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Ruchitha S, Gupta N, Singh K. Exploring the multifaceted side effects of isotretinoin: a deep dive into case reports and observational studies. Arch Dermatol Res 2025; 317:499. [PMID: 40009222 DOI: 10.1007/s00403-025-04019-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Revised: 02/03/2025] [Accepted: 02/12/2025] [Indexed: 02/27/2025]
Abstract
This review addresses gaps in understanding isotretinoin's side effects for acne vulgaris. While effective, the risks are often underestimated. It emphasizes careful patient selection and monitoring to optimize outcomes and minimize harm. By providing a comprehensive evaluation, the review aims to enhance patient safety and inform clinical decision-making. This review examined isotretinoin's side effects through case reports and observational studies. A literature search on Google Scholar, PubMed, Scopus, and Web of Science covered publications from 2000 to 2024 using terms like "isotretinoin" and "side effects," focusing on English-language studies. Inclusion criteria targeted studies detailing adverse effects across dermatological, musculoskeletal, psychiatric, ocular, gastrointestinal, endocrine, and renal areas. Data included population size, dosage, treatment duration, and side effects. No statistical analysis was performed. This review underscores a wide array of side effects associated with isotretinoin, ranging from common issues such as dry skin and cheilitis to more serious conditions including psychiatric disorders, musculoskeletal complications, and autoimmune diseases. Notably, rare side effects like psychosis and rhabdomyolysis have also been observed. The review emphasizes the necessity for meticulous patient selection, thorough risk assessment, and vigilant monitoring, especially for at-risk populations such as women of reproductive age. This review emphasizes the need for personalized evaluations and monitoring during isotretinoin treatment, particularly for high-risk groups like women of reproductive age. Healthcare providers must consider the risk-benefit ratio due to potential side effects. Regular check-ups and proactive management are crucial to optimize outcomes and minimize risks.
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Affiliation(s)
- S Ruchitha
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai, 400 056, India
| | - Neha Gupta
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai, 400 056, India
| | - Kavita Singh
- Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai, 400 056, India.
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Zhang D, Lv W, Xu Y, Zhang Z, Zeng S, Zhang W, Gong L, Shao L, Zhang M, He T, Liu Y, Wang Y, Liu L, Hu X. Microbial bile acid metabolite ameliorates mycophenolate mofetil-induced gastrointestinal toxicity through vitamin D3 receptor. Am J Transplant 2024; 24:1132-1145. [PMID: 38452932 DOI: 10.1016/j.ajt.2024.02.029] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 02/24/2024] [Accepted: 02/26/2024] [Indexed: 03/09/2024]
Abstract
Mycophenolate mofetil (MMF) is one of the most used immunosuppressive drugs in organ transplantation, but frequent gastrointestinal (GI) side effects through unknown mechanisms limit its clinical use. Gut microbiota and its metabolites were recently reported to play a vital role in MMF-induced GI toxicity, but the specific mechanism of how they interact with the human body is still unclear. Here, we found that secondary bile acids (BAs), as bacterial metabolites, were significantly reduced by MMF administration in the gut of mice. Microbiome data and fecal microbiota transfer model supported a microbiota-dependent effect on the reduction of secondary BAs. Supplementation of the secondary BA lithocholic acid alleviated MMF-induced weight loss, colonic inflammation, and oxidative phosphorylation damage. Genetic deletion of the vitamin D3 receptor (VDR), which serves as a primary colonic BA receptor, in colonic epithelial cells (VDRΔIEC) abolished the therapeutic effect of lithocholic acid on MMF-induced GI toxicity. Impressively, we discovered that paricalcitol, a Food and Drug Administration-approved VDR agonist that has been used in clinics for years, could effectively alleviate MMF-induced GI toxicity. Our study reveals a previously unrecognized mechanism of gut microbiota, BAs, and VDR signaling in MMF-induced GI side effects, offering potential therapeutic strategies for clinics.
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Affiliation(s)
- Di Zhang
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; Institute of Urology, Capital Medical University, Beijing, China
| | - Wei Lv
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yue Xu
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; Institute of Urology, Capital Medical University, Beijing, China
| | - Zijian Zhang
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; Institute of Urology, Capital Medical University, Beijing, China
| | - Song Zeng
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; Institute of Urology, Capital Medical University, Beijing, China
| | - Weixun Zhang
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; Institute of Urology, Capital Medical University, Beijing, China
| | - Lian Gong
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; Institute of Urology, Capital Medical University, Beijing, China
| | - Limei Shao
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Min Zhang
- Department of Research Ward, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Tian He
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yingying Liu
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yuxuan Wang
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; Institute of Urology, Capital Medical University, Beijing, China
| | - Ling Liu
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
| | - Xiaopeng Hu
- Department of Urology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China; Institute of Urology, Capital Medical University, Beijing, China.
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Balde A, Ramya CS, Nazeer RA. A review on current advancement in zebrafish models to study chronic inflammatory diseases and their therapeutic targets. Heliyon 2024; 10:e31862. [PMID: 38867970 PMCID: PMC11167310 DOI: 10.1016/j.heliyon.2024.e31862] [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: 11/15/2023] [Revised: 04/02/2024] [Accepted: 05/22/2024] [Indexed: 06/14/2024] Open
Abstract
Chronic inflammatory diseases are caused due to prolonged inflammation at a specific site of the body. Among other inflammatory diseases, bacterial meningitis, chronic obstructive pulmonary disease (COPD), atherosclerosis and inflammatory bowel diseases (IBD) are primarily focused on because of their adverse effects and fatality rates around the globe in recent times. In order to come up with novel strategies to eradicate these diseases, a clear understanding of the mechanisms of the diseases is needed. Similarly, detailed insight into the mechanisms of commercially available drugs and potent lead compounds from natural sources are also important to establish efficient therapeutic effects. Zebrafish is widely accepted as a model to study drug toxicity and the pharmacokinetic effects of the drug. Moreover, researchers use various inducers to trigger inflammatory cascades and stimulate physiological changes in zebrafish. The effect of these inducers contrasts with the type of zebrafish used in the investigation. Hence, a thorough analysis is required to study the current advancements in the zebrafish model for chronic inflammatory disease suppression. This review presents the most common inflammatory diseases, commercially available drugs, novel therapeutics, and their mechanisms of action for disease suppression. The review also provides a detailed description of various zebrafish models for these diseases. Finally, the future prospects and challenges for the same are described, which can help the researchers understand the potency of the zebrafish model and its further exploration for disease attenuation.
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Affiliation(s)
- Akshad Balde
- Biopharmaceuticals Lab, Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603203, Tamil Nadu, India
| | - Cunnathur Saravanan Ramya
- Biopharmaceuticals Lab, Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603203, Tamil Nadu, India
| | - Rasool Abdul Nazeer
- Biopharmaceuticals Lab, Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603203, Tamil Nadu, India
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Bonfils L, Sandri AK, Poulsen GJ, Agrawal M, Ward DJ, Colombel JF, Jess T, Allin KH. Medication-Wide Study: Exploring Medication Use 10 Years Before a Diagnosis of Inflammatory Bowel Disease. Am J Gastroenterol 2023; 118:2220-2229. [PMID: 37410928 PMCID: PMC11148653 DOI: 10.14309/ajg.0000000000002399] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Accepted: 06/14/2023] [Indexed: 07/08/2023]
Abstract
INTRODUCTION There is growing interest in the prediagnostic phase of inflammatory bowel disease (IBD) and in the overlap of IBD with other diseases. We described and compared use of any prescription medication between individuals with and without IBD in a 10-year period preceding diagnosis. METHODS Based on cross-linked nationwide registers, we identified 29,219 individuals diagnosed with IBD in Denmark between 2005 and 2018 and matched to 292,190 IBD-free individuals. The primary outcome was use of any prescription medication in years 1-10 before IBD diagnosis/matching date. Participants were considered as medication users if they redeemed ≥1 prescription for any medication in the World Health Organization Anatomical Therapeutic Chemical (ATC) main groups or subgroups before diagnosis/matching. RESULTS The IBD population had a universally increased use of medications compared with the matched population before IBD diagnosis. At 10 years before diagnosis, the proportion of users was 1.1-fold to 1.8-fold higher in the IBD population in 12 of 14 ATC main groups of medication ( P -value < 0.0001). This applied across age, sex, and IBD subtypes, although it was the most pronounced for Crohn's disease (CD). Two years before diagnosis, the IBD population had a steep increase in medication use for several organ systems. When analyzing therapeutic subgroups of medication, the CD population exhibited 2.7, 2.3, 1.9, and 1.9 times more users of immunosuppressants, antianemic preparations, analgesics, and psycholeptics, respectively, than the matched population 10 years before diagnosis ( P -value < 0.0001). DISCUSSION Our findings demonstrate universally increased medication use years before IBD, especially CD, diagnosis and indicates multiorgan involvement in IBD.
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Affiliation(s)
- Linéa Bonfils
- Center for Molecular Prediction of Inflammatory Bowel Disease (PREDICT), Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
| | - Anastasia Karachalia Sandri
- Center for Molecular Prediction of Inflammatory Bowel Disease (PREDICT), Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
| | - Gry J. Poulsen
- Center for Molecular Prediction of Inflammatory Bowel Disease (PREDICT), Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
| | - Manasi Agrawal
- Center for Molecular Prediction of Inflammatory Bowel Disease (PREDICT), Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York NY
| | - Daniel J. Ward
- Center for Molecular Prediction of Inflammatory Bowel Disease (PREDICT), Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
| | - Jean-Frederic Colombel
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York NY
| | - Tine Jess
- Center for Molecular Prediction of Inflammatory Bowel Disease (PREDICT), Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
- Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark
| | - Kristine H. Allin
- Center for Molecular Prediction of Inflammatory Bowel Disease (PREDICT), Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
- Department of Gastroenterology & Hepatology, Aalborg University Hospital, Aalborg, Denmark
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Zhou Y, Yang Z, Ou Y, Cai H, Liu Z, Lin G, Liang S, Hua L, Yan Y, Zhang X, Wu R, Qin A, Hu W, Sun P. Discovery of a selective NLRP3-targeting compound with therapeutic activity in MSU-induced peritonitis and DSS-induced acute intestinal inflammation. Cell Mol Life Sci 2023; 80:230. [PMID: 37498355 PMCID: PMC11073129 DOI: 10.1007/s00018-023-04881-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Revised: 07/03/2023] [Accepted: 07/16/2023] [Indexed: 07/28/2023]
Abstract
The aberrant activation of the nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is known to contribute to the pathogenesis of various human inflammation-related diseases. However, to date, no small-molecule NLRP3 inhibitor has been used in clinical settings. In this study, we have identified SB-222200 as a novel direct NLRP3 inhibitor through the use of drug affinity responsive target stability assay, cellular thermal shift assay, and surface plasmon resonance analysis. SB-222200 effectively inhibits the activation of the NLRP3 inflammasome in macrophages, while having no impact on the activation of NLRC4 or AIM2 inflammasome. Furthermore, SB-222200 directly binds to the NLRP3 protein, inhibiting NLRP3 inflammasome assembly by blocking the NEK7 - NLRP3 interaction and NLRP3 oligomerization. Importantly, treatment with SB-222200 demonstrates alleviation of NLRP3-dependent inflammatory diseases in mouse models, such as monosodium urate crystal-induced peritonitis and dextran sulfate sodium-induced acute intestinal inflammation. Therefore, SB-222200 holds promise as a lead compound for the development of NLRP3 inhibitors to combat NLRP3-driven disease and serves as a versatile tool for pharmacologically investigating NLRP3 biology.
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Affiliation(s)
- Yinghua Zhou
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Zhongjin Yang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Yitao Ou
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Haowei Cai
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Zhuorong Liu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Geng Lin
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Shuli Liang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Lei Hua
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Yuyun Yan
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Xiuxiu Zhang
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Ruiwen Wu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Aiping Qin
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China
| | - Wenhui Hu
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China.
| | - Ping Sun
- Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, the NMPA and State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, 511436, China.
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Aktas H, Bahçe ZŞ. Evaluation of the Incidence of Anal Fissures in Patients who Systemic Isotretinoin Therapy for Acne. Dermatol Pract Concept 2023; 13:e2023133. [PMID: 37557107 PMCID: PMC10412088 DOI: 10.5826/dpc.1303a133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/11/2023] [Indexed: 08/11/2023] Open
Abstract
INTRODUCTION Isotretinoin is an effective drug widely used in the treatment of severe acne. In this study, we tried to evaluate the incidence of anal fissures with clinical and laboratory side effects associated with isotretinoin. METHODS The study evaluated 210 patients who received systemic isotretinoin treatment. Especially patients with constipation and anal bleeding were evaluated by the General Surgery clinic to arrange appropriate treatments. RESULTS Of 210 patients included in the study, 138 (65.7%) were female and 72 (34.3%) were male, with a mean age of 23.7 years. The most common adverse event was dry lips in 206 (98.1%) patients. The mucocutaneous side effects were constipation 36 (17.1%), anal bleeding 18 (8.6%), mucosal erosion 10 (4.7%), anal fissure 7 (3.3%). Treatment was discontinued due to elevated liver function tests in 5 patients (2.3%), and because anal bleeding could not be controlled in 1 patient. CONCLUSIONS Isotretinoin is the most effective acne medicine used today. Clarification of the patients about the rarely seen side effects such as dryness, erosion, fissure and bleeding in the anal mucosa in addition to the common mucocutaneous side effects will ensure that patients are more cautious and increase their tolerance to the treatment.
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Affiliation(s)
- Hamza Aktas
- Private Memorial Hospital, Department of Dermatology, Diyarbakır, Turkey
| | - Zeynep Şener Bahçe
- Private Memorial Hospital, Department of General Surgery, Diyarbakır, Turkey
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González Delgado S, Garza-Veloz I, Trejo-Vazquez F, Martinez-Fierro ML. Interplay between Serotonin, Immune Response, and Intestinal Dysbiosis in Inflammatory Bowel Disease. Int J Mol Sci 2022; 23:ijms232415632. [PMID: 36555276 PMCID: PMC9779345 DOI: 10.3390/ijms232415632] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/05/2022] [Accepted: 12/06/2022] [Indexed: 12/14/2022] Open
Abstract
Inflammatory Bowel Disease (IBD) is a chronic gastrointestinal disorder characterized by periods of activity and remission. IBD includes Crohn's disease (CD) and ulcerative colitis (UC), and even though IBD has not been considered as a heritable disease, there are genetic variants associated with increased risk for the disease. 5-Hydroxytriptamine (5-HT), or serotonin, exerts a wide range of gastrointestinal effects under both normal and pathological conditions. Furthermore, Serotonin Transporter (SERT) coded by Solute Carrier Family 6 Member 4 (SLC6A4) gene (located in the 17q11.1-q12 chromosome), possesses genetic variants, such as Serotonin Transporter Gene Variable Number Tandem Repeat in Intron 2 (STin2-VNTR) and Serotonin-Transporter-linked promoter region (5-HTTLPR), which have an influence over the functionality of SERT in the re-uptake and bioavailability of serotonin. The intestinal microbiota is a crucial actor in normal human gut physiology, exerting effects on serotonin, SERT function, and inflammatory processes. As a consequence of abnormal serotonin signaling and SERT function under these inflammatory processes, the use of selective serotonin re-uptake inhibitors (SSRIs) has been seen to improve disease activity and extraintestinal manifestations, such as depression and anxiety. The aim of this study is to integrate scientific data linking the intestinal microbiota as a regulator of gut serotonin signaling and re-uptake, as well as its role in the pathogenesis of IBD. We performed a narrative review, including a literature search in the PubMed database of both review and original articles (no date restriction), as well as information about the SLC6A4 gene and its genetic variants obtained from the Ensembl website. Scientific evidence from in vitro, in vivo, and clinical trials regarding the use of selective serotonin reuptake inhibitors as an adjuvant therapy in patients with IBD is also discussed. A total of 194 articles were used between reviews, in vivo, in vitro studies, and clinical trials.
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Herlihy N, Feakins R. Gut inflammation induced by drugs: Can pathology help to differentiate from inflammatory bowel disease? United European Gastroenterol J 2022; 10:451-464. [PMID: 35633273 PMCID: PMC9189468 DOI: 10.1002/ueg2.12242] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2021] [Accepted: 04/24/2022] [Indexed: 12/13/2022] Open
Abstract
Drug‐induced mucosal injury (DIMI) in the gastrointestinal tract is important to recognise, partly because cessation of the culprit agent alone may result in resolution of symptoms. An ever‐growing list of medications, including newer immunotherapeutic agents and targeted therapies, can cause gastrointestinal inflammation of varying severity. However, the diagnosis of DIMI is challenging, as a single drug can induce a variety of histopathological patterns of injury including acute colitis, chronic colitis, microscopic colitis, apoptotic colopathy, and ischaemic‐type colitis. An additional consideration is the potential clinical, endoscopic and histological overlap of DIMI with gastrointestinal mucosal injury secondary to other entities such as inflammatory bowel disease (IBD). We discuss DIMI of the gastrointestinal tract with an emphasis on histological patterns that mimic IBD, histological features which may distinguish the two entities, and the diagnostic role and limitations of the pathologist.
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Affiliation(s)
- Naoimh Herlihy
- Department of Cellular Pathology, Royal Free Hospital, London, UK
| | - Roger Feakins
- Department of Cellular Pathology, Royal Free Hospital, London and University College London, London, UK
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Del Sordo R, Lougaris V, Bassotti G, Armuzzi A, Villanacci V. Therapeutic agents affecting the immune system and drug-induced inflammatory bowel disease (IBD): A review on etiological and pathogenetic aspects. Clin Immunol 2022; 234:108916. [PMID: 34971840 DOI: 10.1016/j.clim.2021.108916] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Revised: 12/23/2021] [Accepted: 12/23/2021] [Indexed: 01/02/2023]
Abstract
In recent years, therapeutic agents affecting the immune system have been largely implemented in the treatment of various hematological, rheumatological and dermatological disorders. Their clinical use has offered important benefits for affected patients and has also ameliorated clinical outcome and prognosis in many cases. Nonetheless, as any treatment, the use of these drugs may be associated with side effects. One of the target organs in such cases is the gastrointestinal tract. In particular, the exacerbation or the onset of inflammatory bowel disease (IBD) in treated patients is not infrequent, although the mechanism of action of these agents may be different. In this review we will focus on the use of therapeutic agents affecting the immune system and the development or exacerbation of IBD, with a mention on the possible underlying pathogenetic mechanisms.
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Affiliation(s)
- Rachele Del Sordo
- Department of Medicine and Surgery, Section of Anatomic Pathology and Histology, Medical School, University of Perugia, Perugia, Italy
| | - Vassilios Lougaris
- Pediatrics Clinic, Department of Clinical and Experimental Sciences, University of Brescia and Children's Hospital, ASST-Spedali Civili, Brescia, Italy..
| | - Gabrio Bassotti
- Gastroenterology & Hepatology Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Alessandro Armuzzi
- IBD Center, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy
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10
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Han N, Oh JM, Kim IW. Adverse Events Related to Off-Label Drugs Using Spontaneous Adverse Event Reporting Systems. Ther Clin Risk Manag 2021; 17:877-887. [PMID: 34456568 PMCID: PMC8387311 DOI: 10.2147/tcrm.s321789] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 08/10/2021] [Indexed: 12/16/2022] Open
Abstract
Purpose The purpose of this study was to investigate the adverse events (AEs) related to the use of off-label drugs. Materials and Methods A cross-sectional study was carried out using available data pertaining to off-label drug were sourced from U.S. FDA spontaneous adverse drug reaction reporting database (FAERS) and Korea Adverse Event Reporting System database (KIDS-KD) for the years 2014 to 2018. The number and frequencies of AE cases were calculated. Disproportionality was analyzed using the proportional reporting ratio (PRR), the reporting odds ratio (ROR), the information component (IC), and the empirical Bayes geometric mean (EBGM) methods. Results The reported AEs associated with off-label drug use were more common among older patients compared with younger patients. Gastric nonspecific symptoms and therapeutic procedure (4.16–4.57%) and haemorrage term (4.16–5.29%) were the most common AE symptoms and antithrombotic agents and immunosuppressants were the drugs most commonly reported to cause AEs in FAERS. Secondary term events (43.45–48.62%) including inappropriate schedule of drug administration and medication error were the most common AEs, and immunosuppressants and antipsychotics were the most common AE-related drugs from KIDS-KD. The numbers of reported AEs in new drug categories such as other antineoplastic agents trended to increase from 2014 to 2018 in both datasets. Conclusion The numbers of reported AEs with off-label drug increased annually. AEs associated with off-label drugs may have a significant impact on older patients. Healthcare experts should be concerned about prescriptions of off-label drugs, especially anticoagulants and newly developed drugs such as immunosuppressants and antineoplastic agents.
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Affiliation(s)
- Nayoung Han
- Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.,College of Pharmacy, Jeju National University, Jejusi, Jeju Special Self-Governing Province, Republic of Korea
| | - Jung Mi Oh
- Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea.,College of Pharmacy, Seoul National University, Seoul, Republic of Korea
| | - In-Wha Kim
- Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea
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11
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Hijos-Mallada G, Sostres C, Gomollón F. NSAIDs, gastrointestinal toxicity and inflammatory bowel disease. GASTROENTEROLOGIA Y HEPATOLOGIA 2021; 45:215-222. [PMID: 34157367 DOI: 10.1016/j.gastrohep.2021.06.003] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 06/11/2021] [Indexed: 01/06/2023]
Abstract
Non-steroidal antiinflammatory drugs (NSAIDs) are currently one of the most widely used drugs. The use of NSAIDs is associated with gastrointestinal toxicity, affecting both upper gastrointestinal tract (peptic ulcer disease) and lower gastrointestinal tract (NSAID-induced enteropathy). NSAIDs use has been associated with an increased risk of clinical relapse in inflammatory bowel disease patients. In this article, we review the upper and lower gastrointestinal toxicity of NSAIDs, with a focus on the risks and specific data of these drugs in inflammatory bowel disease patients, giving recommendations for its appropriate use in the clinical practice. Although evidence is scarce, short-term use of NSAIDs appears to be safe, and the data available suggest that selective COX-2 inhibitors are the safer option. NSAIDs should be avoided as long-term treatment or with high doses, especially in patients with active inflammation.
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Affiliation(s)
- Gonzalo Hijos-Mallada
- Servicio de Aparato Digestivo, Hospital Clínico Universitario Lozano Blesa, Zaragoza, España; Instituto de Investigación Sanitaria (ISS) Aragón, Zaragoza, España.
| | - Carlos Sostres
- Servicio de Aparato Digestivo, Hospital Clínico Universitario Lozano Blesa, Zaragoza, España; Instituto de Investigación Sanitaria (ISS) Aragón, Zaragoza, España
| | - Fernando Gomollón
- Servicio de Aparato Digestivo, Hospital Clínico Universitario Lozano Blesa, Zaragoza, España; Instituto de Investigación Sanitaria (ISS) Aragón, Zaragoza, España; Departamento de Medicina, Facultad de Medicina, Universidad de Zaragoza, Zaragoza, España
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12
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Lui FCW, Lo OSH. Rare complication of inflammatory bowel disease-like colitis from glycogen storage disease type 1b and its surgical management: A case report. World J Clin Cases 2021; 9:4081-4089. [PMID: 34141769 PMCID: PMC8180209 DOI: 10.12998/wjcc.v9.i16.4081] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 03/10/2021] [Accepted: 03/24/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Glycogen storage disease (GSD) is an autosomal recessive inborn metabolic disorder. Patients with GSD are prone to hypoglycaemia, hyperlactacidemia and bleeding. GSD type 1b (GSD-1b) patients specifically can develop neutropenia, recurrent bacterial infection and inflammatory bowel disease (IBD). Documentation of the long-term outcomes of surgical management of GSD-1b has been scarce, especially for Asian patients. We herein describe a case of GSD-1b complicated by IBD-like colitis and coloduodenal fistula. The patient was managed successfully with surgical intervention.
CASE SUMMARY A 20-year-old Chinese lady confirmed by genetic testing to have GSD-1b was initially managed with uncooked cornstarch and granulocyte-colony stimulating factor. With recurrent abdominal symptoms, her condition was treated as clinical “Crohn’s disease” with mesalazine, prednisolone and azathioprine conservatively. Colonoscopy showed a tight stricture at the hepatic flexure. Subsequent computerized tomographic colonography revealed a phlegmon at the ileocaecal region with a suspected coloduodenal fistula. Eventually an exploratory laparotomy was performed and severe colitis at the ascending colon with coloduodenal fistula was confirmed. Right hemicolectomy with primary anastomosis and repair of the duodenum were performed. Surgical management of complications from GSD-1b associated IBD-like colitis has rarely been described. First-line treatment would usually be conservative. Surgical intervention like hemicolectomy is mainly reserved for refractory cases.
CONCLUSION Surgical management of coloduodenal fistula in GSD-1b patients is a feasible and safe option when failed conservative management.
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Affiliation(s)
- Frederick Chi-Wai Lui
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Oswens Siu-Hung Lo
- Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
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13
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van Lint JA, Jessurun NT, Tas SW, van den Bemt BJF, Nurmohamed MT, van Doorn MBA, Spuls PI, van Tubergen AM, Ten Klooster PM, van Puijenbroek EP, Hoentjen F, Vonkeman HE. Gastrointestinal Adverse Drug Reaction Profile of Etanercept: Real-world Data From Patients and Healthcare Professionals. J Rheumatol 2021; 48:1388-1394. [PMID: 33993115 DOI: 10.3899/jrheum.201373] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/26/2021] [Indexed: 02/07/2023]
Abstract
OBJECTIVE We aimed to describe the nature and frequency of gastrointestinal adverse drug reactions (GI-ADRs) of etanercept (ETN) using patient-reported and healthcare professional (HCP)-registered data and compared this frequency with the GI-ADR frequency of the widely used tumor necrosis factor-α inhibitor adalimumab (ADA). METHODS Reported GI-ADRs of ETN for rheumatic diseases were collected from the Dutch Biologic Monitor and DREAM registries. We described the clinical course of GI-ADRs and compared the frequency with ADA in both data sources using Fisher exact test. RESULTS Out of 416 patients using ETN for inflammatory rheumatic diseases in the Dutch Biologic Monitor, 25 (6%) patients reported 36 GI-ADRs. In the DREAM registries 11 GI-ADRs were registered for 9 patients (2.3%), out of 399 patients using ETN, with an incidence of 7.1 per 1000 patient-years. Most GI-ADRs consisted of diarrhea, nausea, and abdominal pain. GI-ADRs led to ETN discontinuation in 1 patient (4%) and dose adjustment in 4 (16%) in the Dutch Biologic Monitor. Eight GI-ADRs (73%) led to ETN discontinuation in the DREAM registries. The frequency of GI-ADRs of ETN did not significantly differ from GI-ADRs of ADA in both data sources (Dutch Biologic Monitor: ETN 8.7% vs ADA 5.3%, P = 0.07; DREAM: ETN 2.8% vs ADA 4.7%, P = 0.16). CONCLUSION Most GI-ADRs associated with ETN concerned gastrointestinal symptoms. These ADRs may lead to dose adjustment or ETN discontinuation. The frequency of ETN-associated GI-ADRs was comparable to the frequency of ADA-associated GI-ADRs. Knowledge about these previously unknown ADRs can facilitate early recognition and improve patient communication.
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Affiliation(s)
- Jette A van Lint
- J.A. van Lint, PharmD, N.T. Jessurun, PharmD, Netherlands Pharmacovigilance Centre Lareb, 's-Hertogenbosch;
| | - Naomi T Jessurun
- J.A. van Lint, PharmD, N.T. Jessurun, PharmD, Netherlands Pharmacovigilance Centre Lareb, 's-Hertogenbosch
| | - Sander W Tas
- S.W. Tas, MD, PhD, Department of Rheumatology & Clinical Immunology, Amsterdam UMC, location Academic Medical Center, University of Amsterdam, Amsterdam Infection & Immunity Institute and Amsterdam Rheumatology & immunology Center (ARC), Amsterdam
| | - Bart J F van den Bemt
- B.J.F. van den Bemt, PharmD, Prof. Dr., Department of Pharmacy, Sint Maartenskliniek, and Department of Pharmacy, Radboud University Medical Center, Nijmegen
| | - Michael T Nurmohamed
- M.T. Nurmohamed, MD, Prof. Dr., Amsterdam Rheumatology & immunology Center (ARC), Reade, and Department of Rheumatology, Amsterdam Rheumatology and Immunology Center, VU University Medical Center, Amsterdam
| | - Martijn B A van Doorn
- M.B. van Doorn, MD, PhD, Department of Dermatology, Erasmus MC, University Medical Center, Rotterdam
| | - Phyllis I Spuls
- P.I. Spuls, MD, Prof. Dr., Department of Dermatology, Public Health and Epidemiology, Immunity and Infections, Amsterdam UMC, location Academic Medical Center, Amsterdam
| | - Astrid M van Tubergen
- A.M. van Tubergen, MD, Prof. Dr., Department of Rheumatology, Maastricht University Medical Center, and Care and Public Health Research Institute (CAPHRI), Maastricht University, Maastricht
| | - Peter M Ten Klooster
- P.M. ten Klooster, PhD, Transparency in Healthcare BV, Hengelo, and Department of Psychology, Health & Technology, University of Twente, Enschede
| | - Eugene P van Puijenbroek
- E.P. van Puijenbroek, MD, Prof. Dr., Netherlands Pharmacovigilance Centre Lareb, 's-Hertogenbosch, and Department of Pharmacotherapy, Epidemiology & Economics, University of Groningen, Groningen
| | - Frank Hoentjen
- F. Hoentjen, MD, PhD, Department of Gastroenterology, Radboud University Medical Center, Nijmegen
| | - Harald E Vonkeman
- H.E. Vonkeman, MD, PhD, Department of Psychology, Health & Technology, University of Twente, and Department of Rheumatology and Clinical Immunology, Medisch Spectrum Twente, Enschede, the Netherlands
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14
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Giudici F, Cavalli T, Luceri C, Russo E, Zambonin D, Scaringi S, Ficari F, Fazi M, Amedei A, Tonelli F, Malentacchi C. Long-Term Follow-Up, Association between CARD15/NOD2 Polymorphisms, and Clinical Disease Behavior in Crohn's Disease Surgical Patients. Mediators Inflamm 2021; 2021:8854916. [PMID: 33708009 PMCID: PMC7932801 DOI: 10.1155/2021/8854916] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 02/04/2021] [Accepted: 02/08/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND CARD15/NOD2 is the most significant genetic susceptibility in Crohn's disease (CD) even though a relationship between the different polymorphisms and clinical phenotype has not been described yet. The study is aimed at analyzing, in a group of CD patients undergoing surgery, the relationship between CARD15/NOD2 polymorphisms and the clinical CD behavior after a long-term follow-up, in order to identify potential clinical biomarkers of prognosis. METHODS 191 surgical CD patients were prospectively characterized both for the main single nucleotide polymorphisms of CARD15/NOD2 and for many other environmental risk factors connected with the severe disease form. After a mean follow-up of 7.3 years, the correlations between clinical features and CD natural history were analyzed. RESULTS CARD15/NOD2 polymorphisms were significantly associated with younger age at diagnosis compared to wild type cases (p < 0.05). Moreover, patients carrying a 3020insC polymorphism presented a larger Δ between diagnosis and surgery (p = 0.0344). Patients carrying an hz881 and a 3020insC exhibited, respectively, a lower rate of responsiveness to azathioprine (p = 0.012), but no difference was found in biologic therapy. Finally, the risk of surgical recurrence was significantly associated, respectively, to age at diagnosis, to familial CD history, to diagnostic delay, to arthritis, and to the presence of perioperative complications. CONCLUSIONS 3020insC CARD15 polymorphism is associated with an earlier CD onset, and age at CD diagnosis < 27 years was confirmed to have a detrimental effect on its clinical course. In addition, the familiarity seems to be connected with a more aggressive postoperative course. Finally, for the first time, we have observed a lower rate of responsiveness to azathioprine in patients carrying an hz881 and a 3020insC.
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Affiliation(s)
- Francesco Giudici
- Department of Clinical and Experimental Medicine, Surgical Unit, University of Florence, Italy
| | - Tiziana Cavalli
- Department of Clinical and Experimental Medicine, Surgical Unit, University of Florence, Italy
| | - Cristina Luceri
- Department of Neuroscience, Psychology, Pharmacology and Child Health (NEUROFARBA), Italy
| | - Edda Russo
- Department of Clinical and Experimental Medicine, Surgical Unit, University of Florence, Italy
| | - Daniela Zambonin
- Department of Clinical and Experimental Medicine, Surgical Unit, University of Florence, Italy
| | - Stefano Scaringi
- Department of Clinical and Experimental Medicine, Surgical Unit, University of Florence, Italy
| | - Ferdinando Ficari
- Department of Clinical and Experimental Medicine, Surgical Unit, University of Florence, Italy
| | - Marilena Fazi
- Department of Clinical and Experimental Medicine, Surgical Unit, University of Florence, Italy
| | - Amedeo Amedei
- Department of Clinical and Experimental Medicine, Surgical Unit, University of Florence, Italy
| | - Francesco Tonelli
- Department of Clinical and Experimental Medicine, Surgical Unit, University of Florence, Italy
| | - Cecilia Malentacchi
- Department of Biomedical Experimental and Clinical Sciences, “Mario Serio”, Italy
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15
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Almon E, Shaaltiel Y, Sbeit W, Fich A, Schwartz D, Waterman M, Szlaifer M, Reuveni H, Amit-Cohen BC, Alon S, Chertkoff R, Paz A, Ilan Y. Novel Orally Administered Recombinant Anti-TNF Alpha Fusion Protein for the Treatment of Ulcerative Colitis: Results From a Phase 2a Clinical Trial. J Clin Gastroenterol 2021; 55:134-140. [PMID: 32501868 PMCID: PMC7803480 DOI: 10.1097/mcg.0000000000001314] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 12/23/2019] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND OBJECTIVE OPRX-106 is an orally administered BY2 plant cell-expressing recombinant TNF fusion protein (TNFR). Oral administration of OPRX-106 was shown to be safe and effective in inducing favorable anti-inflammatory immune modulation in humans. The current study was aimed at determining the safety and efficacy of OPRX-106 in patients with ulcerative colitis (UC). METHODS Twenty-five patients with active mild-to-moderate UC were enrolled in an open-label trial. Patients were randomized to receive 2 or 8 mg of OPRX-106 administered orally once daily, for 8 weeks. Patients were monitored for safety and efficacy including clinical response or clinical remission, based on the Mayo score. The histopathological improvement in Geboes score, calprotectin level and hs-CRP, and exploratory immune parameters by means of fluorescence-activated cell sorting and cytokine levels were monitored. RESULTS Oral administration of OPRX-106 was found to be safe and well tolerated without absorption into the circulation. Out of 24 patients, 18 completed the trial. The analysis of the patients completing treatment demonstrated clinical efficacy as measured by clinical response or remission in 67% and 28%, respectively. Reduction in calprotectin levels and improved Geboes score were noted in the majority of the treated patients. The beneficial clinical effect was associated with an increase in a CD4+CD25+FoxP3 subset of suppressor lymphocytes and a reduction in interleukin 6 and interferon gamma serum levels. CONCLUSIONS Oral administration of the nonabsorbable OPRX-106 is safe and effective in mild-to-moderate UC, and not associated with immune suppression, while inducing favorable anti-inflammatory immune modulation.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | - Yaron Ilan
- Hadassah Medical Center, Jerusalem, Israel
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16
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Kristjánsson VB, Lund SH, Gröndal G, Sveinsdóttir SV, Agnarsson HR, Jónasson JG, Björnsson ES. Increased risk of inflammatory bowel disease among patients treated with rituximab in Iceland from 2001 to 2018. Scand J Gastroenterol 2021; 56:46-52. [PMID: 33280485 DOI: 10.1080/00365521.2020.1854847] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Immune-mediated diseases are on the rise after the introduction of powerful immunomodulating drugs. The objective of this study was to determine the population-based incidence rate of inflammatory bowel disease (IBD) among patients treated with the monoclonal antibody rituximab in Iceland and compare it to the baseline incidence rate of IBD in the general population. METHODS We identified all patients treated with rituximab in Iceland from 2001 to 2018 through a central medicine database. IBD cases were indexed from medical records and ICD-10 codes and further confirmed by colonoscopy- and pathology reports. An experienced pathologist compared the pathology of IBD cases with matched controls of IBD patients. RESULTS Lymphomas and related neoplasms were the most frequent indication for treatment with rituximab (n = 367) among the 651 patients included in the analysis. Following treatment, seven patients developed IBD: two cases of Crohn's disease, three with ulcerative colitis, and two with indeterminate IBD. The incidence rate of IBD among rituximab treated patients was 202 cases per 100,000 person-years. Comparing our data to IBD incidence in Iceland, rituximab treated patients have an age-adjusted hazard ratio of 6.6 for developing IBD. The risk did not correlate with dose or treatment duration. Prior diagnosis of an autoimmune illness did not increase the risk of IBD in rituximab treated patients. CONCLUSIONS Patients on rituximab have a sixfold increased risk of developing IBD compared to the general population. This risk was not affected by the indication for treatment and was not associated with concurrent immune-mediated diseases. Summary This population-based retrospective cohort study included all patients receiving treatment with rituximab between 2001 and 2018 in Iceland and identified a sixfold increased risk of developing IBD when compared to the general population.
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Affiliation(s)
| | - Sigrún H Lund
- Faculty of Medicine, University of Iceland, Reykjavík, Iceland
| | - Gerður Gröndal
- Faculty of Medicine, University of Iceland, Reykjavík, Iceland.,Department of Internal Medicine, National University Hospital, Reykjavík, Iceland
| | - Signý V Sveinsdóttir
- Department of Internal Medicine, National University Hospital, Reykjavík, Iceland
| | - Hjálmar R Agnarsson
- Department of Internal Medicine, National University Hospital, Reykjavík, Iceland
| | - Jón G Jónasson
- Faculty of Medicine, University of Iceland, Reykjavík, Iceland.,Department of Pathology, National University Hospital, Reykjavík, Iceland
| | - Einar S Björnsson
- Faculty of Medicine, University of Iceland, Reykjavík, Iceland.,Department of Internal Medicine, National University Hospital, Reykjavík, Iceland.,Division of Gastroenterology and Hepatology, Department of Internal Medicine, National University Hospital, Reykjavík, Iceland
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17
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Importance of Not MSing Cerebral White Matter Disease in Patients with Inflammatory Bowel Disease. Dig Dis Sci 2020; 65:2527-2532. [PMID: 32651742 DOI: 10.1007/s10620-020-06449-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
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18
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Ghouri YA, Tahan V, Shen B. Secondary causes of inflammatory bowel diseases. World J Gastroenterol 2020; 26:3998-4017. [PMID: 32821067 PMCID: PMC7403802 DOI: 10.3748/wjg.v26.i28.3998] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 05/15/2020] [Accepted: 07/16/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel diseases (IBD), conventionally consist of Crohn's disease (CD) and ulcerative colitis. They occur in individuals with high risk genotype for the disease in the setting of appropriate environmental factors. The pathogenesis of IBD involves a dysregulated autoimmune response to gut dysbiosis, which in turn is triggered due to exposure to various inciting environmental factors. But there is no clearly defined etiology of IBD and this type of disease is termed as "idiopathic IBD", "classic IBD", or "primary IBD". We reviewed the current medical literature and found that certain etiological factors may be responsible for the development of IBD or IBD-like conditions, and we consider this form of de novo IBD as "secondary IBD". Currently known factors that are potentially responsible for giving rise to secondary IBD are medications; bowel altering surgeries and transplantation of organs, stem cells or fecal microbiome. Medications associated with the development of secondary IBD include; immunomodulators, anti-tumor necrosis factor alpha agents, anti-interleukin agents, interferons, immune stimulating agents and checkpoint inhibitors. Colectomy can in some cases give rise to de novo CD, pouchitis of the ileal pouch, or postcolectomy enteritis syndrome. After solid organ transplantation or hematopoietic stem cell transplantation, the recipient may develop de novo IBD or IBD flare. Fecal microbiota transplantation has been widely used to treat patients suffering from recurrent Clostridium difficile infection but can also causes IBD flares.
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Affiliation(s)
- Yezaz A Ghouri
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Missouri- School of Medicine, Columbia, MO 65201, United States
| | - Veysel Tahan
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Missouri- School of Medicine, Columbia, MO 65201, United States
| | - Bo Shen
- Department of Medicine and Surgery, Interventional IBD Center, Columbia University Irving Medical Center/New York Presbyterian Hospital, New York, NY 10032, United States
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19
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Landis MN. Optimizing Isotretinoin Treatment of Acne: Update on Current Recommendations for Monitoring, Dosing, Safety, Adverse Effects, Compliance, and Outcomes. Am J Clin Dermatol 2020; 21:411-419. [PMID: 32107726 DOI: 10.1007/s40257-020-00508-0] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Acne vulgaris is the most common skin disease treated by dermatologists. It can be severe and result in permanent scars. Isotretinoin is the most effective treatment for acne and has the potential for long-term clearance. Prescribing and monitoring protocols can vary widely among prescribers. Recent studies, reports, and consensus statements help shed light on optimizing the use of isotretinoin for acne. A recent literature review is summarized in this article to help the practitioner optimize isotretinoin use for acne. The article outlines the advantages and disadvantages of standard, high-dose, and low-dose isotretinoin regimens; discusses the current status of controversies surrounding isotretinoin (including depression/suicide, pregnancy, and inflammatory bowel disease); reviews monitoring recommendations and treatment for hypertriglyceridemia and elevated transaminase levels; and discusses common adverse effects seen with isotretinoin, along with their treatment and prevention.
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Affiliation(s)
- Megan N Landis
- Department of Medicine (Dermatology), University of Louisville School of Medicine, Louisville, KY, USA.
- The Dermatology and Skin Cancer Center of Southern Indiana, Corydon, IN, USA.
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20
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Wang T, Yang JY, Buse JB, Pate V, Tang H, Barnes EL, Sandler RS, Stürmer T. Dipeptidyl Peptidase 4 Inhibitors and Risk of Inflammatory Bowel Disease: Real-world Evidence in U.S. Adults. Diabetes Care 2019; 42:2065-2074. [PMID: 31471377 PMCID: PMC6804610 DOI: 10.2337/dc19-0162] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 08/01/2019] [Indexed: 02/06/2023]
Abstract
OBJECTIVE A recent study raises concerns that dipeptidyl peptidase 4 inhibitors (DPP4i) are associated with increased risk of inflammatory bowel disease (IBD). We evaluated the association between new use of DPP4i and IBD risk compared with other second-line antihyperglycemics. RESEARCH DESIGN AND METHODS We implemented an active-comparator, new-user cohort design using two U.S. administrative claims databases for commercially insured (MarketScan) and older adult (Medicare fee-for-service, 20% random sample) patients from January 2007 to December 2016. We identified patients, aged ≥18 years, who initiated DPP4i versus sulfonylureas (SUs) or initiated DPP4i versus thiazolidinediones (TZDs) and were without prior diagnosis, treatment, or procedure for IBD. The primary outcome was incident IBD, defined by IBD diagnosis preceded by colonoscopy and biopsy and followed by IBD treatment. We performed propensity score weighting to control for measured baseline confounding, estimated adjusted hazard ratios (aHRs [95% CI]) using weighted Cox proportional hazards models, and used random-effects meta-analysis models to pool aHRs across cohorts. RESULTS We identified 895,747 eligible patients initiating DPP4i, SU, or TZD; IBD incidence rates ranged from 11.6 to 32.3/100,000 person-years. Over a median treatment duration of 1.09-1.69 years, DPP4i were not associated with increased IBD risk across comparisons. The pooled aHRs for IBD were 0.82 (95% CI 0.41-1.61) when comparing DPP4i (n = 161,612) to SU (n = 310,550) and 0.76 (0.46-1.26) when comparing DPP4i (n = 205,570) to TZD (n = 87,543). CONCLUSIONS Our population-based cohort study of U.S. adults with diabetes suggests that short-term DPP4i treatment does not increase IBD risk.
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Affiliation(s)
- Tiansheng Wang
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Jeff Y Yang
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - John B Buse
- Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Virginia Pate
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Huilin Tang
- Institute for Drug Evaluation, Peking University Health Science Center, Beijing, China
| | - Edward L Barnes
- Center for Gastrointestinal Biology and Disease, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Robert S Sandler
- Center for Gastrointestinal Biology and Disease, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - Til Stürmer
- Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC
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22
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Radel JA, Pender DN, Shah SA. Dipeptidyl Peptidase-4 Inhibitors and Inflammatory Bowel Disease Risk: A Meta-analysis. Ann Pharmacother 2019; 53:697-704. [PMID: 30700100 DOI: 10.1177/1060028019827852] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Dipeptidyl peptidase 4 (DPP-4) inhibitors are a popular second-line treatment for type 2 diabetes mellitus. Several studies have reported on the association between DPP-4 inhibitors and the risk of developing inflammatory bowel disease (IBD), with conflicting results. OBJECTIVE This meta-analysis aims to elucidate the risk for IBD with DPP-4 inhibitor therapy. METHODS A comprehensive search of PubMed/MEDLINE, CINAHL, the Cochrane Database, ClinicalTrials.gov, and the European Clinical Trials Database was performed (December 2018). All controlled clinical trials and observational studies of DPP-4 inhibitors that reported events of IBD, Crohn's disease (CD), ulcerative colitis (UC) or colitis and had a duration ≥52 weeks were included. The DerSimonian and Laird random-effects model was utilized to assess the relative risk (RR) for IBD post DPP-4 inhibitor exposure. RESULTS A total of 16 individual studies evaluating a total of 198 404 patients were included for analysis. Studies ranged from 52 weeks through 5 years. In the primary random-effects analysis, DPP-4 inhibitor exposure resulted in a nonsignificant increase in the risk of IBD (RR = 1.52; 95% CI = 0.72 to 3.24; I2 = 54.2%). Sensitivity analysis using a fixed-effects model demonstrated significantly increased risk (RR = 3.01; 95% CI = 2.30-3.93). DPP-4 inhibitor use significantly increased the risk of CD (RR = 2.47; 95% CI = 1.36 to 4.48). All findings were driven by the inclusion of 1 large study. Conclusion and Relevance: Based on a conservative random-effects analysis, DPP-4 inhibitors do not appear to increase the risk of developing inflammatory bowel disease. However, long-term postmarketing surveillance is warranted.
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Affiliation(s)
- Joshua A Radel
- 1 David Grant USAF Medical Center, Travis Air Force Base, CA, USA
| | | | - Sachin A Shah
- 1 David Grant USAF Medical Center, Travis Air Force Base, CA, USA.,2 University of the Pacific, Stockton, CA, USA
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23
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Ribaldone DG, Pellicano R, Actis GC. Pathogenesis of Inflammatory Bowel Disease: Basic Science in the Light of Real-World Epidemiology. GASTROINTESTINAL DISORDERS 2018; 1:129-146. [DOI: 10.3390/gidisord1010010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Major advances in the last few decades have favored the view of inflammatory bowel disease (IBD) as a disease of hyper- or, more often, paradoxical hyporesponsiveness of the gut-associated immune system. The relevant pivot seems to be the loss of the balance between gut-associated pro-inflammatory lymphocytes and the indwelling microbiome species, with inner regulatory circuits (regulatory T-lymphocytes, T-reg) and outer factors (such as drugs, tobacco, diet components) contributing to complicate the matter. Light might be shed by the observation of the real-world IBD epidemiology, which may help unveil the factors that tend to cluster IBD cases to certain geographical areas. A transitional mind frame between bench and real-world gastroenterology could hopefully contribute to restrain the mounting epidemic of IBD in the Western world and to halt the more recent increases seen in many Eastern countries.
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Affiliation(s)
| | - Rinaldo Pellicano
- Department of General and Specialist Medicine, Molinette Medical Center, 10126 Turin, Italy
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Flannigan KL, Taylor MR, Pereira SK, Rodriguez-Arguello J, Moffat AW, Alston L, Wang X, Poon KK, Beck PL, Rioux KP, Jonnalagadda M, Chelikani PK, Galipeau HJ, Lewis IA, Workentine ML, Greenway SC, Hirota SA. An intact microbiota is required for the gastrointestinal toxicity of the immunosuppressant mycophenolate mofetil. J Heart Lung Transplant 2018; 37:1047-1059. [PMID: 30173823 DOI: 10.1016/j.healun.2018.05.002] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Revised: 04/04/2018] [Accepted: 05/07/2018] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Mycophenolate mofetil (MMF) is commonly prescribed after transplantation and has major advantages over other immunosuppressive drugs, but frequent gastrointestinal (GI) side-effects limit its use. The mechanism(s) underlying MMF-related GI toxicity have yet to be elucidated. METHODS To investigate MMF-related GI toxicity, experimental mice were fed chow containing MMF (0.563%) and multiple indices of toxicity, including weight loss and colonic inflammation, were measured. Changes in intestinal microbial composition were detected using 16S rRNA Illumina sequencing, and downstream PICRUSt analysis was used to predict metagenomic pathways involved. Germ-free (GF) mice and mice treated with orally administered broad-spectrum antibiotics (ABX) were utilized to interrogate the importance of the microbiota in MMF-induced GI toxicity. RESULTS Mice treated with MMF exhibited significant weight loss, related to loss of body fat and muscle, and marked colonic inflammation. MMF exposure was associated with changes in gut microbial composition, as demonstrated by a loss of overall diversity, expansion of Proteobacteria (specifically Escherichia/Shigella), and enrichment of genes involved in lipopolysaccharide (LPS) biosynthesis, which paralleled increased levels of LPS in the feces and serum. MMF-related GI toxicity was dependent on the intestinal microbiota, as MMF did not induce weight loss or colonic inflammation in GF mice. Furthermore, ABX prevented and reversed MMF-induced weight loss and colonic inflammation. CONCLUSIONS An intact intestinal microbiota is required to initiate and sustain the GI toxicity of MMF. MMF treatment causes dynamic changes in the composition of the intestinal microbiota that may be a targetable driver of the GI side-effects of MMF.
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Affiliation(s)
- Kyle L Flannigan
- Department of Physiology and Pharmacology, Cumming School of Medicine; Snyder Institute for Chronic Diseases.
| | - Michael R Taylor
- Department of Paediatrics and Alberta Children's Hospital Research Institute, Cumming School of Medicine
| | - Sheldon K Pereira
- Snyder Institute for Chronic Diseases; Department of Paediatrics and Alberta Children's Hospital Research Institute, Cumming School of Medicine
| | - Jimena Rodriguez-Arguello
- Department of Paediatrics and Alberta Children's Hospital Research Institute, Cumming School of Medicine
| | - Andrew W Moffat
- Department of Paediatrics and Alberta Children's Hospital Research Institute, Cumming School of Medicine
| | - Laurie Alston
- Department of Physiology and Pharmacology, Cumming School of Medicine; Snyder Institute for Chronic Diseases
| | - Xuemei Wang
- Department of Paediatrics and Alberta Children's Hospital Research Institute, Cumming School of Medicine; Department of Cardiac Sciences and the Libin Cardiovascular Institute of Alberta, Cumming School of Medicine
| | - Karen K Poon
- Snyder Institute for Chronic Diseases; Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine
| | - Paul L Beck
- Department of Physiology and Pharmacology, Cumming School of Medicine; Snyder Institute for Chronic Diseases; Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Kevin P Rioux
- Snyder Institute for Chronic Diseases; Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine; Division of Gastroenterology and Hepatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Mahesh Jonnalagadda
- Laboratory of Animal Medical Services, University of Cincinnati, Cincinnati, Ohio, USA
| | - Prasanth K Chelikani
- Department of Production, Animal Health, Faculty of Veterinary Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Heather J Galipeau
- Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | | | | | - Steven C Greenway
- Department of Paediatrics and Alberta Children's Hospital Research Institute, Cumming School of Medicine; Department of Cardiac Sciences and the Libin Cardiovascular Institute of Alberta, Cumming School of Medicine; Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Simon A Hirota
- Department of Physiology and Pharmacology, Cumming School of Medicine; Snyder Institute for Chronic Diseases; Department of Microbiology, Immunology and Infectious Diseases, Cumming School of Medicine
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25
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Rohr M, Narasimhulu CA, Sharma D, Doomra M, Riad A, Naser S, Parthasarathy S. Inflammatory Diseases of the Gut. J Med Food 2018; 21:113-126. [PMID: 29389238 DOI: 10.1089/jmf.2017.0138] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are chronic inflammatory disorders of the gastrointestinal tract whose prevalence has been dramatically increasing over the past decade. New studies have shown that IBD is the second most common chronic inflammatory disease worldwide after rheumatoid arthritis, affecting millions of people mainly in industrialized countries. Symptoms of IBD include frequent bloody diarrhea, abdominal cramping, anorexia, abdominal distension, and emesis. Although the exact etiology is unknown, it has been postulated that immunological, microbial, environmental, nutritional, and genetic factors contribute to the pathogenesis and severity of IBD. Today, no treatment has consistently been shown to be successful in treating IBD. This review summarizes current research on the epidemiology, etiology, pathophysiology, and existing treatment approaches, including pharmaceutical and nutritional options for IBD.
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Affiliation(s)
- Michael Rohr
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida , Orlando, Florida, USA
| | | | - Dhara Sharma
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida , Orlando, Florida, USA
| | - Mitsushita Doomra
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida , Orlando, Florida, USA
| | - Aladdin Riad
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida , Orlando, Florida, USA
| | - Saleh Naser
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida , Orlando, Florida, USA
| | - Sampath Parthasarathy
- Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida , Orlando, Florida, USA
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26
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Biopsy diagnosis of colitis: an algorithmic approach. Virchows Arch 2017; 472:67-80. [DOI: 10.1007/s00428-017-2274-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 11/06/2017] [Accepted: 11/19/2017] [Indexed: 12/17/2022]
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Akel R, Anouti B, Tfayli A. Late-Onset Inflammatory Bowel Disease-Like Syndrome after Ipilimumab Therapy: A Case Report. Case Rep Oncol 2017. [PMID: 28626406 PMCID: PMC5471790 DOI: 10.1159/000475709] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Antitumor immunotherapy has become a major player in cancer therapy. Ipilimumab is a humanized monoclonal antibody against the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), an important downregulator of T-cell activation. Ipilimumab has demonstrated tumor regression and improvement in overall survival in patients with metastatic melanoma. Unfortunately, immune activation induced by this drug has been associated with several immune-mediated adverse effects, namely diarrhea and colitis. CASE PRESENTATION We report the case of a 71-year-old male patient diagnosed with BRAF wild-type metastatic melanoma treated with three cycles of ipilimumab, after which he developed grade 3 enteritis. The patient improved on treatment with steroids, and ipilimumab was permanently discontinued at this point. Three years later, the patient's diarrhea returned and colonoscopy revealed active chronic colitis with ulceration resembling inflammatory bowel disease. He was started on Asacol (mesalamine). The patient did not report extraintestinal symptoms typically associated with inflammatory bowel disease, nor did he have a personal or family history of bowel disorders. Moreover, his presentation was not typical of inflammatory bowel disease in the elderly. CONCLUSION Our findings suggest a link between ipilimumab-induced grade 3 enteritis and late-onset inflammatory bowel disease-like syndrome. To our knowledge, the case is the first in the literature to report late-onset inflammatory bowel disease-like syndrome years after discontinuation of ipilimumab treatment.
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Affiliation(s)
- Reem Akel
- Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut, Beirut, Lebanon
| | - Bilal Anouti
- Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut, Beirut, Lebanon
| | - Arafat Tfayli
- Division of Hematology and Oncology, Department of Internal Medicine, American University of Beirut, Beirut, Lebanon
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28
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Wang B, Wu C. Dietary soy isoflavones alleviate dextran sulfate sodium-induced inflammation and oxidative stress in mice. Exp Ther Med 2017; 14:276-282. [PMID: 28672925 PMCID: PMC5488499 DOI: 10.3892/etm.2017.4469] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2015] [Accepted: 02/24/2017] [Indexed: 01/10/2023] Open
Abstract
It has been hypothesized that soy isoflavones exhibit anti-oxidative and anti-inflammatory functions, however, the effects of soy isoflavones on inflammatory bowel diseases remain unknown. Therefore, the present study aimed to investigate the effect and underlying mechanism of dietary soy isoflavones on dextran sulfate sodium (DSS)-induced colitis. Mice were administered DSS and soy isoflavones, and histomorphometry, oxidative stress, inflammation and intestinal tight junctions were determined. The current study demonstrated that dietary soy isoflavones alleviated DSS-induced growth suppression, colonic inflammatory response, oxidative stress and colonic barrier dysfunction. DSS treatment was indicated to activate Toll-like receptor 4 (TRL4) and myeloid differentiation protein 88 (MyD88) in mice, whereas dietary soy isoflavones inhibited Myd88 expression in DSS-challenged mice. In conclusion, dietary soy isoflavones alleviate DSS-induced inflammation in mice, which may be associated with enhancing antioxidant function and inhibiting the TLR4/MyD88 signal.
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Affiliation(s)
- Bin Wang
- Department of Food and Nutritional Engineering, Jiangsu Food and Pharmaceutical Science College, Huaian, Jiangsu 223005, P.R. China
| | - Cunbing Wu
- Department of Food Engineering, Jiangsu Polytechnic of Finance and Economics, Huaian, Jiangsu 223005, P.R. China
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Chen X, Liu XS. Hydrogen sulfide from a NaHS source attenuates dextran sulfate sodium (DSS)-induced inflammation via inhibiting nuclear factor-κB. J Zhejiang Univ Sci B 2016; 17:209-17. [PMID: 26984841 DOI: 10.1631/jzus.b1500248] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
This study investigated the alleviating effects of hydrogen sulfide (H2S), derived from sodium hydrosulfide (NaHS), on inflammation induced by dextran sulfate sodium (DSS) in both in vivo and in vitro models. We found that NaHS injection markedly decreased rectal bleeding, diarrhea, and histological injury in DSS-challenged mice. NaHS (20 μmol/L) reversed DSS-induced inhibition in cell viability in Caco-2 cells and alleviated pro-inflammation cytokine expression in vivo and in vitro, indicating an anti-inflammatory function for H2S. It was also found that H2S may regulate cytokine expression by inhibiting the nuclear factor-κB (NF-κB) signaling pathway. In conclusion, our results demonstrated that H2S alleviated DSS-induced inflammation in vivo and in vitro and that the signal mechanism might be associated with the NF-κB signaling pathway.
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Affiliation(s)
- Xi Chen
- Medical College, Qingdao University, Qingdao 266021, China.,Department of Gastroenterology, Yantai Municipal Laiyang Central Hospital, Yantai 265200, China
| | - Xi-shuang Liu
- Medical College, Qingdao University, Qingdao 266021, China.,Department of Gastroenterology, the Affiliated Hospital of Qingdao University, Qingdao 266071, China
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Abstract
PURPOSE OF REVIEW Extraintestinal manifestations (EIMs) of inflammatory bowel disease (IBD) are numerous and can often involve the eye. This review highlights the ocular complications associated with IBD including the critical role the ophthalmologist can play in the diagnosis of IBD, the pathogenesis of IBD, its ocular complications, and the treatment of ocular inflammation associated with IBD. RECENT FINDINGS Polygenic and environmental influences, as well as gut microbial dysbiosis, have been implicated in the pathogenesis of IBD. IBD and its EIMs appear to respond well to TNFα-targeted biologics. SUMMARY IBD is thought to be caused by polygenic and environmental influences, including a dysbiotic gut microbiota. It is a systemic immune-mediated disease with varying types of ocular manifestations that can precede, occur simultaneously, or follow intestinal involvement. The diagnosis of IBD can be confused with other seronegative spondyloarthropathies as well as Behçet's disease. Treatment of IBD-associated ocular inflammation can range from corticosteroids to steroid-sparing immunosuppression such as azathioprine or methotrexate. Refractory disease can respond well to TNFα inhibitors.
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Affiliation(s)
- Akshay S Thomas
- Casey Eye Institute, Oregon Health and Sciences University, Portland, Oregon, USA
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31
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Ilan Y, Gingis-Velitski S, Ben Ya'aco A, Shabbat Y, Zolotarov L, Almon E, Shaaltiel Y. A plant cell-expressed recombinant anti-TNF fusion protein is biologically active in the gut and alleviates immune-mediated hepatitis and colitis. Immunobiology 2016; 222:544-551. [PMID: 27832933 DOI: 10.1016/j.imbio.2016.11.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2016] [Revised: 11/01/2016] [Accepted: 11/02/2016] [Indexed: 01/02/2023]
Abstract
The orally administered BY-2 plant cell-expressed recombinant anti-TNF fusion protein (PRX-106) (n=6) consists of the soluble form of the human TNF receptor (TNFR) fused to the Fc component of a human antibody IgG1 domain. AIM To evaluate the immune modulatory effect of the oral administration of plant cells expressing PRX-106. METHODS Mice treated with Concanavalin A (ConA) to induce immune hepatitis was orally treated with cells expressing PRX-106 containing 0.5 or 5μg PRX 106. In the colitis model, TNBS-colitis was induced in mice followed by the oral administration of plant cells expressing PRX-106. The immune modulatory effect was determined through follow-up to assess the clinical effect, histology, and serum cytokine levels and by FACS analysis for lymphocyte subsets. RESULTS The oral administration of BY-2 cells expressing PRX-106 alleviated immune-mediated liver injury. Serum AST and ALT levels decreased and were comparable to those of mice that had received high-dose steroids. The beneficial effect was also observed as a marked decrease in hepatic necrosis. In the colitis model, the oral administration of BY-2 plant cells expressing PRX-106 alleviated weight loss associated with immune-mediated colitis and improved bowel histology. A reduction in I-IkB-alpha phosphorylation in treated mice was also observed. These effects were associated with a significant alteration in the distribution of CD4+CD25+FOXP3+ cells. CONCLUSIONS Plant cells expressing recombinant anti-TNF fusion protein show biological activity when orally administered, exerting an immune modulatory effect through the alleviation of immune-mediated hepatitis and immune-mediated colitis.
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Affiliation(s)
- Yaron Ilan
- Gastroenterology and Liver Units, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
| | | | - Ami Ben Ya'aco
- Gastroenterology and Liver Units, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Yehudit Shabbat
- Gastroenterology and Liver Units, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Lidya Zolotarov
- Gastroenterology and Liver Units, Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel
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The role of small bowel capsule endoscopy and ileocolonoscopy in patients with nonspecific but suggestive symptoms of Crohn's disease. Eur J Gastroenterol Hepatol 2016; 28:882-9. [PMID: 27183502 DOI: 10.1097/meg.0000000000000644] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Ileocolonoscopy (IC) and small bowel capsule endoscopy (SBCE) are essential tools in the investigation of suspected small bowel Crohn's disease (CD). Overutilization of SBCE should be avoided as it leads to unwanted healthcare expenses; thus, it is recommended when IC is normal and CD is still highly suspected. Our aim was to compare the role of SBCE and IC in the investigation of suspected CD irrespective of its location and assess the additional diagnostic benefit of SBCE over IC. METHODS This was a retrospective study of 91 patients with chronic abdominal pain and/or diarrhea. All patients were evaluated with both colonoscopy (with terminal ileum intubation where possible) and SBCE. The severity of inflammation on SBCE was assessed using the Lewis Score. Endoscopic findings were analyzed toward CD diagnosis. RESULTS The sensitivity of IC and SBCE in the diagnosis of either small bowel or colonic CD was 81.82 and 63.64%, whereas the specificity was 77.50 and 92.50%, respectively. Positive and negative predictive value was 33.33 and 96.88% for IC, as well as 53.85 and 94.87% for SBCE. Area under receiver operating characteristic curve was 0.797 for IC and 0.781 for SBCE. IC was superior to SBCE in diagnosing small and large bowel CD. SBCE showed the true extent of CD in one patient missed by IC. It identified lesions suggestive of CD in three patients with normal IC, one of whom was finally diagnosed with CD. CONCLUSION IC should be the initial diagnostic test in patients with nonspecific, but suggestive symptoms of CD. SBCE offers additional information on small bowel mucosa and disease extent.
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Vlachos C, Gaitanis G, Katsanos KH, Christodoulou DK, Tsianos E, Bassukas ID. Psoriasis and inflammatory bowel disease: links and risks. PSORIASIS-TARGETS AND THERAPY 2016; 6:73-92. [PMID: 29387596 PMCID: PMC5683131 DOI: 10.2147/ptt.s85194] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Psoriasis and the spectrum of inflammatory bowel diseases (IBD) are chronic, inflammatory, organotropic conditions. The epidemiologic coexistence of these diseases is corroborated by findings at the level of disease, biogeography, and intrafamilial and intrapatient coincidence. The identification of shared susceptibility loci and DNA polymorphisms has confirmed this correlation at a genetic level. The pathogenesis of both diseases implicates the innate and adaptive segments of the immune system. Increased permeability of the epidermal barrier in skin and intestine underlies the augmented interaction of allergens and pathogens with inflammatory receptors of immune cells. The immune response between psoriasis and IBD is similar and comprises phagocytic, dendritic, and natural killer cell, along with a milieu of cytokines and antimicrobial peptides that stimulate T-cells. The interplay between dendritic cells and Th17 cells appears to be the core dysregulated immune pathway in all these conditions. The distinct similarities in the pathogenesis are also reflected in the wide overlapping of their therapeutic approaches. Small-molecule pharmacologic immunomodulators have been applied, and more recently, biologic treatments that target proinflammatory interleukins have been introduced or are currently being evaluated. However, the fact that some treatments are quite selective for either skin or gut conditions also highlights their crucial pathophysiologic differences. In the present review, a comprehensive comparison of risk factors, pathogenesis links, and therapeutic strategies for psoriasis and IBD is presented. Specific emphasis is placed on the role of the immune cell species and inflammatory mediators participating in the pathogenesis of these diseases.
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Affiliation(s)
| | | | - Konstantinos H Katsanos
- Division of Gastroenterology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Dimitrios K Christodoulou
- Division of Gastroenterology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
| | - Epameinondas Tsianos
- Division of Gastroenterology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece
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Tabanlioğlu Onan D, Hazar Tantoğlu B, Alli N, Özkan S, Samsar U, Köseoğlu HT, Artüz RF. Evaluation of the gastrointestinal findings of nodulocystic acnepatients during systemic isotretinoin therapy. Turk J Med Sci 2016; 46:820-4. [PMID: 27513262 DOI: 10.3906/sag-1412-142] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Accepted: 08/22/2015] [Indexed: 11/03/2022] Open
Abstract
BACKGROUND/AIM Systemic isotretinoin treatment is an effective treatment modality for nodulocystic acne, the clinical use of which has been associated with reports of adverse events. We conducted a prospective study with the aim of determining the possible gastrointestinal and laboratory findings of nodulocystic acne patients during systemic isotretinoin treatment. MATERIALS AND METHODS Seventy patients with nodulocystic acne completed the study. During the monthly follow-up visits, liver function tests and lipid profiles of the patients were evaluated and gastrointestinal system complaints were examined. RESULTS We recorded a significant elevation in liver function tests and lipid profiles of the patients, the most prominent elevation being in plasma triglyceride concentrations. We observed that nausea, dyspepsia, abdominal pain, and diarrhea were the rare gastrointestinal symptoms encountered during systemic isotretinoin therapy. Constipation and anorectal bleeding were relatively more common symptoms and there seemed to be a relation between these two symptoms. CONCLUSION Our study is the first to analyze the gastrointestinal findings of patients during systemic isotretinoin treatment. Dermatologists and gastroenterologists must keep in mind that, as well as known laboratory findings like hypertriglyceridemia and elevated liver function tests, systemic isotretinoin therapy may also cause significant clinical gastrointestinal findings.
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Affiliation(s)
- Duru Tabanlioğlu Onan
- Department of Dermatology, Ankara Numune Training and Research Hospital, Ankara, Turkey
| | - Burcu Hazar Tantoğlu
- Department of Dermatology, Ankara Numune Training and Research Hospital, Ankara, Turkey
| | - Nuran Alli
- Department of Dermatology, Ankara Numune Training and Research Hospital, Ankara, Turkey
| | - Seçil Özkan
- Department of Public Health, Faculty of Medicine, Gazi University, Ankara, Turkey
| | - Ufuk Samsar
- Gastroenterology Unit, Konya Numune Hospital, Konya, Turkey
| | - Hasan Tankut Köseoğlu
- Department of Gastroenterology, Ankara Numune Training and Research Hospital, Ankara, Turkey
| | - Refika Ferda Artüz
- Department of Dermatology, Ankara Numune Training and Research Hospital, Ankara, Turkey
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Zaenglein AL, Pathy AL, Schlosser BJ, Alikhan A, Baldwin HE, Berson DS, Bowe WP, Graber EM, Harper JC, Kang S, Keri JE, Leyden JJ, Reynolds RV, Silverberg NB, Stein Gold LF, Tollefson MM, Weiss JS, Dolan NC, Sagan AA, Stern M, Boyer KM, Bhushan R. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol 2016; 74:945-73.e33. [PMID: 26897386 DOI: 10.1016/j.jaad.2015.12.037] [Citation(s) in RCA: 778] [Impact Index Per Article: 86.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 12/15/2015] [Indexed: 02/06/2023]
Abstract
Acne is one of the most common disorders treated by dermatologists and other health care providers. While it most often affects adolescents, it is not uncommon in adults and can also be seen in children. This evidence-based guideline addresses important clinical questions that arise in its management. Issues from grading of acne to the topical and systemic management of the disease are reviewed. Suggestions on use are provided based on available evidence.
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Affiliation(s)
| | | | | | | | | | - Diane S Berson
- Weill Cornell Medical College, New York, New York; New York Presbyterian Hospital, New York, New York
| | - Whitney P Bowe
- SUNY Down State Medical Center-Brooklyn, New York, New York
| | - Emmy M Graber
- Boston University School of Medicine, Boston, Massachusetts; Boston Medical Center, Boston, Massachusetts
| | | | - Sewon Kang
- Johns Hopkins Medicine, Baltimore, Maryland
| | - Jonette E Keri
- University of Miami Health System, Miami, Florida; Miami VA Hospital, Miami, Florida
| | | | - Rachel V Reynolds
- Harvard Medical Faculty Physicians, Boston, Massachusetts; Beth Israel Deaconess Medical Center, Boston, Massachusetts
| | - Nanette B Silverberg
- Mount Sinai Health System-Beth Israel, New York, New York; St. Lukes-Roosevelt, New York, New York
| | | | | | | | | | | | | | - Kevin M Boyer
- American Academy of Dermatology, Schaumburg, Illinois
| | - Reva Bhushan
- American Academy of Dermatology, Schaumburg, Illinois.
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36
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Legaki E, Gazouli M. Influence of environmental factors in the development of inflammatory bowel diseases. World J Gastrointest Pharmacol Ther 2016; 7:112-125. [PMID: 26855817 PMCID: PMC4734944 DOI: 10.4292/wjgpt.v7.i1.112] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2015] [Revised: 10/20/2015] [Accepted: 12/03/2015] [Indexed: 02/06/2023] Open
Abstract
Idiopathic inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), are multifactorial diseases that are manifested after disruption of a genetic predisposed individual and its intestinal microflora through an environmental stimulus. Urbanization and industrialization are associated with IBD. Epidemiological data, clinical observations and family/immigrants studies indicate the significance of environmental influence in the development of IBD. Some environmental factors have a different effect on the subtypes of IBD. Smoking and appendectomy is negatively associated with UC, but they are aggravating factors for CD. A westernized high fat diet, full of refined carbohydrates is strongly associated with the development of IBD, contrary to a high in fruit, vegetables and polyunsaturated fatty acid-3 diet that is protective against these diseases. High intake of nonsteroidal antiinflammatory drug and oral contraceptive pills as well as the inadequacy of vitamin D leads to an increased risk for IBD and a more malignant course of disease. Moreover, other factors such as air pollution, psychological factors, sleep disturbances and exercise influence the development and the course of IBD. Epigenetic mechanism like DNA methylation, histone modification and altered expression of miRNAS could explain the connection between genes and environmental factors in triggering the development of IBD.
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Annese V, Beaugerie L, Egan L, Biancone L, Bolling C, Brandts C, Dierickx D, Dummer R, Fiorino G, Gornet JM, Higgins P, Katsanos KH, Nissen L, Pellino G, Rogler G, Scaldaferri F, Szymanska E, Eliakim R. European Evidence-based Consensus: Inflammatory Bowel Disease and Malignancies. J Crohns Colitis 2015; 9:945-965. [PMID: 26294789 DOI: 10.1093/ecco-jcc/jjv141] [Citation(s) in RCA: 318] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2015] [Accepted: 08/10/2015] [Indexed: 02/07/2023]
Affiliation(s)
- Vito Annese
- University Hospital Careggi, Department of Gastroenterology, Florence, Italy
| | - Laurent Beaugerie
- Department of Gastroenterology, AP-HP Hôpital Saint-Antoine, and UPMC Univ Paris 06, Paris, France
| | - Laurence Egan
- Pharmacology and Therapeutics, School of Medicine, National University of Ireland, Galway, Ireland
| | - Livia Biancone
- University Tor Vergata of Rome, GI Unit, Department of Systems Medicine, Rome, Italy
| | - Claus Bolling
- Agaplesion Markus Krankenhaus, Medizinische Klinik I, Frankfurt am Main, Germany
| | - Christian Brandts
- Department of Medicine, Hematology/Oncology, Goethe University, Frankfurt am Main, Germany
| | - Daan Dierickx
- Department of Haematology, University Hospital Leuven, Leuven, Belgium
| | - Reinhard Dummer
- Department of Dermatology, University Zürich, Zürich, Switzerland
| | - Gionata Fiorino
- Gastroenterology Department, Humanitas Research Hospital, Rozzano, Italy
| | - Jean Marc Gornet
- Service d'hépatogastroentérologie, Hopital Saint-Louis, Paris, France
| | - Peter Higgins
- University of Michigan, Department of Internal Medicine, Ann Arbor, USA
| | | | - Loes Nissen
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Gianluca Pellino
- Second University of Naples, Unit of Colorectal Surgery, Department of Medical, Surgical, Neurological, Metabolic and Ageing Sciences, Naples, Italy
| | - Gerhard Rogler
- Klinik für Gastroenterologie und Hepatologie, UniversitätsSpital Zürich, Zürich, Switzerland
| | - Franco Scaldaferri
- Università Cattolica del Sacro Cuore, Department of Internal Medicine, Gastroenterology Division, Roma, Italy
| | - Edyta Szymanska
- Department of Pediatrics, Nutrition and Metabolic Disorders, Children's Memorial Health Institute, Warsaw, Poland
| | - Rami Eliakim
- Department of Gastroenterology and Hepatology, Sheba Medical Center & Sackler School of Medicine, Israel
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C. JAIMELUBASCHER. ERRORES FRECUENTES EN EL DIAGNÓSTICO Y TRATAMIENTO DE LOS PACIENTES CON ENFERMEDAD INFLAMATORIA INTESTINAL. REVISTA MÉDICA CLÍNICA LAS CONDES 2015. [DOI: 10.1016/j.rmclc.2015.08.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Gupta A, De Felice KM, Loftus EV, Khanna S. Systematic review: colitis associated with anti-CTLA-4 therapy. Aliment Pharmacol Ther 2015; 42:406-417. [PMID: 26079306 DOI: 10.1111/apt.13281] [Citation(s) in RCA: 199] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Revised: 03/11/2015] [Accepted: 05/27/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) has an important role in T-cell regulation, proliferation and tolerance. Anti-CTLA-4 agents, such as ipilimumab and tremelimumab, have been shown to prolong overall survival in patients with metastatic melanoma, and their use is being investigated in the treatment of other malignancies. Their novel immunostimulatory mechanism, however, predisposes patients to immune-related adverse effects, of which gastrointestinal effects such as diarrhoea and colitis are the most common. AIMS To discuss the existing literature and summarise the epidemiology, pathogenesis and clinical features of anti-CTLA-4-associated colitis, and to present a management algorithm for it. METHODS We searched PubMed for studies published through October 2014 using the terms 'anti-CTLA,' 'ipilimumab,' 'tremelimumab,' 'colitis,' 'gastrointestinal,' 'immune-related adverse effect,' 'immunotherapy,' 'melanoma,' and 'diarrhoea.' RESULTS Watery diarrhoea is commonly associated with anti-CTLA-4 therapy (27-54%), and symptoms occur within a few days to weeks of therapy. Diffuse acute and chronic colitis are the most common findings on endoscopy (8-22%). Concomitant infectious causes of diarrhoea must be evaluated. Most cases may be successfully managed with discontinuation of anti-CTLA-4 and conservative therapy. Those with persistent grade 2 and grade 3/4 diarrhoea should undergo endoscopic evaluation and require corticosteroid therapy. Corticosteroid-resistant cases may respond to anti-tumour necrosis factor-alpha therapy such as infliximab. Surgery is reserved for patients with bowel perforation or failure of medical therapy. CONCLUSION Given the increasing use of anti-CTLA-4 therapy, clinicians must be aware of related adverse events and their management.
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Affiliation(s)
- A Gupta
- Department of Internal Medicine, University of Texas, Southwestern Medical Center, Dallas, TX, USA
| | - K M De Felice
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - E V Loftus
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - S Khanna
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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Enterococcus faecalis Gelatinase Mediates Intestinal Permeability via Protease-Activated Receptor 2. Infect Immun 2015; 83:2762-70. [PMID: 25916983 DOI: 10.1128/iai.00425-15] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Accepted: 04/17/2015] [Indexed: 12/11/2022] Open
Abstract
Microbial protease-mediated disruption of the intestinal epithelium is a potential mechanism whereby a dysbiotic enteric microbiota can lead to disease. This mechanism was investigated using the colitogenic, protease-secreting enteric microbe Enterococcus faecalis. Caco-2 and T-84 epithelial cell monolayers and the mouse colonic epithelium were exposed to concentrated conditioned media (CCM) from E. faecalis V583 and E. faecalis lacking the gelatinase gene (gelE). The flux of fluorescein isothiocyanate (FITC)-labeled dextran across monolayers or the mouse epithelium following exposure to CCM from parental or mutant E. faecalis strains indicated paracellular permeability. A protease-activated receptor 2 (PAR2) antagonist and PAR2-deficient (PAR2(-/-)) mice were used to investigate the role of this receptor in E. faecalis-induced permeability. Gelatinase (GelE) purified from E. faecalis V583 was used to confirm the ability of this protease to induce epithelial cell permeability and activate PAR2. The protease-mediated permeability of colonic epithelia from wild-type (WT) and PAR2(-/-) mice by fecal supernatants from ulcerative colitis patients was assessed. Secreted E. faecalis proteins induced permeability in epithelial cell monolayers, which was reduced in the absence of gelE or by blocking PAR2 activity. Secreted E. faecalis proteins induced permeability in the colonic epithelia of WT mice that was absent in tissues from PAR2(-/-) mice. Purified GelE confirmed the ability of this protease to induce epithelial cell permeability via PAR2 activation. Fecal supernatants from ulcerative colitis patients induced permeability in the colonic epithelia of WT mice that was reduced in tissues from PAR2(-/-) mice. Our investigations demonstrate that GelE from E. faecalis can regulate enteric epithelial permeability via PAR2.
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Krishnan A, Stobaugh DJ, Deepak P. Assessing the likelihood of new-onset inflammatory bowel disease following tumor necrosis factor-alpha inhibitor therapy for rheumatoid arthritis and juvenile rheumatoid arthritis. Rheumatol Int 2014; 35:661-8. [DOI: 10.1007/s00296-014-3133-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Accepted: 09/09/2014] [Indexed: 02/06/2023]
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Philpott HL, Nandurkar S, Lubel J, Gibson PR. Drug-induced gastrointestinal disorders. Frontline Gastroenterol 2014; 5:49-57. [PMID: 28839751 PMCID: PMC5369702 DOI: 10.1136/flgastro-2013-100316] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2013] [Accepted: 05/16/2013] [Indexed: 02/04/2023] Open
Abstract
Drug-induced gastrointestinal disorders can mimic conditions, such as inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) and, hence, recognition can prevent unnecessary investigations and treatment. While the knowledge and awareness relating to the adverse gastrointestinal effects of some medications, such as non-steroidal anti-inflammatory drugs are well established, other commonly prescribed drugs, such as antipsychotics, antidepressants and metformin are less well understood and warrant further study. This review attempts to integrate recent information regarding adverse drug reactions and place this in a useful clinical context.
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Affiliation(s)
- H L Philpott
- Department of Gastroenterology, Monash University, Eastern Health, Melbourne, Victoria, Australia,Box Hill Hospital, Melbourne, Australia,The Alfred Hospital, Melbourne, Australia
| | - S Nandurkar
- Department of Gastroenterology, Monash University, Eastern Health, Melbourne, Victoria, Australia,Box Hill Hospital, Melbourne, Australia
| | - J Lubel
- Department of Gastroenterology, Monash University, Eastern Health, Melbourne, Victoria, Australia,Box Hill Hospital, Melbourne, Australia
| | - P R Gibson
- Department of Gastroenterology, Monash University, Eastern Health, Melbourne, Victoria, Australia,Box Hill Hospital, Melbourne, Australia,The Alfred Hospital, Melbourne, Australia
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Carroll IM, Maharshak N. Enteric bacterial proteases in inflammatory bowel disease- pathophysiology and clinical implications. World J Gastroenterol 2013; 19:7531-7543. [PMID: 24431894 PMCID: PMC3837251 DOI: 10.3748/wjg.v19.i43.7531] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2013] [Revised: 10/05/2013] [Accepted: 11/05/2013] [Indexed: 02/06/2023] Open
Abstract
Numerous reports have identified a dysbiosis in the intestinal microbiota in patients suffering from inflammatory bowel diseases (IBD), yet the mechanism(s) in which this complex microbial community initiates or perpetuates inflammation remains unclear. The purpose of this review is to present evidence for one such mechanism that implicates enteric microbial derived proteases in the pathogenesis of IBD. We highlight and discuss studies demonstrating that proteases and protease receptors are abundant in the digestive system. Additionally, we investigate studies demonstrating an association between increased luminal protease activity and activation of protease receptors, ultimately resulting in increased intestinal permeability and exacerbation of colitis in animal models as well as in human IBD. Proteases are essential for the normal functioning of bacteria and in some cases can serve as virulence factors for pathogenic bacteria. Although not classified as traditional virulence factors, proteases originating from commensal enteric bacteria also have a potential association with intestinal inflammation via increased enteric permeability. Reports of increased protease activity in stools from IBD patients support a possible mechanism for a dysbiotic enteric microbiota in IBD. A better understanding of these pathways and characterization of the enteric bacteria involved, their proteases, and protease receptors may pave the way for new therapeutic approaches for these diseases.
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Abstract
Acne vulgaris is a commonly seen dermatologic condition that plagues millions and can be very psychosocially disabling. Severe and recalcitrant acne is typically treated with isotretinoin. Isotretinoin is a synthetic vitamin A derivative that has been available since 1982.This therapeutic option has been the most effective at putting severe and recalcitrant acne vulgaris into remission. Despite its effectiveness,it has been associated with inflammatory bowel disease, depression, suicidality, and teratogenicity. We review the current literature on isotretinoin's role in inflammatory bowel disease, depression, and suicidality. In addition, we review whether or not the iPledge program has been successful at reducing pregnancy rates while on isotretinoin.
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