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Pavel C, Diculescu MM, Ilie M, Plotogea OM, Sandru V, Enache V, Gheonea DI, Jichitu A, Constantinescu A, Serban RE, Bogu CV, Liscu HD, Stepan AE. Immunohistochemistry Analysis in Inflammatory Bowel Disease-Should We Bring to Light Interleukin-10? Biomedicines 2025; 13:406. [PMID: 40002819 PMCID: PMC11853417 DOI: 10.3390/biomedicines13020406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Revised: 01/26/2025] [Accepted: 01/31/2025] [Indexed: 02/27/2025] Open
Abstract
Background/Objectives: Inflammatory bowel diseases (IBDs) are chronic intestinal disorders with an unpredictable course. In parallel with the advent of new biologic therapies targeting specific interleukin pathways, end-point targets have become more stringent, aiming for mucosal and even histologic healing. Methods: We conducted a prospective study assessing immunohistochemical (IHC) parameters in 46 IBD patients treated with biologic therapy. A similar IHC analysis was performed for comparison with a cohort of 10 "non-IBD" patients. Results: The highest integrated optical density (IOD) of TNF-α was observed in patients with dysplasia, abscesses, mucin depletion and basal plasmacytosis. Non-responders had higher pre- and post-treatment TNF-α expression in both UC and CD compared to responders. On the contrary, the same analysis conducted in the subpopulation treated with anti-TNF-α therapy (Infliximab and Adalimumab) did not reveal a substantial difference in TNF-α expression between responders and non-responders. High pre-treatment interleukin-10 expression was associated with biologic therapy failure, histological inflammatory activity and longer disease duration. Conclusions: Pre-treatment assessment of IL-10 might be a useful tool for identifying a high-risk subset of IBD patients and determining a more aggressive therapy and intensive monitoring strategy.
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Affiliation(s)
- Christopher Pavel
- Department 5, Gastroenterology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.P.); (M.I.); (O.-M.P.); (V.S.); (A.C.)
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania; (A.J.); (C.V.B.)
| | - Mircea Mihai Diculescu
- Department 5, Gastroenterology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.P.); (M.I.); (O.-M.P.); (V.S.); (A.C.)
- Department of Gastroenterology, Fundeni Clinical Institute, 022328 Bucharest, Romania
| | - Madalina Ilie
- Department 5, Gastroenterology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.P.); (M.I.); (O.-M.P.); (V.S.); (A.C.)
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania; (A.J.); (C.V.B.)
| | - Oana-Mihaela Plotogea
- Department 5, Gastroenterology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.P.); (M.I.); (O.-M.P.); (V.S.); (A.C.)
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania; (A.J.); (C.V.B.)
| | - Vasile Sandru
- Department 5, Gastroenterology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.P.); (M.I.); (O.-M.P.); (V.S.); (A.C.)
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania; (A.J.); (C.V.B.)
| | - Valentin Enache
- Department of Pathology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania;
| | - Dan-Ionut Gheonea
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (D.-I.G.); (R.-E.S.)
| | - Alexandra Jichitu
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania; (A.J.); (C.V.B.)
| | - Alexandru Constantinescu
- Department 5, Gastroenterology, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania; (C.P.); (M.I.); (O.-M.P.); (V.S.); (A.C.)
| | - Robert-Emmanuel Serban
- Department of Gastroenterology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania; (D.-I.G.); (R.-E.S.)
| | - Cosmin Viorel Bogu
- Department of Gastroenterology, Clinical Emergency Hospital of Bucharest, 014461 Bucharest, Romania; (A.J.); (C.V.B.)
| | - Horia-Dan Liscu
- Discipline of Oncological Radiotherapy and Medical Imaging, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Alex-Emilian Stepan
- Department of Pathology, University of Medicine and Pharmacy of Craiova, 200349 Craiova, Romania;
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Cui M, Shi C, Yao P. Protective effect of appendectomy against the onset of ulcerative colitis: A case-control study. World J Gastrointest Surg 2024; 16:3675-3684. [PMID: 39734436 PMCID: PMC11650250 DOI: 10.4240/wjgs.v16.i12.3675] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Revised: 09/18/2024] [Accepted: 10/18/2024] [Indexed: 11/27/2024] Open
Abstract
BACKGROUND Previous studies suggest that appendectomy has a protective effect against ulcerative colitis (UC); however, relatively few studies focusing on this topic have been reported in China. AIM To explore the correlation between appendectomy and the onset of UC. METHODS A total of 313 patients with newly diagnosed UC and 313 healthy individuals were selected for this study. According to whether their appendix was removed before the diagnosis of UC, patients were divided into appendectomized and non-appendectomized groups. Their general clinical data, appendectomy history, disease severity, extent of involvement, and blood routine test results were collected to evaluate the relationship between appendectomy and the onset of UC. RESULTS The study revealed that the average time interval for the diagnosis of UC after appendectomy was 14.72 ± 13.87 years. 55.81% patients were diagnosed with UC five years after appendectomy. Among them, eight patients underwent appendectomy before the age of 20 years and were diagnosed with UC five years later. In the appendectomized group, the onset age of UC was higher, and the degree of disease activity was significantly lower. This group had a higher proportion of patients in clinical remission or with mild disease and a lower proportion of patients with severe disease. The extent of lesions in the appendectomized group was limited, with a higher proportion of E1 and E2, whereas a lower proportion of E3 lesions. CONCLUSION Appendectomy may delay the onset of UC, reduce disease severity, and lessen the scope of involvement.
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Affiliation(s)
- Min Cui
- Department of Gastroenterology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830000, Xinjiang Uygur Autonomous Region, China
| | - Chen Shi
- The First Clinical Medical College, Xinjiang Medical University, Urumqi 830000, Xinjiang Uygur Autonomous Region, China
| | - Ping Yao
- Department of Gastroenterology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830000, Xinjiang Uygur Autonomous Region, China
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Feng YL, Xu XR, Zhu QM, Chang J, Zhang HL, Wang N, Sun JB, Liu J, Zhang J, Sun CP. Aucklandiae radix targeted PKM2 to alleviate ulcerative colitis: Insights from the photocrosslinking target fishing technique. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 134:155973. [PMID: 39241384 DOI: 10.1016/j.phymed.2024.155973] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 07/19/2024] [Accepted: 08/19/2024] [Indexed: 09/09/2024]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is a chronic and relapsing disease marked by chronic tissue inflammation that alters the integrity and function of the gut, seriously impacting patient health and quality of life. Aucklandiae Radix (AR), known as Mu Xiang in Chinese, is a traditional Chinese medicine documented in Chinese Pharmacopoeia with effects of strengthening the intestine and stopping diarrhea. However, the potential of AR in treating intestinal inflammation and its underlying mechanism have yet to be further elucidated. PURPOSE The objective of this study was to explore the protective effect and the potential mechanism attributable to AR for treating ulcerative colitis (UC). STUDY DESIGN AND METHODS A murine model of UC was constructed using dextran sulfate sodium (DSS) to examine the therapeutic potential of AR in alleviating inflammation and modulating the immune response. Advanced techniques such as photocrosslinking target fishing technique, click chemistry, Western blot analysis, real-time quantitative PCR, flow cytometry, immunofluorescence, and immunohistochemistry were employed to unveil the therapeutic mechanism of AR for treating IBD. RESULTS AR decreased disease activity index (DAI) score to alleviate the course of IBD through ameliorating intestinal barrier function in DSS-induced mice. Furthermore, AR suppressed NF-κB and NLRP3 pathways to reduce the release of pro-inflammatory factors interleukin-6 and 1β (IL-6 and IL-1β) and tumor necrosis factor α (TNF-α), allowing to alleviate the inflammatory response. Flow cytometry revealed that AR could reduce the accumulation of intestinal macrophages and neutrophils, maintaining intestinal immune balance by regulating the ratio of Treg to Th17 cells. It was worth noting that pyruvate kinase isozyme type M2 (PKM2) served as a potential target of AR using the photocrosslinking target fishing technology, which was further supported by cellular thermal shift assay (CETSA), drug affinity target stability (DARTS), and PKM2 knockdown experiments. CONCLUSION AR targeted PKM2 to inhibit NF-κB and NLRP3 pathways, thereby modulating the inflammatory response and immunity to alleviate DSS-induced UC. These findings suggested the potential of AR in the treatment of UC and AR as a candidate for developing PKM2 regulators.
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Affiliation(s)
- Yan-Li Feng
- School of Chinese Materia Medica, Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China
| | - Xin-Rong Xu
- School of Chinese Materia Medica, Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China
| | - Qi-Meng Zhu
- School of Chinese Materia Medica, Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China
| | - Jing Chang
- School of Chinese Materia Medica, Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China
| | - Hui-Lin Zhang
- School of Chinese Materia Medica, Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; College of Pharmacy, Dalian Medical University, Dalian 116044, PR China
| | - Na Wang
- School of Chinese Materia Medica, Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China
| | - Jian-Bo Sun
- School of Chinese Materia Medica, Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; College of Pharmacy, Dalian Medical University, Dalian 116044, PR China
| | - Jing Liu
- College of Pharmacy, Dalian Medical University, Dalian 116044, PR China.
| | - Juan Zhang
- School of Chinese Materia Medica, Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China; School of Medical Technology, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China.
| | - Cheng-Peng Sun
- School of Chinese Materia Medica, Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, PR China.
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Vieujean S, Laharie D, Buisson A, Roblin X, Fumery M, Nancey S, Wils P, Altwegg R, Seidel L, Caron B, Peyrin-Biroulet L. Histological healing induced by tofacitinib in ulcerative colitis: A multicentre study. Dig Liver Dis 2024; 56:613-621. [PMID: 38065698 DOI: 10.1016/j.dld.2023.11.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 11/18/2023] [Accepted: 11/20/2023] [Indexed: 03/25/2024]
Abstract
BACKGROUND While the efficacy of tofacitinib to induce and maintain clinical and endoscopic remission is well established in ulcerative colitis (UC), little is known about its efficacy to induce histological remission. METHODS We conducted a retrospective multicentric cohort study. UC patients ≥ 16 years treated by tofacitinib in whom histological activity has been evaluated before and after induction were eligible. The primary endpoint was the histological remission at the end of induction, assessed by the Nancy index and the epithelial neutrophilic infiltrate. RESULTS A total of 42 patients with UC (93% previously exposed to an anti-TNF and 81% to vedolizumab) were included between July 2018 and April 2022 and were followed for a median duration of 84 weeks [IQR, 35-134]. At the end of induction period (whether prolonged or not), 19% and 24% of patients achieved histological remission, using the Nancy index and the epithelial neutrophilic infiltrate, respectively. Survival without tofacitinib discontinuation was significantly longer in patients without epithelial neutrophilic infiltrate at the end of induction (whether prolonged or not) compared with patients with epithelial neutrophilic infiltrate (p = 0.036). CONCLUSION Tofacitinib induced histological remission in one fifth to one quarter of patients with UC who have previously failed anti-TNF or/and vedolizumab after induction (whether prolonged or not).
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Affiliation(s)
- Sophie Vieujean
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
| | - David Laharie
- CHU de Bordeaux, Centre Medico-chirurgical Magellan, Hôpital Haut-Lévêque, Gastroenterology department, Université de Bordeaux, INSERM CIC 1401, Bordeaux, France
| | - Anthony Buisson
- Université Clermont Auvergne, Inserm, CHU Clermont-Ferrand, 3iHP, Service d'Hépato-Gastro Entérologie, Clermont-Ferrand, France
| | - Xavier Roblin
- Department of Gastroenterology, University Hospital of Saint-Etienne, Saint-Etienne, France
| | - Mathurin Fumery
- Gastroenterology Unit, Amiens University Hospital and PeriTox, Université de Picardie Jules Verne, Amiens UMR-IO1, France
| | - Stephane Nancey
- Gastroenterology Department CHU Lyon-Sud, Hospices Civils de Lyon, University Claude Bernard Lyon 1, INSERM U1111 - CIRI, Lyon, France
| | - Pauline Wils
- Univ. Lille, Inserm, CHU Lille, U1286 - Institute for Translational Research in Inflammation, Lille F-59000, France
| | - Romain Altwegg
- Hepato-gastroenterology Department, CHU Montpellier, Montpellier, France
| | - Laurence Seidel
- Biostatistics and medico-economic information department, Liège, Belgium
| | - Bénédicte Caron
- Department of Gastroenterology, Nancy University Hospital, Vandœuvre-lès-Nancy F-54500, France; INSERM, NGERE, University of Lorraine, Nancy F-54000, France; NFINY Institute, Nancy University Hospital, Vandœuvre-lès-Nancy F-54500, France; FHU-CURE, Nancy University Hospital, Vandœuvre-lès-Nancy F-54500, France
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Nancy University Hospital, Vandœuvre-lès-Nancy F-54500, France; INSERM, NGERE, University of Lorraine, Nancy F-54000, France; NFINY Institute, Nancy University Hospital, Vandœuvre-lès-Nancy F-54500, France; FHU-CURE, Nancy University Hospital, Vandœuvre-lès-Nancy F-54500, France; Groupe Hospitalier privé Ambroise Paré - Hartmann, Paris IBD centre, Neuilly sur Seine 92200, France; Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, QC, Canada.
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Salvatori S, Neri B, Marafini I, Brigida M, Monteleone G. Emerging oral drug options for ulcerative colitis. Expert Opin Emerg Drugs 2023; 28:191-201. [PMID: 37668153 DOI: 10.1080/14728214.2023.2254686] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/22/2023] [Accepted: 08/30/2023] [Indexed: 09/06/2023]
Abstract
INTRODUCTION Despite the availability of a variety of therapeutic compounds and improved management strategies, one-third of UC patients with moderate-to-severe disease do not benefit from the existing treatments or experience drug-related side effects. This has boosted intensive research focusing on the development of new drugs for UC therapy. This article aims to summarize the available evidence on oral drugs, which are now being explored in clinical trials or are ready to enter the clinics. AREAS COVERED From May 15 to June 11, we searched on PubMed using the keywords 'oral drugs ulcerative colitis,' 'ulcerative colitis clinical trials,' 'UC phase 2 and 3 trials' excluding case reports, case series, phase 1 and 4 studies, and studies about approved therapies. EXPERT OPINION The findings discussed in this article suggest that the future treatment of UC patients will be probably characterized by the possibility of using various small-molecule drugs. All these new compounds, even those belonging to the same class, differ in terms of efficacy and safety. Identification of predictors of response could help optimize the efficacy and safety of these treatments, thus improving resource allocation through a pretreatment stratification of patients.
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Affiliation(s)
- Silvia Salvatori
- Gastroenterology Unit, Policlinico Universitario Tor Vergata, Rome, Italy
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Benedetto Neri
- Gastroenterology Unit, Policlinico Universitario Tor Vergata, Rome, Italy
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Irene Marafini
- Gastroenterology Unit, Policlinico Universitario Tor Vergata, Rome, Italy
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Mattia Brigida
- Gastroenterology Unit, Policlinico Universitario Tor Vergata, Rome, Italy
| | - Giovanni Monteleone
- Gastroenterology Unit, Policlinico Universitario Tor Vergata, Rome, Italy
- Department of Systems Medicine, University of Rome Tor Vergata, Rome, Italy
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Viola A, Demarzo MG, Abbruzzese A, Muscianisi M, Chiappetta MF, Costantino G, Ksissa O, Alibrandi A, Fries W. Low Adherence is Associated with Chronic Active Disease in Ulcerative Colitis: A Retrospective Study from a Single Referral Center. Patient Prefer Adherence 2023; 17:807-816. [PMID: 36992866 PMCID: PMC10041981 DOI: 10.2147/ppa.s390349] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 02/18/2023] [Indexed: 03/31/2023] Open
Abstract
PURPOSE New therapeutic approaches for ulcerative colitis (UC) are now available, but there is still no robust evidence for predictors of poor outcomes. We aimed to evaluate the factors associated with a chronic active UC disease course. PATIENTS AND METHODS Data of all UC outpatients followed for at least 3 years after diagnosis between 2005 and 2018 were retrospectively collected. The primary aim was to identify risk factors for chronic active disease 3 years after diagnosis. Moreover, the following variables were investigated: proximal disease extension or disease regression, proctocolectomy, early use of biologics (BIO) or immunomodulators (IMM), hospitalization, colorectal cancer, and adherence. We defined adherence as both, taking the prescribed therapy and constancy in scheduled follow-up visits. RESULTS A total of 345 UC patients followed for a median period of 82 months were included. Patients with extensive colitis at diagnosis had a higher rate of chronic active disease 3 years after diagnosis (p<0.012) together with a higher rate of surgery (p<0.001) at maximum follow-up. Patients with pancolitis showed significant disease regression over time (51%) without differences in treatment. The only factor associated with chronic active disease was non-adherence (p < 0.03; OR 0.49, 95% CI: 0.26-0.95). Adherent patients developed chronic active disease (p<0.025) less frequently but did receive more frequent IMM (p<0.045) or BIO (p<0.009) therapy. CONCLUSION Patients diagnosed with pancolitis were more likely to have chronic active disease and to undergo colectomy. The only predictor for developing chronically active UC regardless of disease extension was the lack of adherence to therapy within the first 3 years after diagnosis, underlining the importance of tight control of UC patients and the need to timely identify potential risk factors for non-adherence.
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Affiliation(s)
- Anna Viola
- Department of Clinical and Experimental Medicine, IBD-Unit, University of Messina, Messina, Italy
| | - Maria Giulia Demarzo
- Department of Clinical and Experimental Medicine, IBD-Unit, University of Messina, Messina, Italy
- Department of Internal Medicine, Ospedale Policlinico San Martino-IRCCS per l’Oncologia, Gastroenterology Unit, University of Genoa, Genoa, Italy
| | - Alfredo Abbruzzese
- Department of Clinical and Experimental Medicine, IBD-Unit, University of Messina, Messina, Italy
- Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, PROMISE, Gastroenterology & Hepatology Unit, University of Palermo, Palermo, Italy
| | - Marco Muscianisi
- Department of Clinical and Experimental Medicine, IBD-Unit, University of Messina, Messina, Italy
| | - Michele Francesco Chiappetta
- Department of Clinical and Experimental Medicine, IBD-Unit, University of Messina, Messina, Italy
- Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, PROMISE, Gastroenterology & Hepatology Unit, University of Palermo, Palermo, Italy
| | - Giuseppe Costantino
- Department of Clinical and Experimental Medicine, IBD-Unit, University of Messina, Messina, Italy
| | - Omar Ksissa
- Department of Clinical and Experimental Medicine, IBD-Unit, University of Messina, Messina, Italy
- Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, PROMISE, Gastroenterology & Hepatology Unit, University of Palermo, Palermo, Italy
| | - Angela Alibrandi
- Department of Economics; Unit of Statistical and Mathematical Sciences, University of Messina, Messina, Italy
| | - Walter Fries
- Department of Clinical and Experimental Medicine, IBD-Unit, University of Messina, Messina, Italy
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Mortlock S, Lord A, Montgomery G, Zakrzewski M, Simms LA, Krishnaprasad K, Hanigan K, Doecke JD, Walsh A, Lawrance IC, Bampton PA, Andrews JM, Mahy G, Connor SJ, Sparrow MP, Bell S, Florin TH, Begun J, Gearry RB, Radford-Smith GL. An Extremes of Phenotype Approach Confirms Significant Genetic Heterogeneity in Patients with Ulcerative Colitis. J Crohns Colitis 2023; 17:277-288. [PMID: 36111848 PMCID: PMC10024548 DOI: 10.1093/ecco-jcc/jjac121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS Ulcerative colitis [UC] is a major form of inflammatory bowel disease globally. Phenotypic heterogeneity is defined by several variables including age of onset and disease extent. The genetics of disease severity remains poorly understood. To further investigate this, we performed a genome wide association [GWA] study using an extremes of phenotype strategy. METHODS We conducted GWA analyses in 311 patients with medically refractory UC [MRUC], 287 with non-medically refractory UC [non-MRUC] and 583 controls. Odds ratios [ORs] were calculated for known risk variants comparing MRUC and non-MRUC, and controls. RESULTS MRUC-control analysis had the greatest yield of genome-wide significant single nucleotide polymorphisms [SNPs] [2018], including lead SNP = rs111838972 [OR = 1.82, p = 6.28 × 10-9] near MMEL1 and a locus in the human leukocyte antigen [HLA] region [lead SNP = rs144717024, OR = 12.23, p = 1.7 × 10-19]. ORs for the lead SNPs were significantly higher in MRUC compared to non-MRUC [p < 9.0 × 10-6]. No SNPs reached significance in the non-MRUC-control analysis (top SNP, rs7680780 [OR 2.70, p = 5.56 × 10-8). We replicate findings for rs4151651 in the Complement Factor B [CFB] gene and demonstrate significant changes in CFB gene expression in active UC. Detailed HLA analyses support the strong associations with MHC II genes, particularly HLA-DQA1, HLA-DQB1 and HLA-DRB1 in MRUC. CONCLUSIONS Our MRUC subgroup replicates multiple known UC risk variants in contrast to non-MRUC and demonstrates significant differences in effect sizes compared to those published. Non-MRUC cases demonstrate lower ORs similar to those published. Additional risk and prognostic loci may be identified by targeted recruitment of individuals with severe disease.
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Affiliation(s)
- Sally Mortlock
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
| | - Anton Lord
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- Centre for Health Services Research, University of Queensland, Brisbane, QLD, Australia
| | - Grant Montgomery
- Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
| | | | - Lisa A Simms
- QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | | | | | - James D Doecke
- Australian eHealth Research Centre, CSIRO, Brisbane, QLD, Australia
| | - Alissa Walsh
- Department of Gastroenterology, John Radcliffe Hospital, Headington, Oxford, UK
| | - Ian C Lawrance
- Centre of Inflammatory Bowel Diseases, Saint John of God Hospital Subiaco, University of Western Australia, WA, Australia
| | | | - Jane M Andrews
- Department of Gastroenterology and Hepatology, Royal Adelaide Hospital & University of Adelaide, Adelaide, SA, Australia
| | - Gillian Mahy
- Department of Gastroenterology and Hepatology, Townsville University Hospital, Townsville, QLD, Australia
| | - Susan J Connor
- Department of Gastroenterology and Hepatology, Liverpool Hospital, Sydney, NSW, Australia
- South Western Sydney Clinical School, University of New South Wales, Sydney, NSW, Australia
| | - Miles P Sparrow
- Department of Gastroenterology, Alfred Health, Melbourne, VIC, Australia
| | - Sally Bell
- Department of Gastroenterology and Hepatology, Monash Health, Melbourne, VIC, Australia
| | - Timothy H Florin
- Inflammatory Bowel Diseases Group, Translational Research Institute, Brisbane, QLD, Australia
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Jakob Begun
- Inflammatory Bowel Diseases Group, Translational Research Institute, Brisbane, QLD, Australia
- Inflammatory Disease Biology and Therapeutics Group, Translational Research Institute, Brisbane, QLD, Australia
- Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia
| | - Richard B Gearry
- Department of Medicine, University of Otago, Christchurch, New Zealand
| | - Graham L Radford-Smith
- Corresponding author: Graham Radford-Smith, Gut Health Lab, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia. Tel: +617 3362 0499; Fax: +617 3009 0053;
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Shelygin YA, Ivashkin VT, Belousova EA, Reshetov IV, Maev IV, Achkasov SI, Abdulganieva DI, Alekseeva OA, Bakulin IG, Barysheva OY, Bolikhov KV, Vardanyan AV, Veselov AV, Veselov VV, Golovenko OV, Gubonina IV, Denisenko VL, Dolgushina AI, Kashnikov VN, Knyazev OV, Kostenko NV, Lakhin AV, Makarchuk PA, Moskalev AI, Nanaeva BA, Nikitin IG, Nikitina NV, Odintsova AK, Omelyanovskiy VV, Оshchepkov AV, Pavlenko VV, Poluektova EA, Sitkin SI, Sushkov OI, Tarasova LV, Tkachev AV, Тimerbulatov VM, Uspenskaya YB, Frolov SA, Khlynova OV, Chashkova EY, Chesnokova OV, Shapina MV, Sheptulin AA, Shifrin OS, Shkurko TV, Shchukina OB. Ulcerative colitis (K51), adults. KOLOPROKTOLOGIA 2023; 22:10-44. [DOI: 10.33878/2073-7556-2023-22-1-10-44] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/26/2023]
Affiliation(s)
- Yu. A. Shelygin
- Ryzhikh National Medical Research Center of Coloproctology; Russian Medical Academy of Continous Professional Education
| | - V. T. Ivashkin
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | | | - I. V. Reshetov
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - I. V. Maev
- Moscow State University of Medicine and Dentistry named after A.I. Evdokimov
| | - S. I. Achkasov
- Ryzhikh National Medical Research Center of Coloproctology; Russian Medical Academy of Continous Professional Education
| | | | | | - I. G. Bakulin
- North-Western State Medical University named after I.I. Mechnikov
| | | | | | | | | | - V. V. Veselov
- Ryzhikh National Medical Research Center of Coloproctology; Russian Medical Academy of Continous Professional Education
| | - O. V. Golovenko
- Ryzhikh National Medical Research Center of Coloproctology; Russian Medical Academy of Continous Professional Education
| | | | - V. L. Denisenko
- Educational Establishment Vitebsk State Order of Peoples’ Friendship Medical University
| | - A. I. Dolgushina
- Federal State Budgetary Educational Institution of Higher Education «South-Ural State Medical University» of the Ministry of Healthcare of the Russian Federation
| | | | - O. V. Knyazev
- GBUZ Moscow Clinical Scientific Center named after Loginov MHD
| | - N. V. Kostenko
- Federal State Budgetary Educational Institution of Higher Education «Astrakhan State Medical University» of the Ministry of Health of the Russian Federation
| | | | | | - A. I. Moskalev
- Ryzhikh National Medical Research Center of Coloproctology
| | - B. A. Nanaeva
- Ryzhikh National Medical Research Center of Coloproctology
| | - I. G. Nikitin
- Pirogov Russian National Research Medical University
| | | | - A. Kh. Odintsova
- GAUZ «RCH» of the Ministry of Health of the Republic of Tatarstan
| | | | - A. V. Оshchepkov
- GBUZ SO «SOKB No. 1» of the Ministry of Health of the Sverdlovsk Region
| | | | - E. A. Poluektova
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - S. I. Sitkin
- North-Western State Medical University named after I.I. Mechnikov
| | - O. I. Sushkov
- Ryzhikh National Medical Research Center of Coloproctology
| | - L. V. Tarasova
- Federal State Budgetary Educational Institution of Higher Education «Chuvash State University named after I.N. Ulyanov»
| | - A. V. Tkachev
- Federal State Budgetary Educational Institution of Higher Education «Rostov State Medical University» of the Ministry of Health of the Russian Federation
| | | | | | - S. A. Frolov
- Ryzhikh National Medical Research Center of Coloproctology
| | - O. V. Khlynova
- Perm State Medical University named after E.A. Wagner (PSMU) of the Ministry of Healthcare of the Russian Feaderation
| | - E. Yu. Chashkova
- Federal State Budgetary Scientific Institution «Irkutsk Scientific Center for Surgery and Traumatology»
| | | | - M. V. Shapina
- Ryzhikh National Medical Research Center of Coloproctology; Russian Medical Academy of Continous Professional Education
| | - A. A. Sheptulin
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - O. S. Shifrin
- I.M. Sechenov First Moscow State Medical University (Sechenov University)
| | - T. V. Shkurko
- Ryzhikh National Medical Research Center of Coloproctology
| | - O. B. Shchukina
- First St. Petersburg State Medical University named after Academician I.P. Pavlov of the Ministry of Health of Russia
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Ramos L, Teo-Loy J, Barreiro-de Acosta M. Disease clearance in ulcerative colitis: Setting the therapeutic goals for future in the treatment of ulcerative colitis. Front Med (Lausanne) 2023; 9:1102420. [PMID: 36698823 PMCID: PMC9868775 DOI: 10.3389/fmed.2022.1102420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Accepted: 12/13/2022] [Indexed: 01/11/2023] Open
Abstract
Ulcerative colitis, one of the phenotypic patterns of inflammatory bowel disease, should be considered a progressive disease with an increased risk of complications if intestinal inflammation is not adequately controlled. The advent of new lines of treatment for this condition has changed and expanded the therapeutic goals to modify its natural history and evolution. The concept of "disease clearance" in ulcerative colitis aims to achieve clinical and biological remission as well as mucosal healing (endoscopic, histological, and in future molecular) in these patients. This review provides the available data on each of the goals of disease clearance in ulcerative colitis to be considered for application in clinical practice in the coming years.
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Affiliation(s)
- Laura Ramos
- IBD Unit, Department of Gastroenterology, Hospital Universitario de Canarias, Santa Cruz de Tenerife, Spain,Department of Internal Medicine, University of La Laguna, Santa Cruz de Tenerife, Spain,*Correspondence: Laura Ramos,
| | - Jeny Teo-Loy
- IBD Unit, Department of Gastroenterology, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain
| | - Manuel Barreiro-de Acosta
- IBD Unit, Department of Gastroenterology, University Hospital of Santiago de Compostela, Santiago de Compostela, Spain
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10
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Shah R, Kelley J, Amundsen T, Coggins K, Edwards A, Johnson CM. Medical and social determinants of health as predictors of adverse outcomes in patients with inflammatory bowel disease. Proc AMIA Symp 2023; 36:165-170. [PMID: 36876274 PMCID: PMC9980680 DOI: 10.1080/08998280.2022.2156025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
There is a growing recognition that social determinants of health (SDOH) influence outcomes in patients with chronic diseases. This study aimed to investigate the influence of SDOH on outcomes in patients with inflammatory bowel disease (IBD). We conducted a retrospective cohort study of adult patients with IBD from 1996 to 2019. Patients were identified using ICD-10 codes for ulcerative colitis and Crohn's disease, and chart review was performed to validate the diagnosis and extract clinical information. SDOH factors including food security, financial resources, and transportation were self-reported by the patient. Random forest models were trained and tested in R to predict either IBD-related hospitalization or surgery. A total of 175 patients were studied, and the majority reported no financial resource, food security, or transportation concerns. For the model using clinical predictors, the sensitivity was 0.68 and specificity was 0.77 with an area under the receiver operating characteristic curve (AUROC) of 0.77. The model's performance did not significantly improve with the addition of SDOH information (AUROC of 0.78); however, model performance did vary by phenotype (AUROC of 0.86 for patients with Crohn's disease and AUROC of 0.68 for patients with ulcerative colitis). Further research is needed to understand the role of SDOH factors and IBD-related outcomes.
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Affiliation(s)
- Rajesh Shah
- Division of Gastroenterology, Baylor Scott and White Medical Center - Austin, Austin, Texas
| | - John Kelley
- Department of Medicine, Baylor Scott and White Medical Center - Temple, Temple, Texas
| | - Tyson Amundsen
- Department of Medicine, Baylor Scott and White Medical Center - Temple, Temple, Texas
| | - Kenneth Coggins
- Department of Medicine, Baylor Scott and White Medical Center - Temple, Temple, Texas
| | - Audrene Edwards
- Department of Biostatistics, Baylor Scott and White Health Research Institute, Temple, Texas
| | - Christopher M Johnson
- Division of Gastroenterology, Department of Medicine, Baylor Scott and White Medical Center
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11
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Li Y, Ye Z, He H, Hu Y, Wu M, Li L, Chen L, Qian H, Shi Q, Zhang C, Yu H, Zhao Q, Liu X, Qin K, Ye Q. The application of Tong-fu therapeutic method on ulcerative colitis: A systematic review and meta-analysis for efficacy and safety of rhubarb-based therapy. Front Pharmacol 2022; 13:1036593. [DOI: 10.3389/fphar.2022.1036593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 10/11/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Tong-fu therapeutic method (TFTM) is a traditional Chinese medicine treatment method for ulcerative colitis, which is a novel treatment strategies and have purgative effect. As the most representative medicinal of TFTM, Rhubarb has been reported to have a therapeutic impact on ulcerative colitis by regulating intestinal flora, anti-inflammation, and improving intestinal microcirculation. Although rhubarb has been widely used in Chinese medicine for the treatment of ulcerative colitis, the appropriate protocol is still demanded to its rational use in clinic, which promoted to evaluate the efficacy and safety for rhubarb-based therapy on ulcerative colitis.Method: Clinical trials were searched through PubMed, Cochrane Library, Web of Science, Excerpta Medica Database, Chinese National Knowledge Infrastructure, WAN FANG Database, Chinese Scientific Journal Database, and Chinese Biomedical Literature Database. The subgroup analyses were performed with three groups: medication, course of treatment, and route of administration. The statistical analyses were performed on Review Manager software (version 5.4.1).Results: A total of 2, 475 patients in 30 original studies were analyzed in this article. It was found that rhubarb-based therapy could increase clinical efficacy and reduce the recurrence rate. Subgroup analyses showed that rhubarb-based therapy was more effective than 5-aminosalicylic acid or sulfasalazine alone. In addition, the hypercoagulable state of ulcerative colitis could be ameliorated by decreasing platelet (PLT) and fibrinogen (FIB), and increasing prothrombin time (PT) significantly. Moreover, C-reaction protein (CRP), tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8, and IL-1β expression were significantly reduced, while IL-10 production was increased, which mediated the alleviation of intestinal inflammation stress.Conclusion: Rhubarb-based therapy could effectively improve ulcerative colitis. Of note, the rhubarb-based medicinal formulas combined with 5-ASA or SASP are more effective than the 5-ASA or SASP alone. In addition, although rhubarb has side effect, the results of our analysis showed that rhubarb-based therapy did not exhibit significant side effects. This means it has a high safety profile in clinical use. Moreover, the use of rhubarb-based therapy is recommend to use within 1–13 weeks or 3 months via administered orally or by enema, which is contributes to ensure the curative effect and avoid its toxic and side effects. As an important case of TFTM, rhubarb-based therapy provides evidence for the practical application of TFTM.
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12
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Li N, Zhan S, Liu C, Li T, Tu T, Chen B, He Y, Chen M, Zeng Z, Zhuang X. Development and validation of a nomogram to predict indolent course in patients with ulcerative colitis: a single-center retrospective study. Gastroenterol Rep (Oxf) 2022; 10:goac029. [PMID: 35785264 PMCID: PMC9245125 DOI: 10.1093/gastro/goac029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 05/04/2022] [Accepted: 05/10/2022] [Indexed: 11/30/2022] Open
Abstract
Background The natural disease course for patients with ulcerative colitis (UC) is heterogeneous and few data are available on the indolent course of UC and its related factors. We aimed to develop and validate a nomogram to predict indolent course in patients with UC. Methods Data of patients diagnosed with UC in the First Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) between April 2007 and February 2021 were retrospectively analysed. Indolent course was defined as a disease course without need for strict interventions (steroids, immunomodulators, biological agents, hospitalization, or surgery therapy) during the follow-up period. The whole cohort was randomly divided into training set and validation set. The nomogram was constructed in the training set based on the results of univariate and multivariate Cox regression analyses. The performance of the nomogram was assessed by the concordance index (C-index), area under the receiver-operating characteristic curve (AUC), and calibration plots. In addition, we internally validated the nomogram via the bootstrap method and the validation set. Results Of 969 treatment-naive patients with UC, 771 (79.6%) had an indolent course after diagnosis. Of these, 313 patients were included in the development and validation of the nomogram. The nomogram incorporating age, disease activity, C-reactive protein, and platelet count showed good calibration and discrimination. The C-index was 0.759 (0.741 in bootstrap validation) and the AUC at 2, 4, and 6 years was 0.767, 0.782, and 0.775, respectively. The nomogram performed well when applied to the validation set. Conclusion A majority of patients with UC had an indolent course after diagnosis. The nomogram developed in this study might be useful in therapeutic decision-making and follow-up management for patients with UC.
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Affiliation(s)
- Na Li
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Shukai Zhan
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Caiguang Liu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Tong Li
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Tong Tu
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Baili Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Yao He
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Zhirong Zeng
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Xiaojun Zhuang
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
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13
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Marsal J, Barreiro-de Acosta M, Blumenstein I, Cappello M, Bazin T, Sebastian S. Management of Non-response and Loss of Response to Anti-tumor Necrosis Factor Therapy in Inflammatory Bowel Disease. Front Med (Lausanne) 2022; 9:897936. [PMID: 35783628 PMCID: PMC9241563 DOI: 10.3389/fmed.2022.897936] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 05/25/2022] [Indexed: 11/30/2022] Open
Abstract
Anti-tumor necrosis factor (anti-TNF) therapy has been successfully used as first-line biologic treatment for moderate-to-severe inflammatory bowel disease (IBD), in both "step-up" and "top-down" approaches, and has become a cornerstone of IBD management. However, in a proportion of patients the effectiveness of anti-TNF therapy is sub-optimal. Either patients do not achieve adequate initial response (primary non-response) or they lose response after initial success (loss of response). Therapeutic drug monitoring determines drug serum concentrations and the presence of anti-drug antibodies (ADAbs) and can help guide treatment optimization to improve patient outcomes. For patients with low drug concentrations who are ADAb-negative or display low levels of ADAbs, dose escalation is recommended. Should response remain unchanged following dose optimization the question whether to switch within class (anti-TNF) or out of class (different mechanism of action) arises. If ADAb levels are high and the patient has previously benefited from anti-TNF therapy, then switching within class is a viable option as ADAbs are molecule specific. Addition of an immunomodulator may lead to a decrease in ADAbs and a regaining of response in a proportion of patients. If a patient does not achieve a robust therapeutic response with an initial anti-TNF despite adequate drug levels, then switching out of class is appropriate. In conjunction with the guidance above, other factors including patient preference, age, comorbidities, disease phenotype, extra-intestinal manifestations, and treatment costs need to be factored into the treatment decision. In this review we discuss current evidence in this field and provide guidance on therapeutic decision-making in clinical situations.
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Affiliation(s)
- Jan Marsal
- Department of Gastroenterology, Skåne University Hospital, Lund/Malmö, Sweden
- Department of Immunology, Lund University, Lund, Sweden
| | - Manuel Barreiro-de Acosta
- Gastroenterology Department, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain
| | - Irina Blumenstein
- Department of Internal Medicine 1, Gastroenterology, Hepatology and Clinical Nutrition, University Clinic Frankfurt, Frankfurt, Germany
| | - Maria Cappello
- Gastroenterology and Hepatology Section, Promise, University of Palermo, Palermo, Italy
| | - Thomas Bazin
- Department of Gastroenterology, Université Paris Saclay/UVSQ, INSERM, Infection and Inflammation, UMR 1173, AP-HP, Hôpital Ambroise Paré, Boulogne Billancourt, France
| | - Shaji Sebastian
- Inflammatory Bowel Disease (IBD) Unit, Hull University Teaching Hospitals National Health Service (NHS) Trust, Hull, United Kingdom
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14
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Vavricka SR, Greuter T, Cohen BL, Reinisch W, Steinwurz F, Fellmann M, Guo X, Lawendy N, Paulissen J, Peyrin-Biroulet L. Corticosteroid-free efficacy and safety outcomes in patients receiving tofacitinib in the OCTAVE Sustain maintenance study. Therap Adv Gastroenterol 2022; 15:17562848221090834. [PMID: 35574426 PMCID: PMC9096189 DOI: 10.1177/17562848221090834] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Accepted: 03/10/2022] [Indexed: 02/04/2023] Open
Abstract
Background Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). Here, we report steroid-free efficacy and safety with tofacitinib among patients with UC who received corticosteroids at baseline of the maintenance study (OCTAVE Sustain). Methods This analysis included patients with clinical response following OCTAVE Induction 1 and 2 who were re-randomized to receive placebo, or tofacitinib 5 or 10 mg twice daily (b.d.), in OCTAVE Sustain for 52 weeks and were receiving corticosteroids at OCTAVE Sustain baseline. Corticosteroid tapering was mandatory during OCTAVE Sustain. Rates of steroid-free remission, endoscopic improvement, and clinical response were assessed, stratified by baseline characteristics. Adverse events (AEs) were stratified by treatment and steroid-free remission status. Results Overall, 289/593 patients had corticosteroid use at OCTAVE Sustain baseline. At week 52, steroid-free remission, endoscopic improvement, and clinical response rates were 10.9%, 11.9%, and 17.8% among patients receiving placebo, 27.7%, 29.7%, and 40.6% among patients receiving tofacitinib 5 mg b.d., and 27.6%, 29.9%, and 43.7% among patients receiving tofacitinib 10 mg b.d., respectively (non-responder imputation; all p < 0.05 tofacitinib 5 or 10 mg b.d. versus placebo). Discontinuations due to AEs were lower among patients with steroid-free remission versus without. AEs of special interest were infrequent. Conclusion For patients with baseline corticosteroid use in OCTAVE Sustain, the odds of achieving steroid-free efficacy endpoints were significantly higher for tofacitinib versus placebo, irrespective of tofacitinib dose. There were no apparent differences in AEs of special interest by steroid-free remission status.ClinicalTrials.gov: NCT01458574.
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Affiliation(s)
- Stephan R. Vavricka
- Department of Gastroenterology and Hepatology, University Hospital Zürich and Center for Gastroenterology and Hepatology, Vulkanplatz 8, CH - 8048, Zürich, Switzerland
| | - Thomas Greuter
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Benjamin L. Cohen
- Department of Gastroenterology, Hepatology, and Nutrition, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA
| | | | - Flavio Steinwurz
- Unit of Inflammatory Bowel Disease, Hospital Israelita Albert Einstein, São Paulo, Brazil
| | | | | | | | | | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Inserm U1256 NGERE, Nancy University Hospital, Université de Lorraine, Vandœuvre-lès-Nancy, France
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15
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Wang J, Wang X, Ma X, Xu B, Chen L, Chen C, Liu W, Liu Y, Xiang Z. Therapeutic effect of Patrinia villosa on TNBS-induced ulcerative colitis via metabolism, vitamin D receptor and NF-κB signaling pathways. JOURNAL OF ETHNOPHARMACOLOGY 2022; 288:114989. [PMID: 35032589 DOI: 10.1016/j.jep.2022.114989] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 01/03/2022] [Accepted: 01/09/2022] [Indexed: 06/14/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Ulcerative colitis (UC) is a chronic inflammatory disease affecting the colon. Patrinia villosa Juss. (P.V) is an important traditional Chinese medicine widely used for more than 2000 years from ShenNongBenCaoJing, a famous ancient Chinese medicinal literary. P.V is often used in the treatment of UC, but the pathogenesis is not clear. AIM OF THE STUDY This study was designed to analysis the metabolic pathways and relevant mechanisms of P.V on UC rats induced by TNBS. MATERIALS AND METHODS The rat model of UC was established by 2,4,6-trinitrobenzene sulfonic acid (TNBS)/ethanol method. Three doses of P.V (21 g/kg, 43 g/kg, 64 g/kg) were administrated for 14 days. Disease activity index (DAI) scoring system and H&E staining were used to evaluate the efficacy. A method for simultaneous detection of 96 endogenous metabolic components was established by UPLC-MS. The method was used to detect the metabolites in serum and liver of rats with UC induced by TNBS. PLS-DA and Metaboanalyst were used to analyze the main metabolic pathways involved in the treatment of UC. The contents of IL-1β, TNF-α and IL-6 in the colonic homogenate of rats were detected by enzyme-linked immunosorbent assay (ELISA). The expression levels of VDR, NF-κB, p-NF-κB, NLRP3 and caspase-1 in colon tissues of rats were detected by the method of Western blot. RESULTS DAI scoring system and H&E staining indicated that P.V have the obvious therapeutic effect on UC induced by TNBS as a dosage-dependent manner. 36 potential biomarkers in serum and 26 potential biomarkers in liver were found in positive and negative ion mode of UPLC-MS, which significantly affected Glycine, serine and threonine metabolism, Glycerophospholipid metabolism, Purine metabolism, Histidine metabolism, Alanine, aspartate, and glutamate metabolism, Arginine and proline metabolism in serum, and significantly affected Purine metabolism, Lycine, serine and threonine metabolism, Glutathione metabolism, Glyoxylate and dicarboxylate metabolism in the liver. The contents of pro-inflammatory cytokines and receptors related to NF-κB signaling axis of model group were significantly higher than those of the control group, compared with the model group, their contents of the P.V group were significantly decreased (p < 0.01). Compared with the model group, the expression of NF-κB, p-NF-κB, NLRP3 and caspase-1 in colon tissues of the rats in P.V group were significantly decreased (p < 0.01). The expression of VDR in model group were significantly reduced compared to that in the control group, compared with the model group, the expression of VDR in P.V group were significantly increased (p < 0.01). CONCLUSION P.V has an obvious therapeutic effect on UC induced by TNBS by regulating the energy metabolism, amino acid metabolism, purine metabolism, bile acid metabolism and lipid metabolism. P.V exerts anti-inflammatory effect by impacting bile acid levels, activating VDR, and inhibiting the overactivation of NF-κB signaling pathways.
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Affiliation(s)
- Jiaqi Wang
- School of Pharmaceutical Science, Liaoning University, No.66 Chongshan Middle Road, Shenyang, 110036, PR China
| | - Xin Wang
- School of Pharmaceutical Science, Liaoning University, No.66 Chongshan Middle Road, Shenyang, 110036, PR China
| | - Xiande Ma
- Teaching and Experiment Center, Liaoning University of Traditional Chinese Medicine, No.79 Chongshan East Road, Shenyang, 110847, PR China
| | - Baoli Xu
- Affiliated Zhongshan Hospital of Dalian University, No.6 Jiefang Street, Zhongshan District, Dalian, Liaoning, PR China
| | - Lijiang Chen
- School of Pharmaceutical Science, Liaoning University, No.66 Chongshan Middle Road, Shenyang, 110036, PR China
| | - Changlan Chen
- School of Pharmaceutical Science, Liaoning University, No.66 Chongshan Middle Road, Shenyang, 110036, PR China
| | - Wei Liu
- School of Pharmaceutical Science, Liaoning University, No.66 Chongshan Middle Road, Shenyang, 110036, PR China
| | - Yangcheng Liu
- School of Pharmaceutical Science, Liaoning University, No.66 Chongshan Middle Road, Shenyang, 110036, PR China
| | - Zheng Xiang
- School of Pharmaceutical Science, Liaoning University, No.66 Chongshan Middle Road, Shenyang, 110036, PR China.
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16
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Hao Y, Yzet C, McBride RB, Stock A, Tiratterra E, D'Errico A, Belluzzi A, Scaioli E, Gionchetti P, Roda G, Ungaro R, Colombel JF, Harpaz N, Ko HM. Baseline Histological Findings Do Not Predict the Risk of Subsequent Extension in Patients with Limited Ulcerative Colitis. Dig Dis Sci 2022; 67:1311-1319. [PMID: 33934255 DOI: 10.1007/s10620-021-06970-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 03/24/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND Among patients with limited ulcerative colitis (UC), 30% ultimately extend to pancolitis and are at increased risk of adverse clinical outcomes. Risk of endoscopic extension has been found to correlate with clinical features such as early age of onset. AIMS We sought to determine whether histologic features correlate with disease extension. METHODS The study population consisted of 40 patients with UC from two large academic centers diagnosed between 2006 and 2017. Eligible cases had a diagnosis of endoscopically limited UC (Montreal E1 or E2) at baseline and ≥ 2 subsequent endoscopic examinations with biopsies. Severity of inflammation was scored using both the Mount Sinai Activity Index and Nancy Histological Index. RESULTS Patients were divided into two cohorts: those who progressed to pancolitis (Montreal E3) were defined as "Extenders" (n = 21), whereas "Non-extenders" (n = 19) were cases without progression in the follow-up period. The median follow-up time was 58.4 months. The histologic scores in the endoscopically involved mucosa of the index biopsies were not associated with subsequent extension of disease, overall. However, among extender cohort, the index histology scores correlated with biopsy scores at extension (r = 0.455, P = 0.044) and index severity was associated with a shorter time to extension (r = - 0.611, P = 0.003). Furthermore, female patients had a shorter time to extension (P = 0.013). CONCLUSIONS Histological severity of limited UC is not an independent predictor of extension in UC. However, among patients who subsequently extend, severe inflammation at baseline correlates with shorter progression time and severe inflammation when extension occurs. Patients with limited UC but severe histologic inflammation may warrant more frequent endoscopic surveillance.
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Affiliation(s)
- Yansheng Hao
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Clara Yzet
- Department of Gastroenterology, Amiens University Hospital, Picardie University, Amiens, France
| | - Russell B McBride
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Aryeh Stock
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Elisa Tiratterra
- Department of Medical and Surgical Sciences (DIMEC), Gastroenterology and Endoscopy Unit, Sant'Orsola University Hospital, University of Bologna, Bologna, Italy
| | - Antonietta D'Errico
- 'F Addarii'' Institute of Oncology and Transplantation Pathology, Sant'Orsola Hospital, University of Bologna, Bologna, Italy
| | - Andrea Belluzzi
- Department of Medical and Surgical Sciences, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Eleonora Scaioli
- Department of Medical and Surgical Sciences, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Paolo Gionchetti
- Department of Medical and Surgical Sciences, St. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Giulia Roda
- Inflammatory Bowel Disease Center, Department of Gastroenterology, Humanitas Clinical and Research Center -IRCCS, Milan, Italy
| | - Ryan Ungaro
- Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Jean-Frederic Colombel
- Department of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Noam Harpaz
- Departments of Pathology and Medicine (Gastroenterology), Icahn School of Medicine At Mount Sinai, New York, NY, USA
| | - Huaibin Mabel Ko
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
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Yu J, Park J, Kang EA, Park SJ, Park JJ, Kim TI, Kim WH, Cheon JH. Prognostic Value of Terminal Ileal Inflammation in Patients with Ulcerative Colitis. Gut Liver 2021; 15:858-866. [PMID: 33767032 PMCID: PMC8593494 DOI: 10.5009/gnl20294] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 11/19/2020] [Accepted: 12/18/2020] [Indexed: 11/04/2022] Open
Abstract
BACKGROUND/AIMS Few studies have investigated terminal ileal lesions and their prognostic value in patients with ulcerative colitis (UC). We evaluated the clinical significance of these lesions as a prognostic factor in patients with UC who were in clinical remission. METHODS We retrospectively selected 567 of 4,066 colonoscopy reports that included positive findings from orificial observations of the terminal ileum (TI) and appendix in patients with UC. We finally recruited patients who were in clinical remission (n=204). We compared the clinical courses, including relapse and other prognostic parameters associated with UC, between the groups. RESULTS The baseline patient characteristics were not significantly different between patients with (n=69, TI+ group) and without TI lesions (n=135, TI- group), although there were more never-smokers in the TI+ group (n=57 [82.6%] in the TI+ group; n=86 [63.7%] in the TI- group; p=0.005). Of note, appendiceal orifice inflammation (AOI) was less frequently found in the TI+ group (14.5%) than in the TI- group (71.9%, p<0.001). The cumulative relapse rate was numerically higher in the TI- group, but it was not significantly different according to the Kaplan-Meier analysis (p=0.116). Multivariate Cox regression analysis also revealed advanced age at diagnosis as the most significant factor (adjusted hazard ratio, 0.964; 95% confidence interval, 0.932 to 0.998; p=0.037), but neither TI inflammation nor AOI were significantly associated with the cumulative relapse rate in patients with UC in clinical remission. CONCLUSIONS For patients with UC in clinical remission, neither terminal ileal lesions nor AOI had significant clinical or predictive value for future relapse.
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Affiliation(s)
- Jongwook Yu
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Jihye Park
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Eun Ae Kang
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Soo Jung Park
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Jae Jun Park
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Tae Il Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Won Ho Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
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18
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Characteristic features of ulcerative colitis with concomitant primary sclerosing cholangitis. PRZEGLAD GASTROENTEROLOGICZNY 2021; 16:184-187. [PMID: 34584578 PMCID: PMC8456759 DOI: 10.5114/pg.2021.108983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 01/30/2021] [Indexed: 11/17/2022]
Abstract
Ulcerative colitis is a chronic inflammatory bowel disease of the colon. The most frequent symptoms include bloody diarrhoea with rectal urgency and tenesmus. It is often complicated by the presence of primary sclerosing cholangitis, a chronic, cholestatic liver disease, characterised by the inflammation and fibrosis of bile ducts. The presence of primary sclerosing cholangitis seems to alter the course of ulcerative colitis, changing its natural course.
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Bresteau C, Amiot A, Kirchgesner J, de'Angelis N, Lefevre JH, Bouhnik Y, Panis Y, Beaugerie L, Allez M, Brouquet A, Carbonnel F, Meyer A. Chronic pouchitis and Crohn's disease of the pouch after ileal pouch-anal anastomosis: Incidence and risk factors. Dig Liver Dis 2021; 53:1128-1135. [PMID: 33931341 DOI: 10.1016/j.dld.2021.03.027] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 03/07/2021] [Accepted: 03/24/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Restorative proctocolectomy with ileal-pouch anal-anastomosis (IPAA) is the operation of choice for patients with ulcerative colitis (UC) or with inflammatory bowel diseases unclassified (IBDU). AIMS to assess the incidence and risk factors of chronic pouchitis (CP) and Crohn's disease of the pouch (CDP) in patients with UC or IBDU. METHODS We conducted a retrospective study. We included consecutive patients who underwent IPAA between 2011 and 2019. The main outcome was the occurrence of CP or CDP. We looked for risk factors with multivariable and a least absolute shrinkage and selection operator (LASSO) Cox models. RESULTS 247 patients were included. The 5-year cumulative incidence of CP or CDP was 35.3% (95%CI: 26.2-43.2). In multivariable analysis, diagnosis of IBDU, age less than 35 years at surgery and extra-intestinal manifestations other than articular and primary sclerosing cholangitis were associated with higher incidence. The LASSO analysis identified these three prognostic factors and articular manifestations. In patients with two or more prognostic factors, 5-year cumulative incidence, was 65.2% (95%CI: 41.8-79.2). CONCLUSIONS Five years after IPAA, approximately one-third of patients had either CP or CDP. Risk factors were IBDU, an age less than 35 years at surgery, articular manifestations and other extra-intestinal manifestations.
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Affiliation(s)
- Clément Bresteau
- Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Université Paris Saclay, CHU Bicêtre, 78, rue du Général Leclerc, Le Kremlin Bicêtre 94270, France
| | - Aurélien Amiot
- Assitance-Publique-Hôpitaux de Paris, Hôpitaux Universitaires Henri Mondor, EA7375, Universite Paris Est Creteil, Créteil, France
| | - Julien Kirchgesner
- Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Sorbonne Université, Paris, France
| | - Nicola de'Angelis
- Assitance-Publique-Hôpitaux de Paris, Hôpitaux Universitaires Henri Mondor, EA7375, Universite Paris Est Creteil, Créteil, France
| | - Jérémie H Lefevre
- Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Sorbonne Université, Paris, France
| | - Yoram Bouhnik
- Assistance Publique-Hôpitaux de Paris, Hôpital Beaujon, Université de Paris, Clichy, France
| | - Yves Panis
- Assistance Publique-Hôpitaux de Paris, Hôpital Beaujon, Université de Paris, Clichy, France
| | - Laurent Beaugerie
- Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Sorbonne Université, Paris, France
| | - Matthieu Allez
- Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Louis, Université de Paris, Paris, France
| | - Antoine Brouquet
- Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Université Paris Saclay, CHU Bicêtre, 78, rue du Général Leclerc, Le Kremlin Bicêtre 94270, France
| | - Franck Carbonnel
- Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Université Paris Saclay, CHU Bicêtre, 78, rue du Général Leclerc, Le Kremlin Bicêtre 94270, France.
| | - Antoine Meyer
- Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Université Paris Saclay, CHU Bicêtre, 78, rue du Général Leclerc, Le Kremlin Bicêtre 94270, France
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20
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Vulliemoz M, Brand S, Juillerat P, Mottet C, Ben-Horin S, Michetti P. TNF-Alpha Blockers in Inflammatory Bowel Diseases: Practical Recommendations and a User's Guide: An Update. Digestion 2021; 101 Suppl 1:16-26. [PMID: 32739923 DOI: 10.1159/000506898] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2019] [Accepted: 03/01/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND Anti-tumour necrosis factor-alpha (anti-TNF) antagonists have been the mainstay in the treatment of inflammatory bowel diseases (IBDs) for over 20 years. SUMMARY This review article aimed to provide an update on recent advances in TNF antagonist therapy for IBDs. Key Messages: Their position in the treatment algorithm has evolved to "rapid step-up therapy" or "top-down therapy" according to disease severity and patients' characteristics. Limitations of anti-TNF antagonists include loss of response in up to 30-50% of patients with or without the development of antibodies. Therapeutic drug monitoring should provide a tailored, personalized approach to this scenario. Recently, biosimilar agents have been approved for IBDs and are considered equivalent in efficacy to the originator.
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Affiliation(s)
- Marianne Vulliemoz
- Crohn's and Colitis Center, Gastroenterologie Beaulieu and Division of Gastroenterology and Hepatology, CHUV, Lausanne, Switzerland,
| | - Stephan Brand
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kantonsspital Sankt Gallen, St. Gallen, Switzerland
| | - Pascal Juillerat
- Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Christian Mottet
- Crohn's and Colitis Center, Gastroenterologie Beaulieu and Division of Gastroenterology and Hepatology, CHUV, Lausanne, Switzerland.,Centre sédunois de Gastroentérologie, Sion, Switzerland
| | - Shomron Ben-Horin
- Inflammatory Bowel Disease Unit and Gastro-Immunology Laboratory Sheba Medical Center Tel-Aviv University, Tel-Aviv, Israel
| | - Pierre Michetti
- Crohn's and Colitis Center, Gastroenterologie Beaulieu and Division of Gastroenterology and Hepatology, CHUV, Lausanne, Switzerland
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21
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de Frias Gomes CG, de Almeida ASR, Mendes CCL, Ellul P, Burisch J, Buhagiar T, Attard A, Lo B, Ungaro RC, da Silva Morão BT, Gouveia CF, de Carvalho e Branco JMD, Rodrigues JMMP, Teixeira C, Dias de Castro MFF, Nunes GFD, Brito M, de Sousa Antunes MC, Borralho Nunes PMFB, da Silva Torres JMT. Histological Inflammation in the Endoscopically Uninflamed Mucosa is Associated With Worse Outcomes in Limited Ulcerative Colitis. Inflamm Bowel Dis 2021; 28:350-357. [PMID: 33999195 PMCID: PMC8889288 DOI: 10.1093/ibd/izab069] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND The Montreal classification categorizes patients with ulcerative colitis (UC) based on their macroscopic disease extent. Independent of endoscopic extent, biopsies through all colonic segments should be retrieved during index colonoscopy. However, the prognostic value of histological inflammation at diagnosis in the inflamed and uninflamed regions of the colon has never been assessed. METHODS This was a multicenter retrospective cohort study of newly diagnosed patients with treatment-naïve proctitis and left-sided UC. Biopsies from at least 2 colonic segments (endoscopically inflamed and uninflamed mucosa) were retrieved and reviewed by 2 pathologists. Histological features in the endoscopically inflamed and uninflamed mucosa were scored using the Nancy score. The primary outcomes were disease complications (proximal disease extension, need for hospitalization or colectomy) and higher therapeutic requirements (need for steroids or for therapy escalation). RESULTS Overall, 93 treatment-naïve patients were included, with a median follow-up of 44 months (range, 2-329). The prevalence of any histological inflammation above the endoscopic margin was 71%. Proximal disease extension was more frequent in patients with histological inflammation in the endoscopically uninflamed mucosa at diagnosis (21.5% vs 3.4%, P = 0.04). Histological involvement above the endoscopic margin was the only predictor associated with an earlier need for therapy escalation (adjusted hazard ratio, 3.69; 95% confidence interval, 1.05-13.0); P = 0.04) and disease complications (adjusted hazard ratio, 4.79; 95% confidence interval, 1.10-20.9; P = 0.04). CONCLUSIONS The presence of histological inflammation in the endoscopically uninflamed mucosa at the time of diagnosis was associated with worse outcomes in limited UC.
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Affiliation(s)
| | | | | | | | - Johan Burisch
- Gastrounit, Medical Division, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
| | | | | | - Bobby Lo
- Gastrounit, Medical Division, Hvidovre Hospital, University of Copenhagen, Hvidovre, Denmark
| | - Ryan C Ungaro
- The Dr. Henry Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | | | | | | | | | - Cristina Teixeira
- Gastroenterology Division, Centro Hospitalar de Setúbal, Setúbal, Portugal
| | | | | | - Mariana Brito
- Gastroenterology Division, Hospital Garcia de Orta, Almada, Portugal
| | | | | | - Joana Maria Tinoco da Silva Torres
- Gastroenterology Division, Hospital Beatriz Ângelo, Loures, Portugal,Address correspondence to: Joana Torres, MD, PhD, Gastroenterology Division, Hospital Beatriz Ângelo, Avenida Carlos Teixeira, 3 2674-514 Loures, Portugal ()
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22
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Vermeire S, Chiorean M, Panés J, Peyrin-Biroulet L, Zhang J, Sands BE, Lazin K, Klassen P, Naik SU, Cabell CH, Sandborn WJ. Long-term Safety and Efficacy of Etrasimod for Ulcerative Colitis: Results from the Open-label Extension of the OASIS Study. J Crohns Colitis 2021; 15:950-959. [PMID: 33475734 PMCID: PMC8218705 DOI: 10.1093/ecco-jcc/jjab016] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Etrasimod is an oral, selective, sphingosine 1-phosphate receptor modulator. In a phase 2, randomised, double-blind, placebo-controlled trial in adults with moderately-to-severely active ulcerative colitis [OASIS], etrasimod 2 mg provided significant benefit versus placebo and was generally well tolerated. This open-label extension [OLE] evaluated safety and efficacy of etrasimod for up to 52 weeks. METHODS In OASIS, 156 patients received etrasimod 1 mg, etrasimod 2 mg, or placebo, once daily for 12 weeks. After completing OASIS, patients could enrol in the OLE and receive etrasimod 2 mg for an additional 34-40 weeks. RESULTS In all, 118 patients enrolled in the OLE; 112 patients received etrasimod 2 mg at any point and were evaluated for safety and efficacy. A total of 92 [82%] patients who received etrasimod 2 mg in the OLE completed the study. Treatment-emergent adverse events occurred in 60% [67/112] of patients receiving etrasimod 2 mg at any time, most commonly worsening ulcerative colitis and anaemia; 94% of adverse events were mild/moderate. At end of treatment, 64% of patients met the criteria for clinical response, 33% for clinical remission, and 43% for endoscopic improvement. Week 12 clinical response, clinical remission, or endoscopic improvement was maintained to end of treatment in 85%, 60%, or 69% of patients, respectively. Steroid-free clinical remission occurred in 22% of overall patients. CONCLUSIONS In this long-term extension study, etrasimod 2 mg demonstrated a favourable safety profile. Most patients with clinical response, clinical remission, or endoscopic improvement at Week 12 maintained that status to end of treatment.
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Affiliation(s)
- Séverine Vermeire
- Department of Gastroenterology & Hepatology, University Hospitals Leuven, Leuven, Belgium,Corresponding author: Séverine Vermeire, MD, PhD, University Hospitals Leuven, Department of Gastroenterology & Hepatology, Herestraat 49, B-3000 Leuven, Leuven, Belgium. Tel.: +3216344225; fax: +3216344419;
| | - Michael Chiorean
- Division of Gastroenterology, Virginia Mason Medical Center, Seattle, WA, USA
| | - Julián Panés
- Department of Gastroenterology, Hospital Clinic de Barcelona, IDIBAPS, CIBERehd, Barcelona, Spain
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Nancy University Hospital, Nancy, France,INSERM U1256 NGERE, Lorraine University, Nancy, France
| | | | - Bruce E Sands
- Dr Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | | | | | | | - William J Sandborn
- Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA
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23
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Barnes A, Spizzo P, Mountifield R. Corticosteroid exposure prior to admission and predicting need for rescue therapy in acute severe ulcerative colitis. Intern Med J 2020; 52:828-833. [PMID: 33197107 DOI: 10.1111/imj.15131] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 09/25/2020] [Accepted: 11/07/2020] [Indexed: 11/30/2022]
Abstract
INTRODUCTION Steroid exposure has been associated with poorer outcomes following colectomy in acute severe ulcerative colitis (ASUC). Our centre aimed to examine the effect of prolonged oral corticosteroid therapy immediately prior to admission on the likelihood of requiring rescue therapy along with predictors of intravenous corticosteroid failure on day one of admission. METHODS A retrospective case note and electronic record review was conducted at a tertiary inflammatory bowel disease referral centre of admissions for ASUC meeting Truelove and Witts criteria from 2013 to 2019.The data was analysed for the effect of pre-admission steroid exposure on need for rescue therapy and for predictors of intravenous corticosteroid failure. RESULTS 92 admissions were identified for ASUC meeting Truelove and Witts criteria. Over one week of steroid therapy prior to admission was associated with need for rescue therapy and trended to significance for colectomy at admission and at twelve months. A generalised linear model was constructed with multivariate regression significant for over one week of steroid therapy prior to admission, endoscopic Mayo score, and albumin. The AUROC for this model was 0.86. CONCLUSION Prolonged steroid use prior to ASUC admission is a significant predictor of need for rescue therapy. A generalised linear model incorporating steroid prior to admission, endoscopic Mayo score, and albumin was highly accurate at predicting failure of corticosteroid. Consideration should be given for commencement of rescue therapy prior to day three, especially in those with prolonged steroid prior to admission. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Alex Barnes
- Department of Gastroenterology, Flinders Medical Centre, South Australia, Australia.,College of Medicine and Public Health, Flinders University, South Australia, Australia
| | - Paul Spizzo
- Department of Gastroenterology, Flinders Medical Centre, South Australia, Australia.,College of Medicine and Public Health, Flinders University, South Australia, Australia
| | - Réme Mountifield
- Department of Gastroenterology, Flinders Medical Centre, South Australia, Australia.,College of Medicine and Public Health, Flinders University, South Australia, Australia
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24
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Honap S, Chee D, Chapman TP, Patel M, Kent AJ, Ray S, Sharma E, Kennedy J, Cripps S, Walsh A, Goodhand JR, Ahmad T, Satsangi J, Irving PM, Kennedy NA, O’Neill R, Mawdsley J, Samaan M, Anderson S, Sanderson J, Gordon C, Prasad S, Lin S, Chanchlani N, Elworthy C, Cairnes V, Travis S, Brain O, Palmer R, Ambrose T, Dubois P, Hayee BH, Chung-Faye G, Medcalf L, Begum Y, O’Neill R, Mawdsley J, Samaan M, Anderson S, Sanderson J, Gordon C, Prasad S, Lin S, Chanchlani N, Elworthy C, Cairnes V, Travis S, Brain O, Palmer R, Ambrose T, Dubois P, Hayee BH, Chung-Faye G, Medcalf L. Real-world Effectiveness of Tofacitinib for Moderate to Severe Ulcerative Colitis: A Multicentre UK Experience. J Crohns Colitis 2020; 14:1385-1393. [PMID: 32280965 DOI: 10.1093/ecco-jcc/jjaa075] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Tofacitinib is a partially selective Janus kinase inhibitor approved for the treatment of refractory moderate to severe ulcerative colitis [UC]. We sought to define the effectiveness and adverse effects of tofacitinib in a real-world cohort. METHODS We conducted a retrospective observational cohort study of 134 patients with UC [64% male; median age 37 years [range 16-81]; 83% of patients had previously received at least one biologic] treated with tofacitinib from October 2018 to October 2019 in four UK centres. Disease activity was assessed using the Simple Clinical Colitis Activity Index [SCCAI] or partial Mayo score [PMS], depending on study site. Response and remission were defined as a reduction in SCCAI or PMS of ≥3and SCCAI ≤2 or a PMS ≤1, respectively. RESULTS Overall, 74% (88/119; 95 confidence interval [CI] 65-81%] patients responded to tofacitinib at Week 8 and steroid-free remission was observed in 44% [47/108; 95% CI 3453%] patients at Week 26. Primary non-response was independently associated with younger age [p = 0.014] and higher C-reactive protein [CRP] levels at baseline [p = 0.004]. Only 23% [3/13] of patients who continued tofacitinib in the setting of primary non-response were in steroid-free remission at Week 26. Prior biologic exposure did not influence response or remission rates. Dose escalation, however, recaptured response in approximately half of patients who had lost response. Dyslipidaemia was observed in 20% [27/134; 95% CI 1428%] of patients, but adverse events necessitating drug withdrawal were uncommon and no venous thromboembolic events occurred. CONCLUSIONS In this multicentre real-world cohort, tofacitinib was well tolerated and clinically effective in a treatment-refractory UC population.
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Affiliation(s)
- Sailish Honap
- IBD Centre, Guy's and St Thomas' Hospitals NHS Foundation Trust, London, UK
| | - Desmond Chee
- Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, UK
| | - Thomas P Chapman
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK
| | - Mehul Patel
- Department of Gastroenterology, King's College Hospital NHS Foundation Trust, London, UK
| | - Alexandra J Kent
- Department of Gastroenterology, King's College Hospital NHS Foundation Trust, London, UK
| | - Shuvra Ray
- IBD Centre, Guy's and St Thomas' Hospitals NHS Foundation Trust, London, UK
| | - Esha Sharma
- IBD Centre, Guy's and St Thomas' Hospitals NHS Foundation Trust, London, UK
| | - James Kennedy
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK
| | - Sarah Cripps
- Department of Pharmacy, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK
| | - Alissa Walsh
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK
| | - James R Goodhand
- Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, UK
| | - Tariq Ahmad
- Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, UK
| | - Jack Satsangi
- Translational Gastroenterology Unit, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK
| | - Peter M Irving
- IBD Centre, Guy's and St Thomas' Hospitals NHS Foundation Trust, London, UK.,School of Immunology and Microbial Sciences, King's College London, London, UK
| | - Nicholas A Kennedy
- Department of Gastroenterology, Royal Devon and Exeter Hospital NHS Foundation Trust, Exeter, UK
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25
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Long-term outcome of immunomodulator use in pediatric patients with inflammatory bowel disease. Dig Liver Dis 2020; 52:164-172. [PMID: 31640916 DOI: 10.1016/j.dld.2019.09.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 09/02/2019] [Accepted: 09/09/2019] [Indexed: 12/11/2022]
Abstract
OBJECTIVES In the era where new biologicals are entering the market, the place of immunomodulators in the treatment of pediatric inflammatory bowel disease (IBD) needs to be reassessed. METHODS All children with Crohn's disease (CD) or ulcerative colitis (UC) followed at our center over the last 10 years were reviewed. Children who received conventional therapy (including 5-aminosalicylates, steroids, thiopurines and methotrexate) since diagnosis were included. Primary outcome was steroid-free clinical remission without need for rescue therapy (biologics or surgery) at 6 and 12 months after diagnosis and at last follow-up. Cox proportional hazard modelling was performed to determine variables at diagnosis associated with outcomes. RESULTS In total, 176 IBD patients (121 CD, 55 UC) were identified with a median follow-up of 4.6 [2.0-8.1] years. Remission rates were 79.6% at month 6, but decreased to 60.2% at month 12, and 31.8% at last follow-up. Higher CRP [1.006 (1.001-1.011)], lower albumin [1.050 (1.012-1.086)] and growth impairment [1.214 (1.014-1.373)] in CD patients and higher PUCAI score [1.038 (1.006-1.072)] and low iron [1.023 (1.003-1.043)] in UC patients were associated with treatment failure (all p < 0.05). CONCLUSION Only 32% pediatric IBD patients will remain free of biologics or surgery 5-years after diagnosis. Especially children with a high disease burden at diagnosis were more likely to fail conventional therapy.
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Moore AC, Huang VW, Bourdages R, Fedorak RN, Reinhard C, Leung Y, Bressler B, Rosenfeld G. IBDoc Canadian User Performance Evaluation. Inflamm Bowel Dis 2019; 25:1107-1114. [PMID: 30535387 DOI: 10.1093/ibd/izy357] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Fecal calprotectin (FC) is a stool biomarker that has been shown to be sensitive and specific for mucosal inflammation in patients with inflammatory bowel disease (IBD). The test is limited by the requirement for patients to collect and return stool samples. A home-based FC test may improve test adherence. The aim of this study is to evaluate the usability of the IBDoc, a home-based FC measuring test, and to determine the accuracy of results compared with traditional lab-based ELISA values. METHODS Patients were prospectively enrolled from 3 tertiary sites across Canada between May and August 2017. Patients completed a questionnaire establishing ease-of-use of the IBDoc. Patients completed a FC measurement using the IBDoc, and results were compared with an ELISA-determined FC measurement on the same stool sample. RESULTS Sixty-one participants were enrolled in the study (29 CD, 32 UC). Seventy-nine percent of patients (48 of 61) agreed that the IBDoc was easy to use, with 85% (52 of 61) of patients strongly agreeing that they were willing use the home kit in the future. The IBDoc and ELISA measurement comparison showed an 88% agreement across all values. There were no false positives or negatives using qualitative comparison. CONCLUSIONS The home-based IBDoc FC measuring test is acceptable to patients and correlates extremely well with the standard ELISA-determined FC value. The IBDoc enables clinicians to more easily adopt a treat-to-target approach, improve long-term outcomes, and patients' quality of life with IBD. This study is registered at ClinicalTrials.gov, number NCT03408249.
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Affiliation(s)
- Alice C Moore
- Department of Gastroenterology, University of British Columbia, Vancouver, Canada
| | - Vivian W Huang
- Division of Gastroenterology, University of Toronto, Toronto, Canada
| | | | - Richard N Fedorak
- Division of Gastroenterology, University of Alberta, Edmonton, Canada
| | | | - Yvette Leung
- Department of Gastroenterology, University of British Columbia, Vancouver, Canada
| | - Brian Bressler
- Department of Gastroenterology, University of British Columbia, Vancouver, Canada
| | - Greg Rosenfeld
- Department of Gastroenterology, University of British Columbia, Vancouver, Canada
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Tsuda S, Carreras J, Kikuti YY, Nakae H, Dekiden-Monma M, Imai J, Tsuruya K, Nakamura J, Tsukune Y, Uchida T, Matsushima M, Roncador G, Suzuki T, Nakamura N, Mine T. Prediction of steroid demand in the treatment of patients with ulcerative colitis by immunohistochemical analysis of the mucosal microenvironment and immune checkpoint: role of macrophages and regulatory markers in disease severity. Pathol Int 2019; 69:260-271. [PMID: 30990953 DOI: 10.1111/pin.12794] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 02/24/2019] [Indexed: 12/11/2022]
Abstract
We aimed to characterize the mucosal immune microenvironment and immune checkpoint of Ulcerative colitis (UC) by immunohistochemistry with correlation to prognosis: requirement of second-line steroid-therapy within the 2-years after diagnosis (SR). A series of 72 cases included 56 UC, 43 non-SR (with first-line treatment 5-ASA) and 13 SR, 11 infectious colitis and 5 normal colonic biopsies. Normal mucosa was characterized by low infiltrates but high BTLA and TNFRSF14. Compared to normal, UC had increased pan-immune-markers of CD3, CD8, FOXP3, PD-1, CD68, CD16, CD163, PTX3 and CD11C but had decreased BTLA (P < 0.05); by GSEA analysis comparable results were found in an independent UC gene-expression-data set (GSE38713). Compared to infectious, UC had higher CD4, CD8, PTX3 and CD11C but lower BTLA (P < 0.05). Compared to non-SR, SR had lower FOXP3 + Tregs (Odds-Ratio = 0.114, P = 0.002), PD-1 (OR = 0.176, P = 0.002) and CD163/CD68 M2-ratio (OR, 0.019, P = 0.019) but higher CD68 + pan-macrophages (OR = 6.034, P = 0.002). Higher Baron endoscopic and Geboes histologic disease activity scores also correlated with SR. In summary, UC was characterized by increased pan-immune-markers, normal TNFRSF14 and low BTLA. SR had increased CD68 + pan-macrophages but lower immune inhibitors of FOXP3 + Tregs, PD-1 and CD163/CD68 M2-macrophage ratio. In conclusion, alterations of the immune homeostasis mechanisms are relevant in the UC pathogenesis and steroid-requiring situation.
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Affiliation(s)
- Shingo Tsuda
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Joaquim Carreras
- Department of Pathology, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Yara Y Kikuti
- Department of Pathology, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Hirohiko Nakae
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Makiko Dekiden-Monma
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Jin Imai
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Kota Tsuruya
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Jun Nakamura
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Yoko Tsukune
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Tetsufumi Uchida
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Masashi Matsushima
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Giovanna Roncador
- Monoclonal Antibodies Core Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Takayoshi Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Naoya Nakamura
- Department of Pathology, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
| | - Tetsuya Mine
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Tokai University, School of Medicine, Isehara, Kanagawa, Japan
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Burisch J, Ungaro R, Vind I, Prosberg MV, Bendtsen F, Colombel JF, Vester-Andersen MK. Proximal Disease Extension in Patients With Limited Ulcerative Colitis: A Danish Population-based Inception Cohort. J Crohns Colitis 2017; 11:1200-1204. [PMID: 28486626 PMCID: PMC6279091 DOI: 10.1093/ecco-jcc/jjx066] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2017] [Accepted: 05/06/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Disease extent in ulcerative colitis [UC] is dynamic and can progress over time. Little is known about risk factors for UC extension in the era of biologics. We investigated the risk of UC extension and subsequent risk of surgery in a Danish population-based cohort. METHODS All incident UC cases in a strictly defined Copenhagen area between 2003 and 2004 were followed prospectively through 2011. Disease extension was defined as patients with limited UC [E1 or E2] at diagnosis having progressed from the initial extent by colonoscopy or surgery to E2 or extensive colitis [E3]. Associations between progression or colectomy and multiple covariates were analysed by Cox regression analysis. RESULTS Of 300 UC patients, 220 [73%] had E1 or E2 at diagnosis. During follow-up, 50 [23%] patients with E1/E2 progressed to E3, and 22 [10%] with E1 progressed to E2. Disease extent at diagnosis was the sole predictor of extension to E3. A total of 18 [8%] patients with E1/E2 at diagnosis had a colectomy. Progression from E1/E2 to E3, female gender and a history of smoking were risk factors for colectomy. CONCLUSION After 7 years of follow-up, 33% of patients with limited UC experienced disease extension. Only extent at diagnosis was a clinical predictor for disease extension. The risk of colectomy was increased in former smokers and patients who progressed to extensive colitis. This highlights the need to prevent disease progression in patients with limited UC, and to identify new histological or molecular markers that might help stratify risks for disease progression.
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Affiliation(s)
- Johan Burisch
- Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark,Corresponding author: Johan Burisch, MD, PhD, Gastrounit, Medical Division, Copenhagen University Hospital, Hvidovre, Kettegård Allé 30, 2750 Hvidovre, Denmark.
| | - Ryan Ungaro
- Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Ida Vind
- Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Michelle V Prosberg
- Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Flemming Bendtsen
- Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark
| | - Jean-Frederic Colombel
- Susan and Leonard Feinstein IBD Clinical Center, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Marianne K. Vester-Andersen
- Gastrounit, Medical Division, Copenhagen University Hospital Hvidovre, Hvidovre, Denmark,Department of Internal Medicine, Zealand University Hospital, Køge, Denmark
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29
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Jung YS, Han M, Kim WH, Park S, Cheon JH. Incidence and Clinical Outcomes of Inflammatory Bowel Disease in South Korea, 2011-2014: A Nationwide Population-Based Study. Dig Dis Sci 2017; 62:2102-2112. [PMID: 28593437 DOI: 10.1007/s10620-017-4640-9] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2017] [Accepted: 05/29/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND The incidence of inflammatory bowel disease (IBD) is increasing in East Asia; however, population-based data from this region are lacking. AIM We conducted a nationwide, population-based study to examine the incidence and disease course of IBD in South Korea. METHODS Using the National Health Insurance claims data, we collected data on patients diagnosed with IBD [10,049 with ulcerative colitis (UC) and 5595 with Crohn's disease (CD)] from 2011 to 2014. RESULTS During the study period, the average annual incidence of UC was 5.0 per 105, while that of CD was 2.8 per 105. Among patients with UC, the cumulative rates of surgery 1 and 4 years after diagnosis were 1.0 and 2.0%; those among patients with CD were 9.0 and 13.9%, respectively. The 1- and 4-year cumulative rates of moderate- to high-dose corticosteroid use were, respectively, 26.6 and 45.2% among patients with UC, and 29.9 and 50.8% among those with CD. Similarly, the 1- and 4-year cumulative rates of immunomodulator use were 14.1 and 26.4% among patients with UC, and 58.3 and 76.1% among those with CD, respectively. With regard to biologic use, the 1- and 4-year cumulative rates were 3.0 and 9.0% among patients with UC, and 11.1 and 31.7% among those with CD, respectively. CONCLUSIONS The recent incidence of IBD in South Korea has been the highest in East Asia. Patients who had been diagnosed recently with IBD showed lower rates of surgery and higher rates of immunomodulator and biologic use compared to those reported ever in South Korea.
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Affiliation(s)
- Yoon Suk Jung
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Minkyung Han
- Department of Public Health, Graduate School, Yonsei University, Seoul, Republic of Korea
| | - Won Ho Kim
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea
| | - Sohee Park
- Department of Biostatistics, Graduate School of Public Health, Yonsei University, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
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30
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Freeman K, Taylor-Phillips S, Connock M, Court R, Tsertsvadze A, Shyangdan D, Auguste P, Mistry H, Arasaradnam R, Sutcliffe P, Clarke A. Test accuracy of drug and antibody assays for predicting response to antitumour necrosis factor treatment in Crohn's disease: a systematic review and meta-analysis. BMJ Open 2017; 7:e014581. [PMID: 28674134 PMCID: PMC5734585 DOI: 10.1136/bmjopen-2016-014581] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVE To present meta-analytic test accuracy estimates of levels of antitumour necrosis factor (anti-TNF) and antibodies to anti-TNF to predict loss of response or lack of regaining response in patients with anti-TNF managed Crohn's disease. METHODS MEDLINE, Embase, the Cochrane Library and Science Citation Index were searched from inception to October/November 2014 to identify studies which reported 2×2 table data of the association between levels of anti-TNF or its antibodies and clinical status. Hierarchical/bivariate meta-analysis was undertaken with the user-written 'metandi' package of Harbord and Whiting using Stata V.11 software, for infliximab, adalimumab,anti-infliximab and anti-adalimumab levels as predictors of loss of response. Prevalence of Crohn's disease in included studies was meta-analysed using a random effects model in MetaAnalyst software to calculate positive and negative predictive values. The search was updated in January 2017. RESULTS 31 studies were included in the review. Studies were heterogeneous with respect to the type of test used, criteria for establishing response and loss of response, population examined and results. Meta-analytic summary point estimates for sensitivity and specificity were 65.7% and 80.6% for infliximab trough levels and 56% and 79% for antibodies to infliximab, respectively. Pooled results for adalimumab trough levels and antibodies to adalimumab were similar. Pooled positive and negative predictive values ranged between 70% and 80% implying that between 20% and 30% of both positive and negative test results may be incorrect in predicting loss of response. CONCLUSION The available evidence suggests that these tests have modest predictive accuracy for clinical status; direct test accuracy comparisons in the same population are needed. More clinical trial evidence from test-treat studies is required before the clinical utility of the tests can be reliably evaluated.
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Affiliation(s)
- Karoline Freeman
- Warwick Medical School, University of Warwick, Coventry, Warwickshire, UK
| | | | - Martin Connock
- Warwick Medical School, University of Warwick, Coventry, Warwickshire, UK
| | - Rachel Court
- Warwick Medical School, University of Warwick, Coventry, Warwickshire, UK
| | | | - Deepson Shyangdan
- Warwick Medical School, University of Warwick, Coventry, Warwickshire, UK
| | - Peter Auguste
- Warwick Medical School, University of Warwick, Coventry, Warwickshire, UK
| | - Hema Mistry
- Warwick Medical School, University of Warwick, Coventry, Warwickshire, UK
| | - Ramesh Arasaradnam
- Warwick Medical School, University of Warwick, Coventry, Warwickshire, UK
- Department of Gastroenterology, University Hospital Coventry and Warwickshire, Coventry, UK
| | - Paul Sutcliffe
- Warwick Medical School, University of Warwick, Coventry, Warwickshire, UK
| | - Aileen Clarke
- Warwick Medical School, University of Warwick, Coventry, Warwickshire, UK
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31
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Fattahi MR, Malek-Hosseini SA, Sivandzadeh GR, Safarpour AR, Bagheri Lankarani K, Taghavi AR, Ejtehadi F. Clinical Course of Ulcerative Colitis After Liver Transplantation in Patients with Concomitant Primary Sclerosing Cholangitis and Ulcerative Colitis. Inflamm Bowel Dis 2017; 23:1160-1167. [PMID: 28520586 DOI: 10.1097/mib.0000000000001105] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND The natural history of ulcerative colitis (UC) after liver transplantation (LT) for primary sclerosing cholangitis (PSC) remains ill defined. This study aimed to evaluate the course of UC after LT for PSC. METHODS The course of UC, including the clinical colitis severity index, was evaluated in patients with concomitant PSC and UC who received LT for PSC-induced end-stage liver disease. A total of 167 (55.4%) patients with PSC had concurrent inflammatory bowel disease (IBD). Of 159 cases of IBD that started before LT, 152 (95.5%) had UC and 7 (4.5%) had Crohn's disease. RESULTS The mean duration of patient follow-up after LT was 47.7 ± 33.5 months. The simple clinical colitis activity index scores after LT showed no change in 15.8% of patients, decreased in 78.3%, and increased in 5.9%. Seventy-one (46.7%) patients required no change in their specific UC treatment after LT, whereas 12 (7.9%) had to use more aggressive treatments after LT. In 69 (45.4%) patients, treatment could be tapered although not discontinued. Multiple logistic regression analysis demonstrated that the duration of LT (odds ratio = 1.02; 95% confidence interval, 1.00-1.05, P = 0.03) was significantly associated with aggravation in the clinical course of UC after LT. Posttransplant cyclosporine exposure (odds ratio = 0.14; 95% confidence interval, 0.015-0.79, P = 0.028) and pretransplant body weight (odds ratio = 0.81; 95% confidence interval, 0.71-0.93, P = 0.003) demonstrated a protective effect. CONCLUSIONS Although the clinical course of UC remains unchanged or even improves in the majority of patients after LT, some may experience an aggressive course. The type of immunosuppression after transplantation can affect UC activity after LT. Cyclosporine may have some protective effects post-LT.
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Affiliation(s)
- Mohammad Reza Fattahi
- *Department of Digestive Diseases, Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Namazi Hospital, Shiraz, Iran; †Department of Surgery, Transplant Research Center, Shiraz University of Medical Sciences, Namazi Hospital, Shiraz, Iran; ‡Department of Internal Medicine, Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Namazi Hospital, Shiraz, Iran; §Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran; and ‖Department of Internal Medicine, Healthcare Policy Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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32
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Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel JF. Ulcerative colitis. Lancet 2017; 389:1756-1770. [PMID: 27914657 PMCID: PMC6487890 DOI: 10.1016/s0140-6736(16)32126-2] [Citation(s) in RCA: 2407] [Impact Index Per Article: 300.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2016] [Revised: 07/15/2016] [Accepted: 07/21/2016] [Indexed: 02/06/2023]
Abstract
Ulcerative colitis is a chronic inflammatory disease affecting the colon, and its incidence is rising worldwide. The pathogenesis is multifactorial, involving genetic predisposition, epithelial barrier defects, dysregulated immune responses, and environmental factors. Patients with ulcerative colitis have mucosal inflammation starting in the rectum that can extend continuously to proximal segments of the colon. Ulcerative colitis usually presents with bloody diarrhoea and is diagnosed by colonoscopy and histological findings. The aim of management is to induce and then maintain remission, defined as resolution of symptoms and endoscopic healing. Treatments for ulcerative colitis include 5-aminosalicylic acid drugs, steroids, and immunosuppressants. Some patients can require colectomy for medically refractory disease or to treat colonic neoplasia. The therapeutic armamentarium for ulcerative colitis is expanding, and the number of drugs with new targets will rapidly increase in coming years.
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Affiliation(s)
- Ryan Ungaro
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Saurabh Mehandru
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Patrick B Allen
- Division of Gastroenterology, Ulster Hospital, Belfast, Northern Ireland, UK
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, University Hospital of Nancy-Brabois, Vandoeuvre-les-Nancy, France
| | - Jean-Frédéric Colombel
- Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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Ban H, Bamba S, Nishida A, Inatomi O, Shioya M, Takahashi KI, Imaeda H, Murata M, Sasaki M, Tsujikawa T, Andoh A. Prognostic factors affecting early colectomy in patients with moderate to severe ulcerative colitis treated with calcineurin inhibitors. Exp Ther Med 2016; 12:829-834. [PMID: 27446283 DOI: 10.3892/etm.2016.3341] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2015] [Accepted: 04/29/2016] [Indexed: 12/23/2022] Open
Abstract
Calcineurin inhibitors (CNIs) such as cyclosporine A (CSA) and tacrolimus (FK506) are often used as a second-line drug for steroid-refractory or steroid-dependent patients with ulcerative colitis (UC). The aim of the present study was to determine the prognostic factors for early colectomy. A total of 85 hospitalized patients with UC (CSA, 50 patients; FK506, 35 patients) were enrolled. Colectomy carried out within 60 days of starting CNI therapy was defined as 'early colectomy'. To assess the prognostic factors affecting early colectomy, clinical practical variables, including the Onodera-prognostic nutritional index (O-PNI): 10xAlb+0.005× (total lymphocyte count), were analyzed. The results demonstrated that the significant factors predicting early colectomy were i) disease severity, ii) immunomodulator-naïve history, iii) lower serum hematocrit, iv) lower serum albumin and v) lower O-PNI. In addition, the significant factors predicting overall colectomy were as follows: i) C7-HRP positivity and ii) >10,000 mg of prednisolone used prior to the initiation of CNI treatment. The combination of hematocrit and O-PNI enhanced the prediction of early colectomy. Clinical variables such as hematocrit and O-PNI were the significant factors predicting colectomy. These results may be used as a guide to predict the outcome of patients with UC in clinical settings.
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Affiliation(s)
- Hiromitsu Ban
- Division of Endoscopy, Shiga University of Medical Science, Ōtsu, Shiga 520-2192, Japan
| | - Shigeki Bamba
- Division of Gastroenterology, Shiga University of Medical Science, Ōtsu, Shiga 520-2192, Japan
| | - Atsushi Nishida
- Division of Gastroenterology, Shiga University of Medical Science, Ōtsu, Shiga 520-2192, Japan
| | - Osamu Inatomi
- Division of Gastroenterology, Shiga University of Medical Science, Ōtsu, Shiga 520-2192, Japan
| | - Makoto Shioya
- Division of Gastroenterology, Shiga University of Medical Science, Ōtsu, Shiga 520-2192, Japan
| | - Ken-Ichiro Takahashi
- Division of Gastroenterology, Shiga University of Medical Science, Ōtsu, Shiga 520-2192, Japan
| | - Hirotsugu Imaeda
- Division of Gastroenterology, Shiga University of Medical Science, Ōtsu, Shiga 520-2192, Japan
| | - Masaki Murata
- Division of Gastroenterology, Shiga University of Medical Science, Ōtsu, Shiga 520-2192, Japan
| | - Masaya Sasaki
- Division of Clinical Nutrition, Shiga University of Medical Science, Ōtsu, Shiga 520-2192, Japan
| | - Tomoyuki Tsujikawa
- Department of Comprehensive Internal Medicine, Shiga University of Medical Science, Ōtsu, Shiga 520-2192, Japan
| | - Akira Andoh
- Division of Gastroenterology, Shiga University of Medical Science, Ōtsu, Shiga 520-2192, Japan
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