IL-23; and under small molecules are Janus-kinase inhibitors, and sphingosine-1-phosphate receptor modulators. EXPERT OPINION In CD, clinical response and remission were better with tofacitinib (61.23%) and infliximab (44.86%), respectively, in the induction phase, and these were better with ustekinumab in the maintenance phase. In UC, the maximum rate of response, remission, and mucosal healing were obtained with infliximab during the induction phase (67.49%, 35.99%, and 60.25%, respectively). During the maintenance phase, response rate was better with ustekinumab, but remission and mucosal healing were better with vedolizumab. The combined percentage of AEs was highest with infliximab (174.45%) and least with ozanimod (23.04%), and most commonly belonged to the 'infection and infestation system organ class (SOC).' These efficacy and safety analyses will help in the optimization of biologic treatment in IBD.
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Affiliation(s)
| | - Soumya S Pattnaik
- Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India
| | - Surabhi Sinha
- Department of Pharmacology, All India Institute of Medical Sciences, New Delhi, India
| | - Govindaraj R
- Department of Radiodiagnosis, NEIGRIHMS, Shilong, India
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23
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Skjellerudsveen BM, Skoie IM, Dalen I, Grimstad T, Omdal R. The Effect of Biological Treatment on Fatigue in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Drugs 2023:10.1007/s40265-023-01888-3. [PMID: 37219801 DOI: 10.1007/s40265-023-01888-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/03/2023] [Indexed: 05/24/2023]
Abstract
BACKGROUND Fatigue is a frequent complaint in patients with inflammatory bowel disease. Biological drugs have demonstrated beneficial effects on some extraintestinal manifestations, but the effect on fatigue is not clear. OBJECTIVE This study investigated the effects of biological and small molecule drugs approved for inflammatory bowel disease on fatigue. METHODS We performed a systematic review and meta-analysis of randomized, placebo-controlled trials reporting Federal Drug Agency (FDA)-approved biological and small molecule drugs for use in ulcerative colitis and Crohn's disease in which measures of fatigue were recorded before and after treatment. Only induction studies were included. Maintenance studies were excluded. We searched Embase (Ovid), Medline (Ovid), PsycINFO (Ovid), Cinahl (EBSCOhost), Web of Science Core Collection, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov in May 2022. Risk of bias was analyzed using the Cochrane risk-of-bias tool. Standardized mean difference was used to measure the treatment effect. RESULTS A total of seven randomized controlled trials composed of 3835 patients were included in the meta-analysis. All of the studies included patients with moderately to severely active ulcerative colitis or Crohn's disease. The studies used three different generic fatigue instruments: the Functional Assessment of Chronic Illness Therapy-Fatigue and the Short Form 36 Health Survey Vitality Subscale versions 1 and 2. Overall treatment with biological or small molecule agents showed a beneficial effect compared with placebo, with a standardized mean difference of 0.25 (95% confidence interval 0.15-0.34, p < 0.001). The effect was independent of type of drug or subtype of inflammatory bowel disease. DISCUSSION The risk of bias was considered to be low for all domains except for missing outcome data. Even though the included studies were of high methodological quality, the review is limited by the small number of studies included and that the available studies were not designed to evaluate fatigue specifically. CONCLUSION Biological and small molecule drugs used in inflammatory bowel disease have a consistent, though small, beneficial effect on fatigue.
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Affiliation(s)
| | - Inger Marie Skoie
- Department of Dermatology, Stavanger University Hospital, Stavanger, Norway
| | - Ingvild Dalen
- Department of Research, Stavanger University Hospital, Stavanger, Norway
| | - Tore Grimstad
- Department of Internal Medicine, Stavanger University Hospital, Stavanger, Norway
- Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Roald Omdal
- Department of Research, Stavanger University Hospital, Stavanger, Norway.
- Department of Clinical Science, University of Bergen, Bergen, Norway.
- Department of Rheumatology, Stavanger University Hospital, Stavanger, Norway.
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24
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Bahnam P, Hanzel J, Ma C, Zou L, Narula N, Singh S, Kahan B, Jairath V. Most Placebo-Controlled Trials in Inflammatory Bowel Disease were Underpowered Because of Overestimated Drug Efficacy Rates: Results from a Systematic Review of Induction Studies. J Crohns Colitis 2023; 17:404-417. [PMID: 36219564 DOI: 10.1093/ecco-jcc/jjac150] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Most pharmaceutical clinical trials for inflammatory bowel disease [IBD] are placebo-controlled and require effect size estimation for a drug relative to placebo. We compared expected effect sizes in sample size calculations [SSCs] to actual effect sizes in IBD clinical trials. METHODS MEDLINE, EMBASE, CENTRAL and the Cochrane library were searched from inception to March 26, 2021, to identify placebo-controlled induction studies for luminal Crohn's disease [CD] and ulcerative colitis [UC] that reported an SSC and a primary endpoint of clinical remission/response. Expected effects were subtracted from actual effects, and interquartile ranges [IQRs] for each corresponding median difference were calculated. Linear regression was used to assess whether placebo or drug event rate misspecifications were responsible for these differences. RESULTS Of eligible studies, 36.9% [55/149] were excluded because of incomplete SSC reporting, yielding 94 studies [46 CD, 48 UC]. Treatment effects were overestimated in CD for remission (-12.6% [IQR: -16.3 to -1.6%]), in UC for remission (-10.2% [IQR: -16.5 to -5.6%]) and in CD for response (-15.3% [IQR: -27.1 to -5.8%]). Differences observed were due to overestimated drug event rates, whereas expected and actual placebo event rates were similar. A meta-regression demonstrated associations between overestimated treatment effect sizes and several trial characteristics: isolated ileal disease, longer CD duration, extensive colitis [UC], single-centre, phase 2 and no endoscopic endpoint component [UC]. CONCLUSION Overestimation of IBD therapy efficacy rates resulted in smaller-than-expected treatment effects. These results should be used to inform SSCs and trial design for IBD drug development.
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Affiliation(s)
- Paul Bahnam
- Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
| | - Jurij Hanzel
- Department of Gastroenterology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
- Alimentiv Inc, London, Ontario, Canada
| | - Christopher Ma
- Alimentiv Inc, London, Ontario, Canada
- Division of Gastroenterology & Hepatology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Lily Zou
- Department of Statistics and Actuarial Sciences, University of Waterloo, Waterloo, Ontario, Canada
| | - Neeraj Narula
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Siddharth Singh
- Division of Gastroenterology, University of California San Diego, La Jolla, California, USA
| | | | - Vipul Jairath
- Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada
- Alimentiv Inc, London, Ontario, Canada
- Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada
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25
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Olivera PA, Lasa JS, Zubiaurre I, Jairath V, Abreu MT, Rubin DT, Reinisch W, Magro F, Rahier JF, Danese S, Rabaud C, Peyrin-Biroulet L. Opportunistic Infections in Patients with Inflammatory Bowel Disease Treated with Advanced Therapies: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Crohns Colitis 2023; 17:199-210. [PMID: 36087107 DOI: 10.1093/ecco-jcc/jjac133] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Advanced therapies for inflammatory bowel disease [IBD] could potentially lead to a state of immunosuppression with an increased risk of opportunistic infections [OIs]. We aimed to provide an update on the incidence of OIs among adult IBD patients in randomized controlled trials [RCTs] of approved biologics and small-molecule drugs [SMDs]. Also, we aimed to describe OI definitions utilized in RCTs, to ultimately propose a standardized definition. METHODS Electronic databases were searched from January 1, 1990, until April 16, 2022. Our primary outcome was incidence rate of overall OIs among IBD patients exposed and unexposed to biologics or SMDs. We also describe specific OIs reported in included trials, as well as definitions of OIs within studies when provided. RESULTS Ninety studies were included. The incidence rates of reported OIs were 0.42 and 0.21 per 100 person-years in patients exposed to advanced therapies and placebo, respectively. This was highest for anti-tumour necrosis factors [0.83 per 100 person-years] and Janus kinase inhibitors [0.55 per 100 person-years] and lowest for anti-integrins and ozanimod. On meta-analysis, no increased risk of OIs was observed. None of the studies provided a detailed definition of OIs, or a comprehensive list of infections considered as OIs. CONCLUSION Different mechanisms of action may have specific OI profiles. In the absence of a uniform definition of OIs, these estimates are less reliable. We propose a definition to be used in future studies to help provide standardized reporting. When using this definition, we saw significant differences in incidence rates of OIs across mechanisms of action.
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Affiliation(s)
- Pablo A Olivera
- IBD Unit, Gastroenterology Section, Department of Internal Medicine, Centro de Educación Médica e Investigación Clínica (CEMIC), Buenos Aires, Argentina
- Zane Cohen Centre for Digestive Diseases, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | - Juan S Lasa
- IBD Unit, Gastroenterology Section, Department of Internal Medicine, Centro de Educación Médica e Investigación Clínica (CEMIC), Buenos Aires, Argentina
- Gastroenterology Department, Hospital Británico de Buenos Aires, Argentina
| | - Ignacio Zubiaurre
- Gastroenterology Department, Hospital Británico de Buenos Aires, Argentina
| | - Vipul Jairath
- Division of Gastroenterology, Department of Medicine, Western University, London, ON, Canada
- Department of Epidemiology and Biostatistics, Western University, London, ON, Canada
- Alimentiv Inc., London, ON, Canada
| | - Maria T Abreu
- Department of Medicine, Division of Gastroenterology, Crohn's and Colitis Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - David T Rubin
- University of Chicago Medicine, Inflammatory Bowel Disease Center, Chicago, IL, USA
| | - Walter Reinisch
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Fernando Magro
- Department of Pharmacology & Therapeutics; CINTESIS, Faculty of Medicine University of Porto, and Department of Gastroenterology, Hospital de São João, Porto, Portugal
| | - Jean-François Rahier
- Department of Gastroenterology and Hepatology, CHU UCL Namur, Université Catholique de Louvain, Yvoir, Belgium
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS Ospedale San Raffaele and University Vita-Salute San Raffaele, Milano, Italy
| | - Christian Rabaud
- Department of Infectious Disease, Nancy University Hospital, Lorraine University, Vandoeuvre-lès-Nancy, France
| | - Laurent Peyrin-Biroulet
- INSERM NGERE and Department of Hepatogastroenterology, Nancy University Hospital, Lorraine University, Vandoeuvre-lés-Nancy, France
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26
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Clinical remission in paired phase two and three studies in inflammatory bowel disease: a systematic review with meta-analysis. Eur J Gastroenterol Hepatol 2023; 35:231-240. [PMID: 36708292 DOI: 10.1097/meg.0000000000002490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Discrepancies in phase two and three studies can result in significant patient and financial burden, as well as the nonapproval of potentially efficacious drugs. We aimed to determine whether this discrepancy exists for clinical trials in inflammatory bowel disease (IBD). Electronic databases (MEDLINE and Embase) and clinical trial repositories were searched from 1 January 1946 to 12 March 2021, for paired phase two and three studies of advanced therapies for Crohn's disease and ulcerative colitis. The primary outcome was to compare clinical remission rates between paired phase two and three studies for Crohn's disease and ulcerative colitis. Multivariable mixed-model meta-analysis was performed to calculate odds ratios (OR) with 95% confidence intervals (CI). The Cochrane risk-of-bias tool was used to grade the risk of bias. Of 2642 studies, 29 were included. Fifteen were phase three, 11 were phase two, one was phase one/two, and two were phase two/three. There were no differences in clinical remission rates between phase two and three studies for Crohn's disease (OR, 1.07; 95% CI, 0.86-1.34; P = 0.54) and ulcerative colitis (OR, 0.81; 95% CI, 0.48-1.36; P = 0.43). Furthermore, there was a lack of any appreciable differences in study characteristics, inclusion criteria and patient demographics among paired phase two and three studies. Most studies were considered low risk of bias. Overall, paired phase two and three studies demonstrate similar clinical remission rates for advanced therapies in IBD. Whether this applies to newer outcomes, such as endoscopic and mucosal healing remains to be determined.
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27
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Zundler S, Schulze LL, Neurath MF. Controlling in and out - the future of interfering with immune cell trafficking in inflammatory bowel disease. Expert Rev Clin Immunol 2023; 19:155-167. [PMID: 36427088 DOI: 10.1080/1744666x.2023.2152794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
INTRODUCTION Immune cell trafficking is a key requirement in the pathogenesis of inflammatory bowel diseases. Consistently, therapeutic strategies to target immune cell trafficking have been established and continue to be developed for the treatment of ulcerative colitis and Crohn's disease. AREAS COVERED In this review, we briefly summarize the most important checkpoints of intestinal immune cell trafficking and their importance during IBD. Moreover, we provide an overview of associated therapeutic targets and previous as well as current efforts on treatment strategies related to these targets. EXPERT OPINION Finally, we comment on potential future developments that might shape the field of immune cell trafficking in the context of IBD.
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Affiliation(s)
- Sebastian Zundler
- Department of Medicine 1 and Deutsches Zentrum Immuntherapie, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Lisa Lou Schulze
- Department of Medicine 1 and Deutsches Zentrum Immuntherapie, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1 and Deutsches Zentrum Immuntherapie, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
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Feng Z, Kang G, Wang J, Gao X, Wang X, Ye Y, Liu L, Zhao J, Liu X, Huang H, Cao X. Breaking through the therapeutic ceiling of inflammatory bowel disease: Dual-targeted therapies. Biomed Pharmacother 2023; 158:114174. [PMID: 36587559 DOI: 10.1016/j.biopha.2022.114174] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2022] [Revised: 12/27/2022] [Accepted: 12/28/2022] [Indexed: 01/01/2023] Open
Abstract
Emerging biologics and small-molecule drugs have changed the clinical status quo of inflammatory bowel disease (IBD). However, current treatments remain at a standstill in terms of response and remission in many cases. Accumulating evidence indicates that dual-targeted therapy (DTT) could be promising in overcoming the existing ceiling of IBD treatment. However, data on the efficacy and safety of DTT on Crohn's disease and ulcerative colitis are still limited or insufficient. Moreover, there is a lack of studies delineating the mechanisms of DTT. Given that various targeted drugs have different targets among the extensive redundant inflammatory networks, DTT could result in various outcomes. In this review, we have summarized the current data on the safety, effectiveness, and clinical development status of novel targeted drugs related to refractory IBD, and have explored the mechanism of action of therapy. We have categorized therapeutic agents into "Therapeutic Agents Targeting Cellular Signaling Pathways" and "Therapeutic Agents Targeting Leukocyte Trafficking" based on the different therapeutic targets, and also by classifying therapeutic agents targeting the cellular signaling pathways into "JAK-dependent" and "JAK-independent," and placed the existing drug combinations into 3 categories based on their mechanisms, namely, overlapping, synergistic, and complementary effects. Lastly, we have proposed the possible mechanisms of DTT to conceive a theoretical framework for clinical decision-making and further drug development and research from an IBD standpoint.
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Affiliation(s)
- Zelin Feng
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Guangbo Kang
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China; Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China; Institute of Shaoxing, Tianjin University, Zhejiang 312300, China
| | - Jiewen Wang
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China; Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China; Institute of Shaoxing, Tianjin University, Zhejiang 312300, China
| | - Xingjie Gao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Science, Tianjin Medical University, Tianjin 300070, China
| | - Xiaoli Wang
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Yulin Ye
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Limin Liu
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Jingwen Zhao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China
| | - Xinjuan Liu
- Department of Gastroenterology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100016, China
| | - He Huang
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China; Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China.
| | - Xiaocang Cao
- Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital, Tianjin Institute of Digestive Disease, Tianjin Key Laboratory of Digestive Diseases, Tianjin 300052, China.
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Bai Z, Wang J, Li J, Yuan H, Wang P, Zhang M, Feng Y, Cao X, Cao X, Kang G, de Marco A, Huang H. Design of nanobody-based bispecific constructs by in silico affinity maturation and umbrella sampling simulations. Comput Struct Biotechnol J 2022; 21:601-613. [PMID: 36659922 PMCID: PMC9822835 DOI: 10.1016/j.csbj.2022.12.021] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 12/14/2022] [Accepted: 12/14/2022] [Indexed: 12/23/2022] Open
Abstract
Random mutagenesis is the natural opportunity for proteins to evolve and biotechnologically it has been exploited to create diversity and identify variants with improved characteristics in the mutant pools. Rational mutagenesis based on biophysical assumptions and supported by computational power has been proposed as a faster and more predictable strategy to reach the same aim. In this work we confirm that substantial improvements in terms of both affinity and stability of nanobodies can be obtained by using combinations of algorithms, even for binders with already high affinity and elevated thermal stability. Furthermore, in silico approaches allowed the development of an optimized bispecific construct able to bind simultaneously the two clinically relevant antigens TNF-α and IL-23 and, by means of its enhanced avidity, to inhibit effectively the apoptosis of TNF-α-sensitive L929 cells. The results revealed that salt bridges, hydrogen bonds, aromatic-aromatic and cation-pi interactions had a critical role in increasing affinity. We provided a platform for the construction of high-affinity bispecific constructs based on nanobodies that can have relevant applications for the control of all those biological mechanisms in which more than a single antigen must be targeted to increase the treatment effectiveness and avoid resistance mechanisms.
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Affiliation(s)
- Zixuan Bai
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China
- Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China
| | - Jiewen Wang
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China
- Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China
- Institute of Shaoxing, Tianjin University, Zhejiang 312300, China
| | - Jiaqi Li
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China
- Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China
- Institute of Shaoxing, Tianjin University, Zhejiang 312300, China
| | - Haibin Yuan
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China
- Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China
| | - Ping Wang
- Tianjin Modern Innovative TCM Technology Co. Ltd., Tianjin, China
| | - Miao Zhang
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China
- Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China
- China Resources Biopharmaceutical Company Limited, Beijing, China
| | - Yuanhang Feng
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China
- Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China
| | - Xiangtong Cao
- Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China
| | - Xiangan Cao
- Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China
| | - Guangbo Kang
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China
- Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China
- Institute of Shaoxing, Tianjin University, Zhejiang 312300, China
| | - Ario de Marco
- Laboratory for Environmental and Life Sciences, University of Nova Gorica, Nova Gorica, Slovenia
| | - He Huang
- Department of Biochemical Engineering, School of Chemical Engineering and Technology, Tianjin University, Tianjin 300350, China
- Frontiers Science Center for Synthetic Biology and Key Laboratory of Systems Bioengineering (Ministry of Education), Tianjin University, Tianjin 300072, China
- Institute of Shaoxing, Tianjin University, Zhejiang 312300, China
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30
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Nociti V, Romozzi M. Multiple Sclerosis and Autoimmune Comorbidities. J Pers Med 2022; 12:jpm12111828. [PMID: 36579555 PMCID: PMC9698878 DOI: 10.3390/jpm12111828] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Revised: 10/17/2022] [Accepted: 10/29/2022] [Indexed: 11/06/2022] Open
Abstract
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease of the central nervous system characterized by broad inter- and intraindividual heterogeneity and different prognoses. Multisystem comorbidities are frequent features in people with MS (PwMS) and can affect treatment choices, quality of life, disability and mortality. In this scenario, autoimmune comorbidities play a cardinal role for several reasons, such as the implication on MS pathogenesis, diagnostic delay, disease activity, disability progression, brain atrophy, and treatment choice. However, the impact of an autoimmune comorbid condition on MS is not fully elucidated. This review aims to summarize the currently available data on the incidence and prevalence of autoimmune diseases in PwMS, the possible effect of this association on clinical and neuroradiological MS course and its impact on treatment choice.
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Affiliation(s)
- Viviana Nociti
- Centro Sclerosi Multipla, Fondazione Policlinico Universitario ‘Agostino Gemelli’ IRCCS, 00168 Rome, Italy
- Università Cattolica del Sacro Cuore, 00168 Rome, Italy
- Correspondence:
| | - Marina Romozzi
- Centro Sclerosi Multipla, Fondazione Policlinico Universitario ‘Agostino Gemelli’ IRCCS, 00168 Rome, Italy
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Lin SN, Musso A, Wang J, Mukherjee PK, West GA, Mao R, Lyu R, Li J, Zhao S, Elias M, Haberman Y, Denson LA, Kugathasan S, Chen MH, Czarnecki D, Dejanovic D, Le HT, Chandra J, Lipman J, Steele SR, Nguyen QT, Fiocchi C, Rieder F. Human intestinal myofibroblasts deposited collagen VI enhances adhesiveness for T cells - A novel mechanism for maintenance of intestinal inflammation. Matrix Biol 2022; 113:1-21. [PMID: 36108990 PMCID: PMC10043923 DOI: 10.1016/j.matbio.2022.09.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 09/04/2022] [Accepted: 09/09/2022] [Indexed: 11/29/2022]
Abstract
OBJECTIVE Inflammatory bowel diseases (IBD) cause chronic intestinal damage and extracellular matrix (ECM) remodeling. The ECM may play an active role in inflammation by modulating immune cell functions, including cell adhesion, but this hypothesis has not been tested in IBD. DESIGN Primary human intestinal myofibroblast (HIMF)-derived ECM from IBD and controls, 3D decellularized colon or ECM molecule-coated scaffolds were tested for their adhesiveness for T cells. Matrisome was analysed via proteomics. Functional integrin blockade was used to investigate the underlying mechanism. Analysis of the pediatric Crohn's disease (CD) RISK inception cohort was used to explore an altered ECM gene expression as a potential predictor for a future complicated disease course. RESULTS HIMF-derived ECM and 3D decellularized colonic ECM from IBD bound more T cells compared to control. Control HIMFs exposed to the pro-inflammatory cytokines Iinterleukin-1β (IL-1β) and tumor necrosis factor (TNF) increased, and to transforming growth factor-β1 (TGF-β1) decreased ECM adhesiveness to T cells. Matrisome analysis of the HIMF-derived ECM revealed collagen VI as a major culprit for differences in T cell adhesion. Collagen VI knockdown in HIMF reduced adhesion T cell as did the blockage of integrin αvβ1. Elevated gene expression of collagen VI in biopsies of pediatric CD patients was linked to risk for future stricturing disease. CONCLUSION HIMF-derived ECM in IBD binds a remarkably enhanced number of T cells, which is dependent on Collagen VI and integrin αvβ1. Collagen VI expression is a risk factor for a future complicated CD course. Blocking immune cells retention may represent a novel approach to treatment in IBD.
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Affiliation(s)
- Si-Nan Lin
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Alessandro Musso
- Division of Gastroenterology, Città della Salute e della Scienza di Torino, Molinette Hospital, Turin, Italy
| | - Jie Wang
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Henan Key Laboratory of Immunology and Targeted Drug, Xinxiang Medical University, Xinxiang, Henan, China
| | - Pranab K Mukherjee
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Gail A West
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Ren Mao
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China; Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Ruishen Lyu
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH, USA
| | - Jiannan Li
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Shuai Zhao
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Michael Elias
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Yael Haberman
- Sheba Medical Center, Tel Hashomer, Affiliated with the Tel Aviv University, Tel Aviv, Israel; Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Lee A Denson
- Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | | | - Min-Hu Chen
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Doug Czarnecki
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Dina Dejanovic
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Hongnga T Le
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Jyotsna Chandra
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Jeremy Lipman
- Department of Surgery, MetroHealth Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Scott R Steele
- Department of Colorectal Surgery, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Quang Tam Nguyen
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Claudio Fiocchi
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, 9500 Euclid Avenue - NC22, Cleveland, OH, USA
| | - Florian Rieder
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, 9500 Euclid Avenue - NC22, Cleveland, OH, USA.
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Xiong Y, Cai M, Xu Y, Dong P, Chen H, He W, Zhang J. Joint together: The etiology and pathogenesis of ankylosing spondylitis. Front Immunol 2022; 13:996103. [PMID: 36325352 PMCID: PMC9619093 DOI: 10.3389/fimmu.2022.996103] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 09/28/2022] [Indexed: 08/16/2023] Open
Abstract
Spondyloarthritis (SpA) refers to a group of diseases with inflammation in joints and spines. In this family, ankylosing spondylitis (AS) is a rare but classic form that mainly involves the spine and sacroiliac joint, leading to the loss of flexibility and fusion of the spine. Compared to other diseases in SpA, AS has a very distinct hereditary disposition and pattern of involvement, and several hypotheses about its etiopathogenesis have been proposed. In spite of significant advances made in Th17 dynamics and AS treatment, the underlying mechanism remains concealed. To this end, we covered several topics, including the nature of the immune response, the microenvironment in the articulation that is behind the disease's progression, and the split between the hypotheses and the evidence on how the intestine affects arthritis. In this review, we describe the current findings of AS and SpA, with the aim of providing an integrated view of the initiation of inflammation and the development of the disease.
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Affiliation(s)
- Yuehan Xiong
- Department of Immunology, Chinese Academy of Medical Sciences (CAMS) Key Laboratory of T Cell and Cancer Immunotherapy, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Menghua Cai
- Department of Immunology, Chinese Academy of Medical Sciences (CAMS) Key Laboratory of T Cell and Cancer Immunotherapy, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Yi Xu
- Department of Immunology, Chinese Academy of Medical Sciences (CAMS) Key Laboratory of T Cell and Cancer Immunotherapy, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and School of Basic Medicine, Peking Union Medical College, Beijing, China
| | - Peng Dong
- Changzhou Xitaihu Institute for Frontier Technology of Cell Therapy, Changzhou, China
| | - Hui Chen
- Department of Immunology, Chinese Academy of Medical Sciences (CAMS) Key Laboratory of T Cell and Cancer Immunotherapy, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and School of Basic Medicine, Peking Union Medical College, Beijing, China
- Changzhou Xitaihu Institute for Frontier Technology of Cell Therapy, Changzhou, China
| | - Wei He
- Department of Immunology, Chinese Academy of Medical Sciences (CAMS) Key Laboratory of T Cell and Cancer Immunotherapy, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and School of Basic Medicine, Peking Union Medical College, Beijing, China
- Changzhou Xitaihu Institute for Frontier Technology of Cell Therapy, Changzhou, China
| | - Jianmin Zhang
- Department of Immunology, Chinese Academy of Medical Sciences (CAMS) Key Laboratory of T Cell and Cancer Immunotherapy, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) and School of Basic Medicine, Peking Union Medical College, Beijing, China
- Changzhou Xitaihu Institute for Frontier Technology of Cell Therapy, Changzhou, China
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Na SY, Kim YS. Management of inflammatory bowel disease beyond tumor necrosis factor inhibitors: novel biologics and small-molecule drugs. Korean J Intern Med 2022; 37:906-919. [PMID: 35945034 PMCID: PMC9449214 DOI: 10.3904/kjim.2022.152] [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] [Received: 04/20/2022] [Accepted: 06/15/2022] [Indexed: 11/27/2022] Open
Abstract
The incidence and prevalence of inflammatory bowel disease (IBD), comprising Crohn's disease and ulcerative colitis, have increased in Asia and developing countries. In the past two decades, anti-tumor necrosis factor (TNF) agents have revolutionized the treatment of IBD, in part by decreasing the rates of complications and surgery. Although anti-TNF agents have changed the course of IBD, there are unmet needs in terms of primary and secondary non-responses and side effects such as infections and malignancies. Novel biologics and small-molecule drugs have been developed for IBD, and the medical treatment options have improved. These drugs include sphingosine-1-phosphate receptor modulators and anti-integrins to block immune cell migration, and cytokine and Janus kinase inhibitors to block immune cell communications. In this review, we discuss the approved novel biologics and small-molecule drugs, including several of those in the late stages of development, for the treatment of IBD.
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Affiliation(s)
- Soo-Young Na
- Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon,
Korea
| | - You Sun Kim
- Department of Internal Medicine, Seoul Paik Hospital, Inje University College of Medicine, Seoul,
Korea
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Rathjen T, Kunkemoeller B, Cederquist CT, Wang X, Lockhart SM, Patti JC, Willenbrock H, Olsen GS, Povlsen GK, Beck HC, Rasmussen LM, Li Q, Park K, King GL, Rask-Madsen C. Endothelial Cell Insulin Signaling Regulates CXCR4 (C-X-C Motif Chemokine Receptor 4) and Limits Leukocyte Adhesion to Endothelium. Arterioscler Thromb Vasc Biol 2022; 42:e217-e227. [PMID: 35652755 PMCID: PMC9371472 DOI: 10.1161/atvbaha.122.317476] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND An activated, proinflammatory endothelium is a key feature in the development of complications of obesity and type 2 diabetes and can be caused by insulin resistance in endothelial cells. METHODS We analyzed primary human endothelial cells by RNA sequencing to discover novel insulin-regulated genes and used endothelial cell culture and animal models to characterize signaling through CXCR4 (C-X-C motif chemokine receptor 4) in endothelial cells. RESULTS CXCR4 was one of the genes most potently regulated by insulin, and this was mediated by PI3K (phosphatidylinositol 3-kinase), likely through FoxO1, which bound to the CXCR4 promoter. CXCR4 mRNA in CD31+ cells was 77% higher in mice with diet-induced obesity compared with lean controls and 37% higher in db/db mice than db/+ controls, consistent with upregulation of CXCR4 in endothelial cell insulin resistance. SDF-1 (stromal cell-derived factor-1)-the ligand for CXCR4-increased leukocyte adhesion to cultured endothelial cells. This effect was lost after deletion of CXCR4 by gene editing while 80% of the increase was prevented by treatment of endothelial cells with insulin. In vivo microscopy of mesenteric venules showed an increase in leukocyte rolling after intravenous injection of SDF-1, but most of this response was prevented in transgenic mice with endothelial overexpression of IRS-1 (insulin receptor substrate-1). CONCLUSIONS Endothelial cell insulin signaling limits leukocyte/endothelial cell interaction induced by SDF-1 through downregulation of CXCR4. Improving insulin signaling in endothelial cells or inhibiting endothelial CXCR4 may reduce immune cell recruitment to the vascular wall or tissue parenchyma in insulin resistance and thereby help prevent several vascular complications.
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Affiliation(s)
- Thomas Rathjen
- Joslin Diabetes Center and Harvard Medical School, Boston, MA (T.R., B.K., C.T.C., X.W., S.M.L., J.C.P., Q.L., K.P., G.L.K., C.R.-M.).,Novo Nordisk A/S, Måløv, Denmark (T.R., H.W., G.S.O., G.K.P.)
| | - Britta Kunkemoeller
- Joslin Diabetes Center and Harvard Medical School, Boston, MA (T.R., B.K., C.T.C., X.W., S.M.L., J.C.P., Q.L., K.P., G.L.K., C.R.-M.)
| | - Carly T Cederquist
- Joslin Diabetes Center and Harvard Medical School, Boston, MA (T.R., B.K., C.T.C., X.W., S.M.L., J.C.P., Q.L., K.P., G.L.K., C.R.-M.)
| | - Xuanchun Wang
- Joslin Diabetes Center and Harvard Medical School, Boston, MA (T.R., B.K., C.T.C., X.W., S.M.L., J.C.P., Q.L., K.P., G.L.K., C.R.-M.)
| | - Sam M Lockhart
- Joslin Diabetes Center and Harvard Medical School, Boston, MA (T.R., B.K., C.T.C., X.W., S.M.L., J.C.P., Q.L., K.P., G.L.K., C.R.-M.)
| | - James C Patti
- Joslin Diabetes Center and Harvard Medical School, Boston, MA (T.R., B.K., C.T.C., X.W., S.M.L., J.C.P., Q.L., K.P., G.L.K., C.R.-M.)
| | | | | | | | | | | | - Qian Li
- Joslin Diabetes Center and Harvard Medical School, Boston, MA (T.R., B.K., C.T.C., X.W., S.M.L., J.C.P., Q.L., K.P., G.L.K., C.R.-M.)
| | - Kyoungmin Park
- Joslin Diabetes Center and Harvard Medical School, Boston, MA (T.R., B.K., C.T.C., X.W., S.M.L., J.C.P., Q.L., K.P., G.L.K., C.R.-M.)
| | - George L King
- Joslin Diabetes Center and Harvard Medical School, Boston, MA (T.R., B.K., C.T.C., X.W., S.M.L., J.C.P., Q.L., K.P., G.L.K., C.R.-M.)
| | - Christian Rask-Madsen
- Joslin Diabetes Center and Harvard Medical School, Boston, MA (T.R., B.K., C.T.C., X.W., S.M.L., J.C.P., Q.L., K.P., G.L.K., C.R.-M.)
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Besendorf L, Müller TM, Geppert CI, Schneider I, Mühl L, Atreya I, Vitali F, Atreya R, Neurath MF, Zundler S. Vedolizumab blocks α4β7 integrin-mediated T cell adhesion to MAdCAM-1 in microscopic colitis. Therap Adv Gastroenterol 2022; 15:17562848221098899. [PMID: 35784193 PMCID: PMC9244938 DOI: 10.1177/17562848221098899] [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: 02/07/2022] [Accepted: 04/19/2022] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND In Crohn's disease and ulcerative colitis, the anti-α4β7 integrin antibody vedolizumab has demonstrated efficacy in phase III trials and has been successfully used under real-world conditions. Occasionally, it has also been used in other forms of inflammatory bowel disease (IBD) such as microscopic colitis (MC). However, the mechanisms of vedolizumab in MC have not been studied to date. Therefore, we aimed to investigate the expression and functional role of gut-homing integrins and in particular α4β7 integrin in a cohort study in MC. METHODS We studied the expression of gut homing integrins on T cells from patients with MC and healthy controls by flow cytometry. To investigate the function of α4β7 integrin in MC and the potential of vedolizumab to block it, we used dynamic adhesion assays and transmigrations assays. Moreover, we describe two clinical cases of MC patients treated with vedolizumab. RESULTS A specific profile of gut homing markers can be found on T cells from patients with MC. α4β7 integrin functionally leads to firm adhesion to MAdCAM-1 and supports transmigration. Vedolizumab is able to block both processes. In two cases of MC, we observed reduced clinical symptoms and histologic improvement upon therapy with vedolizumab. CONCLUSION Our data suggest that α4β7 mediates gut homing of T cells also in MC and that, on single cell level, vedolizumab blocks the function of α4β7 in MC. Thus, we provide mechanistic evidence supporting vedolizumab as promising therapeutic option for MC.
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Affiliation(s)
- Laura Besendorf
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Tanja M. Müller
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany,Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Erlangen, Germany
| | - Carol-Immanuel Geppert
- Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Ines Schneider
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Laura Mühl
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Imke Atreya
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany,Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Erlangen, Germany
| | - Francesco Vitali
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany,Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Erlangen, Germany
| | - Raja Atreya
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany,Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Erlangen, Germany
| | - Markus F. Neurath
- Department of Medicine 1, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany,Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Erlangen, Germany
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Health-Related Quality of Life of Patients Treated with Biological Agents and New Small-Molecule Drugs for Moderate to Severe Crohn's Disease: A Systematic Review. J Clin Med 2022; 11:jcm11133743. [PMID: 35807044 PMCID: PMC9267515 DOI: 10.3390/jcm11133743] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 06/10/2022] [Accepted: 06/14/2022] [Indexed: 12/12/2022] Open
Abstract
Crohn’s disease (CD) leads to a poor health-related quality of life (HRQoL). This review aimed to investigate the effect of biological agents and small-molecule drugs in improving the HRQoL of patients with moderate to severe CD. We adopted a systematic protocol to search PubMed and Cochrane Central Register of Controlled Trials (CENTRAL), which was supplemented with manual searches. Eligible studies were RCTs that matched the research objective based on population, intervention, comparison and outcomes. Studies in paediatric populations, reviews and conference abstracts were excluded. Covidence was used for screening and data extraction. We assessed all research findings using RoB2 and reported them narratively. We included 16 multicentre, multinational RCTs in this review. Of the 15 studies that compared the effect of an intervention to a placebo, 9 were induction studies and 6 investigated maintenance therapy. Of these, 13 studies showed a significant (p < 0.05) improvement in the HRQoL of patients with CD. One non-inferiority study compared the intervention with another active drug and favoured the intervention. This systematic review reported a substantial improvement in the HRQoL of patients with CD using biological agents and small-molecule drugs. These pharmaceutical substances have the potential to improve the HRQoL of patients with CD. However, further large clinical trials with long-term follow-up are essential to validate these findings.
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Elhag DA, Kumar M, Saadaoui M, Akobeng AK, Al-Mudahka F, Elawad M, Al Khodor S. Inflammatory Bowel Disease Treatments and Predictive Biomarkers of Therapeutic Response. Int J Mol Sci 2022; 23:ijms23136966. [PMID: 35805965 PMCID: PMC9266456 DOI: 10.3390/ijms23136966] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 06/05/2022] [Accepted: 06/06/2022] [Indexed: 02/08/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic immune-mediated inflammation of the gastrointestinal tract with a highly heterogeneous presentation. It has a relapsing and remitting clinical course that necessitates lifelong monitoring and treatment. Although the availability of a variety of effective therapeutic options including immunomodulators and biologics (such as TNF, CAM inhibitors) has led to a paradigm shift in the treatment outcomes and clinical management of IBD patients, some patients still either fail to respond or lose their responsiveness to therapy over time. Therefore, according to the recent Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE-II) recommendations, continuous disease monitoring from symptomatic relief to endoscopic healing along with short- and long-term therapeutic responses are critical for providing IBD patients with a tailored therapy algorithm. Moreover, considering the high unmet need for novel therapeutic approaches for IBD patients, various new modulators of cytokine signaling events (for example, JAK/TYK inhibitors), inhibitors of cytokines (for example IL-12/IL-23, IL-22, IL-36, and IL-6 inhibitors), anti-adhesion and migration strategies (for example, β7 integrin, sphingosine 1-phosphate receptors, and stem cells), as well as microbial-based therapeutics to decolonize the bed buds (for example, fecal microbiota transplantation and bacterial inhibitors) are currently being evaluated in different phases of controlled clinical trials. This review aims to offer a comprehensive overview of available treatment options and emerging therapeutic approaches for IBD patients. Furthermore, predictive biomarkers for monitoring the therapeutic response to different IBD therapies are also discussed.
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Affiliation(s)
- Duaa Ahmed Elhag
- Research Department, Sidra Medicine, Doha 26999, Qatar; (D.A.E.); (M.K.); (M.S.)
| | - Manoj Kumar
- Research Department, Sidra Medicine, Doha 26999, Qatar; (D.A.E.); (M.K.); (M.S.)
| | - Marwa Saadaoui
- Research Department, Sidra Medicine, Doha 26999, Qatar; (D.A.E.); (M.K.); (M.S.)
| | - Anthony K. Akobeng
- Division of Gastroenterology, Hepatology and Nutrition, Sidra Medicine, Doha 26999, Qatar; (A.K.A.); (F.A.-M.); (M.E.)
| | - Fatma Al-Mudahka
- Division of Gastroenterology, Hepatology and Nutrition, Sidra Medicine, Doha 26999, Qatar; (A.K.A.); (F.A.-M.); (M.E.)
| | - Mamoun Elawad
- Division of Gastroenterology, Hepatology and Nutrition, Sidra Medicine, Doha 26999, Qatar; (A.K.A.); (F.A.-M.); (M.E.)
| | - Souhaila Al Khodor
- Research Department, Sidra Medicine, Doha 26999, Qatar; (D.A.E.); (M.K.); (M.S.)
- Correspondence:
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Abstract
Crohn's disease is a chronic and progressive immune-mediated disease with increasing incidence worldwide. There are no curative therapies. The primary agents used in the treatment of Crohn's disease are aminosalicylates, corticosteroids, immunomodulators, and biologics. Each agent has different roles in the induction and maintenance of remission of disease. The biologics available include anti-TNF agents, anti-integrins, and anti-interleukins. The choice of initial biologic therapy should be determined through shared decision-making between the patient and provider.
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Affiliation(s)
- Stacey Rolak
- Department of Internal Medicine, Mayo Clinic College of Medicine and Science, 200 First Street, Southwest, Rochester, MN 55905, USA.
| | - Sunanda V Kane
- Division of Gastroenterology and Hepatology, Mayo Clinic Rochester, 200 First Street, Southwest, Rochester, MN 55905, USA
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Saleh A, Ansari U, Abughazaleh S, Glassner K, Abraham BP. Biological Therapies for the Management of Enteric Disease: Considerations for the Clinician. Biologics 2022; 16:67-83. [PMID: 35747234 PMCID: PMC9211072 DOI: 10.2147/btt.s335697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Accepted: 05/25/2022] [Indexed: 11/23/2022]
Affiliation(s)
- Adam Saleh
- Engineering Medicine, Texas A&M University, Houston, TX, USA
- Department of Medicine – Division of Gastroenterology, Houston Methodist, Houston, TX, USA
| | - Usman Ansari
- Department of Medicine – Division of Gastroenterology, Houston Methodist, Houston, TX, USA
| | - Shaadi Abughazaleh
- Department of Medicine – Division of Gastroenterology, Houston Methodist, Houston, TX, USA
| | - Kerri Glassner
- Department of Medicine – Division of Gastroenterology, Houston Methodist, Houston, TX, USA
| | - Bincy P Abraham
- Department of Medicine – Division of Gastroenterology, Houston Methodist, Houston, TX, USA
- Correspondence: Bincy P Abraham, Department of Medicine – Division of Gastroenterology, Houston Methodist, 6550 Fannin St. Suite 1201, Houston, TX, 77030, USA, Tel +1-713-441-5042, Fax +1-713-797-0622, Email
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40
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Sedano R, Jairath V, Ma C. Design of Clinical Trials for Mild to Moderate Ulcerative Colitis. Gastroenterology 2022; 162:1005-1018. [PMID: 34998800 DOI: 10.1053/j.gastro.2021.12.284] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 12/19/2021] [Accepted: 12/30/2021] [Indexed: 12/22/2022]
Affiliation(s)
- Rocio Sedano
- Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada; Alimentiv Inc, London, Ontario, Canada
| | - Vipul Jairath
- Division of Gastroenterology, Department of Medicine, Western University, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada; Alimentiv Inc, London, Ontario, Canada
| | - Christopher Ma
- Division of Gastroenterology and Hepatology, Departments of Medicine and Community Health Sciences, University of Calgary, Calgary, Alberta, Canada; Alimentiv Inc, London, Ontario, Canada
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Grossberg LB, Papamichael K, Cheifetz AS. Review article: emerging drug therapies in inflammatory bowel disease. Aliment Pharmacol Ther 2022; 55:789-804. [PMID: 35166398 DOI: 10.1111/apt.16785] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 09/11/2021] [Accepted: 01/12/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND The landscape of inflammatory bowel disease (IBD) treatment is rapidly expanding with the development of new therapeutic options. AIM To review the mechanisms of action and the available clinical trial data on emerging drug therapies for IBD. METHODS Pubmed, Medline and Cochrane databases were queried up to July 2021 using keywords "inflammatory bowel disease," "IBD," "Crohn's disease," "ulcerative colitis" and "trial," "phase" and "study." In addition, we manually reviewed the grey literature including clinical trial registries and abstracts from major gastroenterology conferences in 2020 and 2021 to include pertinent information. RESULTS In ulcerative colitis (UC), phase 2b and/or phase 3 studies met primary endpoints for S1P receptor agonists (estrasimod, ozanimod), anti-IL-23 agent (mirikizumab), anti-lymphocyte trafficking agents (ontamalimab, subcutaneous vedolizumab), JAK inhibitors (upadacitinib, filgotinib) and TLR9 agonist (cobitolimod). In Crohn's disease (CD), anti-IL-23 agents (risankizumab, mirikizumab, guselkumab), JAK inhibitors (upadacitinib, filgotinib) and anti-lymphocyte trafficking agents (ontamalimab, etrolizumab) met primary endpoints in randomised controlled clinical trials. CONCLUSION Several new IBD drug therapies have positive efficacy and safety data in early clinical trials, and there are several drugs in the therapeutic pipeline. As more treatments for CD and UC are approved for clinical use, research to assess predictors of response to therapy and head-to-head trials is needed to inform providers on how to best position therapeutic options for patients with IBD.
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Affiliation(s)
- Laurie B Grossberg
- Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Konstantinos Papamichael
- Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Adam S Cheifetz
- Center for Inflammatory Bowel Diseases, Division of Gastroenterology, Beth-Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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42
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Yu B, Zhao L, Jin S, He H, Zhang J, Wang X. Model-Based Meta-Analysis on the Efficacy of Biologics and Small Targeted Molecules for Crohn’s Disease. Front Immunol 2022; 13:828219. [PMID: 35371027 PMCID: PMC8967940 DOI: 10.3389/fimmu.2022.828219] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 02/14/2022] [Indexed: 11/24/2022] Open
Abstract
Information on comparative drug efficacy is of great importance for drug development as well as clinical practice. Up to now, the relative efficacy of biologics and small targeted molecules for Crohn’s disease (CD) remains unclear. The objective of this study was to quantify the relative efficacy of investigational and approved biological treatments for CD measured in Crohn’s Disease Activity Index (CDAI), Inflammatory Bowel Disease Questionnaire (IBDQ), and C-reactive protein (CRP). The analysis dataset was composed of summary-level data from 46 trials, containing 12,846 patients, with treatment of 24 drugs. Six mathematical models with non-parametric placebo estimations were developed to describe the time course and dose–response of six efficacy measures. The effects of covariate were further evaluated. Time–response relationships were found in outcomes measured in CDAI. The patients’ age, disease duration, baseline CDAI, and CRP showed an impact on the efficacy. Model simulations were performed to compare the efficacies across different drugs. The most achievement in clinical remission (defined as CDAI less than 150) and clinical response (defined as the reduction in CDAI for 100 or 70) was observed in the simulation for PF-04236921 and infliximab, respectively. The most improvement in IBDQ was shown in tofacitinib. In general, tumor necrosis factor (TNF)-α inhibitors were the most effective biologics, and the highest efficacy of small targeted molecules was observed in janus kinase (JAK) inhibitors. These findings have important implications for clinical practice in CD.
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Affiliation(s)
- Boran Yu
- Clinical Research Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
- School of Pharmacy, Capital Medical University, Beijing, China
| | - Libo Zhao
- Clinical Research Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Siyao Jin
- Clinical Research Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
- School of Pharmacy, Capital Medical University, Beijing, China
| | - Huan He
- Clinical Research Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
| | - Jing Zhang
- Department of Gastroenterology, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
- *Correspondence: Jing Zhang, ; Xiaoling Wang,
| | - Xiaoling Wang
- Clinical Research Center, Beijing Children’s Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China
- *Correspondence: Jing Zhang, ; Xiaoling Wang,
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Dunleavy KA, Pardi DS. Biologics: how far can they go in Crohn’s disease? Gastroenterol Rep (Oxf) 2022; 10:goac049. [PMID: 36196255 PMCID: PMC9522383 DOI: 10.1093/gastro/goac049] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 09/01/2022] [Indexed: 11/14/2022] Open
Abstract
Abstract
Crohn’s disease is a chronic gastrointestinal inflammatory disorder, characterized by episodes of relapsing and remitting flares. As the disease mechanism becomes better elucidated, there is a significant increase in the number of available biologic therapies. This article summarizes and synthesizes current Food and Drug Administration-approved biological therapy for Crohn’s disease and examines the positioning of medical therapy as emerging biologics break onto the market.
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Affiliation(s)
- Katie A Dunleavy
- Division of Gastroenterology and Hepatology, Mayo Clinic , Rochester, MN, USA
| | - Darrell S Pardi
- Division of Gastroenterology and Hepatology, Mayo Clinic , Rochester, MN, USA
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Mazza S, Soro S, Verga MC, Elvo B, Ferretti F, Cereatti F, Drago A, Grassia R. Liver-side of inflammatory bowel diseases: Hepatobiliary and drug-induced disorders. World J Hepatol 2021; 13:1828-1849. [PMID: 35069993 PMCID: PMC8727201 DOI: 10.4254/wjh.v13.i12.1828] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 07/16/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatobiliary disorders are among the most common extraintestinal manifestations in inflammatory bowel diseases (IBD), both in Crohn’s disease and ulcerative colitis (UC), and therefore represent a diagnostic challenge. Immune-mediated conditions include primary sclerosing cholangitis (PSC) as the main form, variant forms of PSC (namely small-duct PSC, PSC-autoimmune hepatitis overlap syndrome and IgG4-related sclerosing cholangitis) and granulomatous hepatitis. PSC is by far the most common, presenting in up to 8% of IBD patients, more frequently in UC. Several genetic foci have been identified, but environmental factors are preponderant on disease pathogenesis. The course of the two diseases is typically independent. PSC diagnosis is based mostly on typical radiological findings and exclusion of secondary cholangiopathies. Risk of cholangiocarcinoma is significantly increased in PSC, as well as the risk of colorectal cancer in patients with PSC and IBD-related colitis. No disease-modifying drugs are approved to date. Thus, PSC management is directed against symptoms and complications and includes medical therapies for pruritus, endoscopic treatment of biliary stenosis and liver transplant for end-stage liver disease. Other non-immune-mediated hepatobiliary disorders are gallstone disease, whose incidence is higher in IBD and reported in up to one third of IBD patients, non-alcoholic fatty liver disease, pyogenic liver abscess and portal vein thrombosis. Drug-induced liver injury (DILI) is an important issue in IBD, since most IBD therapies may cause liver toxicity; however, the incidence of serious adverse events is low. Thiopurines and methotrexate are the most associated with DILI, while the risk related to anti-tumor necrosis factor-α and anti-integrins is low. Data on hepatotoxicity of newer drugs approved for IBD, like anti-interleukin 12/23 and tofacitinib, are still scarce, but the evidence from other rheumatic diseases is reassuring. Hepatitis B reactivation during immunosuppressive therapy is a major concern in IBD, and adequate screening and vaccination is warranted. On the other hand, hepatitis C reactivation does not seem to be a real risk, and hepatitis C antiviral treatment does not influence IBD natural history. The approach to an IBD patient with abnormal liver function tests is complex due to the wide range of differential diagnosis, but it is of paramount importance to make a quick and accurate diagnosis, as it may influence the therapeutic management.
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Affiliation(s)
- Stefano Mazza
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
| | - Sara Soro
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
| | - Maria Chiara Verga
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
| | - Biagio Elvo
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
| | - Francesca Ferretti
- Gastroenterology Unit, ASST Fatebenefratelli-Sacco, Department of Biomedical and Clinical Sciences (DIBIC), Università degli Studi di Milano, Milan 20157, Italy
| | - Fabrizio Cereatti
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
| | - Andrea Drago
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
| | - Roberto Grassia
- Gastroenterology and Digestive Endoscopy Unit, ASST Cremona, Cremona 26100, Italy
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Wyatt NJ, Speight RA, Stewart CJ, Kirby JA, Lamb CA. Targeting Leukocyte Trafficking in Inflammatory Bowel Disease. BioDrugs 2021; 35:473-503. [PMID: 34613592 DOI: 10.1007/s40259-021-00496-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/04/2021] [Indexed: 12/11/2022]
Abstract
In the last two decades, understanding of inflammatory bowel disease (IBD) immunopathogenesis has expanded considerably. Histopathological examination of the intestinal mucosa in IBD demonstrates the presence of a chronic inflammatory cell infiltrate. Research has focused on identifying mechanisms of immune cell trafficking to the gastrointestinal tract that may represent effective gut-selective targets for IBD therapy whilst avoiding systemic immunosuppression that may be associated with off-target adverse effects such as infection and malignancy. Integrins are cell surface receptors that can bind to cellular adhesion molecules to mediate both leukocyte homing and retention. In 2014, Vedolizumab (Entyvio®) was the first anti-integrin (anti-α4ß7 monoclonal antibody) treatment to be approved for use in IBD. Several other anti-integrin therapies are currently in advanced stages of development, including novel orally administered small-molecule drugs. Drugs targeting alternative trafficking mechanisms such as mucosal addressin cellular adhesion molecule-1 and sphingosine-1-phosphate receptors are also being evaluated. Here, we summarise key established and emerging therapies targeting leukocyte trafficking that may play an important role in realising the goal of stratified precision medicine in IBD care.
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Affiliation(s)
- Nicola J Wyatt
- Faculty of Medical Sciences, Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.,Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 4LP, UK
| | - R Alexander Speight
- Faculty of Medical Sciences, Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.,Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 4LP, UK
| | - Christopher J Stewart
- Faculty of Medical Sciences, Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - John A Kirby
- Faculty of Medical Sciences, Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK
| | - Christopher A Lamb
- Faculty of Medical Sciences, Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. .,Department of Gastroenterology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 4LP, UK.
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Garlatti V, Lovisa S, Danese S, Vetrano S. The Multiple Faces of Integrin-ECM Interactions in Inflammatory Bowel Disease. Int J Mol Sci 2021; 22:10439. [PMID: 34638778 PMCID: PMC8508809 DOI: 10.3390/ijms221910439] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 09/20/2021] [Accepted: 09/21/2021] [Indexed: 12/03/2022] Open
Abstract
Inflammatory Bowel Disease (IBD) comprises a series of chronic and relapsing intestinal diseases, with Crohn's disease and ulcerative colitis being the most common. The abundant and uncontrolled deposition of extracellular matrix, namely fibrosis, is one of the major hallmarks of IBD and is responsible for the progressive narrowing and closure of the intestine, defined as stenosis. Although fibrosis is usually considered the product of chronic inflammation, the substantial failure of anti-inflammatory therapies to target and reduce fibrosis in IBD suggests that fibrosis might be sustained in an inflammation-independent manner. Pharmacological therapies targeting integrins have recently shown great promise in the treatment of IBD. The efficacy of these therapies mainly relies on their capacity to target the integrin-mediated recruitment and functionality of the immune cells at the damage site. However, by nature, integrins also act as mechanosensitive molecules involved in the intracellular transduction of signals and modifications originating from the extracellular matrix. Therefore, understanding integrin signaling in the context of IBD may offer important insights into mechanisms of matrix remodeling, which are uncoupled from inflammation and could underlie the onset and persistency of intestinal fibrosis. In this review, we present the currently available knowledge on the role of integrins in the etiopathogenesis of IBD, highlighting their role in the context of immune-dependent and independent mechanisms.
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Affiliation(s)
- Valentina Garlatti
- IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy; (V.G.); (S.L.); (S.D.)
- Department of Pharmaceutical Sciences, University of Piemonte Orientale ‘A. Avogadro’, 28100 Novara, Italy
| | - Sara Lovisa
- IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy; (V.G.); (S.L.); (S.D.)
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy
| | - Silvio Danese
- IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy; (V.G.); (S.L.); (S.D.)
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy
| | - Stefania Vetrano
- IRCCS Humanitas Research Hospital, Rozzano, 20089 Milan, Italy; (V.G.); (S.L.); (S.D.)
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, 20072 Milan, Italy
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47
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Rui M, Fei Z, Wang Y, Shi F, Meng R, Shang Y, Ma A, Li H. Will the Inducing and Maintaining Remission of Non-biological Agents and Biological Agents Differ for Crohn's Disease? The Evidence From the Network Meta-Analysis. Front Med (Lausanne) 2021; 8:679258. [PMID: 34540859 PMCID: PMC8440847 DOI: 10.3389/fmed.2021.679258] [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: 03/11/2021] [Accepted: 08/09/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Several drugs currently are available for the treatment of Crohn's disease, including non-biological agents such as anti-inflammatory agents, steroids, immunosuppressive agents, and biologic agents such as anti-tumor necrosis factor (TNF), anti-α4β7 integrin, anti-alpha-4 integrin and anti-interleukin 12/23. However, the choice of treatments for induction and maintenance is still a challenge. The relevant comparison between non-biologic agents and biologic agents is few. In our research, we aimed to help making decisions, as well as providing clinicians and patients with medication references. Methods: We searched MEDLINE, Embase, and the Cochrane Central Register of controlled trials for relevant randomized controlled trials published through to July 2020 and systematic reviews published from January 2011 to December 2020. Search results were screened by 2 independent reviewers first by title and abstract and then by full text. Disagreements were resolved through discussion with a third reviewer. Results: 54 randomized controlled trials were included in our analysis. For induction of remission, azathioprine (OR, 3.5; 95% Crl, 1.4–8.9), infliximab (OR, 4.1; 95% Crl, 1.2–16.0), infliximab + azathioprine (OR, 7.0; 95% Crl, 1.2–41.0) and infliximab+ methotrexate (OR, 7.8; 95% Crl, 1.2–65.0) were more effective in first-line therapy than placebo. Adalimumab showed superiority to placebo in second-line therapy, but the range of SD was wide. For maintenance of remission, adalimumab (OR,2.24;95% Crl,1.17–4.76) and azathioprine (OR,2.05; 95% Crl,1.14–3.96) were more effective than placebo. Adalimumab (OR,0.56; 95%Crl,0.27–1.2), budesonide (OR,0.63; 95%Crl,0.26–1.6) and natalizumab (OR,0.65; 95%Crl,0.30–1.4) was associated with less risk of withdrawals when compared with placebo. Conclusion: For induction of remission, azathioprine, infliximab, and infliximab + azathioprine were more effective in first-line therapy. In second-line therapy, adalimumab was more effective but should be interpreted carefully. For maintenance of remission, adalimumab and azathioprine were more effective. Besides, adalimumab, budesonide, natalizumab had lower withdrawals. Therefore, biological agents were not always better than non-biological agents and they have their own advantages in different treatment methods of Crohn's disease.
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Affiliation(s)
- Mingjun Rui
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China.,Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
| | - Zhengyang Fei
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China.,Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
| | - Yingcheng Wang
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China.,Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
| | - Fenghao Shi
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China.,Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
| | - Rui Meng
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China.,Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
| | - Ye Shang
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China.,Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
| | - Aixia Ma
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China.,Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
| | - Hongchao Li
- School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China.,Center for Pharmacoeconomics and Outcomes Research, China Pharmaceutical University, Nanjing, China
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48
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Brummer T, Ruck T, Meuth SG, Zipp F, Bittner S. Treatment approaches to patients with multiple sclerosis and coexisting autoimmune disorders. Ther Adv Neurol Disord 2021; 14:17562864211035542. [PMID: 34457039 PMCID: PMC8388232 DOI: 10.1177/17562864211035542] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Accepted: 07/08/2021] [Indexed: 12/30/2022] Open
Abstract
The past decades have yielded major therapeutic advances in many autoimmune conditions - such as multiple sclerosis (MS) - and thus ushered in a new era of more targeted and increasingly potent immunotherapies. Yet this growing arsenal of therapeutic immune interventions has also rendered therapy much more challenging for the attending physician, especially when treating patients with more than one autoimmune condition. Importantly, some therapeutic strategies are either approved for several autoimmune disorders or may be repurposed for other conditions, therefore opening new curative possibilities in related fields. In this article, we especially focus on frequent and therapeutically relevant concomitant autoimmune conditions faced by neurologists when treating patients with MS, namely psoriasis, rheumatoid arthritis and inflammatory bowel diseases. We provide an overview of the available disease-modifying therapies, highlight possible contraindications, show pathophysiological overlaps and finally present which therapeutics can be utilized as a combinatory treatment, in order to 'kill two birds with one stone'.
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Affiliation(s)
- Tobias Brummer
- Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Tobias Ruck
- Department of Neurology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
| | - Sven G. Meuth
- Department of Neurology, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany
| | - Frauke Zipp
- Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Stefan Bittner
- Department of Neurology, Focus Program Translational Neuroscience (FTN) and Immunotherapy (FZI), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstr. 1, Rhineland-Palatinate, Mainz 55131, Germany
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49
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Singh S, Proctor D, Scott FI, Falck-Ytter Y, Feuerstein JD. AGA Technical Review on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn's Disease. Gastroenterology 2021; 160:2512-2556.e9. [PMID: 34051985 PMCID: PMC8986997 DOI: 10.1053/j.gastro.2021.04.023] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The incidence and prevalence of Crohn's disease (CD) is rising globally. Patients with moderate to severe CD are at high risk for needing surgery and hospitalization and for developing disease-related complications, corticosteroid dependence, and serious infections. Optimal management of outpatients with moderate to severe luminal and/or fistulizing (including perianal) CD often requires the use of immunomodulator (thiopurines, methotrexate) and/or biologic therapies, including tumor necrosis factor-α antagonists, vedolizumab, or ustekinumab, either as monotherapy or in combination (with immunomodulators) to mitigate these risks. Decisions about optimal drug therapy in moderate to severe CD are complex, with limited guidance on comparative efficacy and safety of different treatments, leading to considerable practice variability. Since the last iteration of these guidelines published in 2013, significant advances have been made in the field, including the regulatory approval of 2 new biologic agents, vedolizumab and ustekinumab. Therefore, the American Gastroenterological Association prioritized updating clinical guidelines on this topic. To inform the clinical guidelines, this technical review was completed in accordance with the GRADE (Grading of Recommendations Assessment, Development and Evaluation) framework. The review addressed the following focused questions (in adult outpatients with moderate to severe luminal CD): overall and comparative efficacy of different medications for induction and maintenance of remission in patients with or without prior exposure to tumor necrosis factor-α antagonists, comparative efficacy and safety of biologic monotherapy vs combination therapy with immunomodulators, comparative efficacy of a top-down (upfront use of biologics and/or immunomodulator therapy) vs step-up treatment strategy (acceleration to biologic and/or immunomodulator therapy only after failure of mesalamine), and the role of corticosteroids and mesalamine for induction and/or maintenance of remission. Finally, in adult outpatients with moderate to severe fistulizing CD, this review addressed the efficacy of pharmacologic interventions for achieving fistula and the role of adjunctive antibiotics without clear evidence of active infection.
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Affiliation(s)
- Siddharth Singh
- Division of Gastroenterology and Division of Biomedical Informatics, Department of Medicine, University of California, San Diego, La Jolla, CA
| | - Deborah Proctor
- Division of Gastroenterology, Department of Medicine, Yale School of Medicine, New Haven, CT
| | - Frank I. Scott
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Yngve Falck-Ytter
- Division of Gastroenterology and Liver Disease, Case Western Reserve University, Cleveland, Ohio CA
| | - Joseph D. Feuerstein
- Division of Gastroenterology and Center for Inflammatory Bowel Diseases, Beth Israel Deaconess Medical Center, Boston, MA
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50
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Wiendl M, Becker E, Müller TM, Voskens CJ, Neurath MF, Zundler S. Targeting Immune Cell Trafficking - Insights From Research Models and Implications for Future IBD Therapy. Front Immunol 2021; 12:656452. [PMID: 34017333 PMCID: PMC8129496 DOI: 10.3389/fimmu.2021.656452] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 04/16/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel diseases (IBDs), including Crohn's disease (CD) and ulcerative colitis (UC) are multifactorial diseases with still unknown aetiology and an increasing prevalence and incidence worldwide. Despite plentiful therapeutic options for IBDs, the lack or loss of response in certain patients demands the development of further treatments to tackle this unmet medical need. In recent years, the success of the anti-α4β7 antibody vedolizumab highlighted the potential of targeting the homing of immune cells, which is now an important pillar of IBD therapy. Due to its complexity, leukocyte trafficking and the involved molecules offer a largely untapped resource for a plethora of potential therapeutic interventions. In this review, we aim to summarise current and future directions of specifically interfering with immune cell trafficking. We will comment on concepts of homing, retention and recirculation and particularly focus on the role of tissue-derived chemokines. Moreover, we will give an overview of the mode of action of drugs currently in use or still in the pipeline, highlighting their mechanisms and potential to reduce disease burden.
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Affiliation(s)
- Maximilian Wiendl
- Department of Medicine 1, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Emily Becker
- Department of Medicine 1, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Tanja M. Müller
- Department of Medicine 1, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Caroline J. Voskens
- Department of Dermatology, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Markus F. Neurath
- Department of Medicine 1, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Sebastian Zundler
- Department of Medicine 1, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
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