View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Hofstra Northwell Academic Works (Hofstra Northwell School of Medicine) Donald and Barbara Zucker School of Medicine Journal Articles Academic Works 2018 Anti-integrin therapy for inflammatory bowel disease S. C. Park Zucker School of Medicine at Hofstra/Northwell Y. T. Jeen Follow this and additional works at: https://academicworks.medicine.hofstra.edu/articles Part of the Ophthalmology Commons Recommended Citation Park SC, Jeen YT. Anti-integrin therapy for inflammatory bowel disease. 2018 Jan 01; 24(17):Article 3452 [ p.]. Available from: https://academicworks.medicine.hofstra.edu/articles/3452. Free full text article. This Article is brought to you for free and open access by Donald and Barbara Zucker School of Medicine Academic Works. It has been accepted for inclusion in Journal Articles by an authorized administrator of Donald and Barbara Zucker School of Medicine Academic Works. For more information, please contact [email protected]. Submit a Manuscript: http://www.f6publishing.com World J Gastroenterol 2018 May 7; 24(17): 1868-1880 DOI: 10.3748/wjg.v24.i17.1868 ISSN 1007-9327 (print) ISSN 2219-2840 (online) MINIREVIEWS Anti-integrin therapy for inflammatory bowel disease Sung Chul Park, Yoon Tae Jeen Sung Chul Park, Division of Gastroenterology and Hepatology, Abstract Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon 24289, South Korea In inflammatory bowel disease (IBD), tumor necro­ sis factor plays an important role in mediating infla­ Yoon Tae Jeen, Division of Gastroenterology and Hepatology, mmation, but several other pathways are also involved Department of Internal Medicine, Korea University Anam Hospital, in eliciting an inflammatory response. One such Korea University College of Medicine, Seoul 02841, South Korea pathway is the invasion of the intestinal mucosa by leukocytes. Leukocytes within the systemic circulation ORCID number: Sung Chul Park (0000-0003-3215-6838); move to sites of inflammation, and blocking this Yoon Tae Jeen (0000-0003-0220-3816). pathway could be an important treatment strategy for IBD. Anti­integrin therapy blocks the action of Author contributions: Park SC and Jeen YT wrote the integrin on the surface of circulating immune cells and manuscript and made the tables and figures. endothelial cell adhesion molecules, thereby inhibiting Conflict­of­interest statement: Authors declare no conflict of the interactions between leukocytes and intestinal blood interests for this article. vessels. Natalizumab, which acts on α4­integrin, was the first such drug to be approved for Crohn’s disease, Open­Access: This article is an open-access article which was but its use is limited due to the risk of progressive selected by an in-house editor and fully peer-reviewed by external multifocal leukoencephalopathy. Vedolizumab produces reviewers. It is distributed in accordance with the Creative few systemic adverse effects because it acts on gut­ Commons Attribution Non Commercial (CC BY-NC 4.0) license, trophic α4β7 integrin, and has been approved and is which permits others to distribute, remix, adapt, build upon this being used to treat IBD. Currently, several anti­integrin work non-commercially, and license their derivative works on drugs, including etrolizumab, which acts on β7­integrin, different terms, provided the original work is properly cited and and PF­00547569, which targets mucosal addressin cell the use is non-commercial. See: http://creativecommons.org/ adhesion molecule­1, are undergoing clinical trials and licenses/by-nc/4.0/ the results are being closely watched. Manuscript source: Invited manuscript Key words: Integrin; Ulcerative colitis; Crohn’s disease; Correspondence to: Yoon Tae Jeen, MD, PhD, Professor, Natalizumab; Abrilumab; Etrolizumab; PF­00547659; Division of Gastroenterology and Hepatology, Department of Inflammatory bowel disease; AJM300; Vedolizumab Internal Medicine, Korea University Anam Hospital, Korea University College of Medicine, 73, Inchon-ro, Seongbuk-gu, © The Author(s) 2018. Published by Baishideng Publishing Seoul 02841, South Korea. [email protected] Group Inc. All rights reserved. Telephone: +82-2-9206555 Fax: +82-2-9531943 Core tip: Anti­integrin therapies have attracted attention as new therapeutic agents in inflammatory bowel dis­ Received: March 23, 2018 ease. They inhibit the extravasation of leukocytes by Peer­review started: March 25, 2018 First decision: April 18, 2018 blocking the interaction between integrins on immune Revised: April 23, 2018 cells and endothelial cell adhesion molecules. The use Accepted: April 26, 2018 of the first developed anti­integrin agent, natalizumab Article in press: April 26, 2018 is now limited due to the risk of progressive multifocal Published online: May 7, 2018 leukoencephalopathy. However, vedolizumab which acts WJG|www.wjgnet.com 1868 May 7, 2018|Volume 24|Issue 17| Park SC et al . Anti­integrin therapy for IBD selectively on the gut has shown few adverse events tokines define and regulate various aspects of the infla­ and is currently used in clinical practice. Newer anti­ mmatory response and play an important role in the integrin drugs that act on different integrins­related pathogenesis of IBD including Crohn’s disease (CD) targets, such as AJM300, abrilumab, etrolizumab, and and ulcerative colitis (UC), with the former mediated PF­00547659 have also been developed and are in by type 1 T helper cells (TH1) and TH17, and the latter clinical trials. reportedly caused by an abnormal TH2 response. The immunopathogenesis of IBD is made more complex Park SC, Jeen YT. Anti-integrin therapy for inflammatory by imbalances in different T cell subsets, such as bowel disease. World J Gastroenterol 2018; 24(17): 1868-1880 regulatory T cells, natural killer T cells, and TH9, as Available from: URL: http://www.wjgnet.com/1007-9327/full/ well as the interactions between these cell populations. v24/i17/1868.htm DOI: http://dx.doi.org/10.3748/wjg.v24. Ultimately, the production of numerous cytokines is i17.1868 disturbed. These cytokines include the well­known TNF­α as well as IL­1β, IL­6, IL­8, IL­10, IL­12, IL­17, IL­23, and transforming growth factor­α[3,6]. The use of TNF antagonists showed that just blocking INTRODUCTION a single cytokine could be sufficient to induce significant clinical remission. Until recently, in moderate­to­severe Causes of inflammatory bowel disease (IBD) have not active IBD patients, especially if initial treatment with yet been clearly elucidated, but it is known that genetic systemic corticosteroids or immunomodulators failed, susceptibility, altered gut microbiota, and environmental anti­TNF agents were the only remaining treatment factors are all involved. It has also been reported that option. a combination of these factors causes an inappropriate Inspired by the treatment outcomes of the first immune response, resulting in impaired intestinal generation anti­TNF agent infliximab, next­generation barrier function[1-3]. TNF antagonists, such as adalimumab, golimumab, As continual research further reveals the immuno­ and certolizumab pegol, were introduced for the treat­ pathogenesis of IBD, the treatment of IBD has shifted ment of IBD, drastically changing this treatment field; from conventional treatments, such as aminosalicylates, however, even these drugs did not show an effect in glucocorticoids, and immunomodulators (thiopurines all IBD patients. Specifically, although reports differ and methotrexate), toward the biological drugs that [4] slightly, anti­TNF agents produce primary non­response target inflammation­related pathways . Anti­tumor (PNR) in approximately 10%­30% of patients[7]. Several necrosis factor (TNF) agents were the first biologics factors have been suggested as causes of PNR. One used to treat IBD, and the objective of IBD treatment known cause of PNR is that TNF is not a major factor in has shifted from controlling symptoms to changing the progression of disease and preserving the intestinal the development of inflammation in some patients, and therefore, there is an increased need for drugs with new function. However, anti­TNF agents are not effective in [8] all IBD patients, and a considerable number of patients mechanisms . experience relapse after stopping medication. The Although anti­TNF agents show an initial effect, pathophysiology of IBD is very complex. This means secondary non­response or loss of response (LOR) is [7,9] that the most appropriate treatment method may vary seen in 23%­46% . LOR is known to occur due to for each patient, and therefore, constant efforts are pharmacokinetic issues or the production of antibodies being made to develop effective drugs[4]. In particular, against the drug; however, it can also be caused by a new biologics that inhibit leukocyte trafficking to the shift in the inflammatory response pathway from TNF site of inflammation have been developed and used. signaling to non­TNF signaling. Moreover, due to their These drugs are called anti­integrin or anti­adhesion comprehensive immunosuppressive effects, the use of agents, or leukocyte­trafficking inhibitors because anti­TNF agents can cause severe adverse reactions, they block the actions of integrin, a cell surface protein including tuberculosis (TB), hepatitis B, pneumonia, expressed by circulating immune cells and endothelial herpes zoster, and other infections, as well as skin cell adhesion molecules (CAMs), thereby selectively