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1
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Wang LF, Chen PR, He SK, Duan SH, Zhang Y. Predictors and optimal management of tumor necrosis factor antagonist nonresponse in inflammatory bowel disease: A literature review. World J Gastroenterol 2023; 29:4481-4498. [PMID: 37621757 PMCID: PMC10445007 DOI: 10.3748/wjg.v29.i29.4481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 06/28/2023] [Accepted: 07/17/2023] [Indexed: 08/02/2023] Open
Abstract
Tumor necrosis factor-α (TNF-α) antagonists, the first biologics approved for treating patients with inflammatory bowel disease (IBD), are effective for the induction and maintenance of remission and significantly improving prognosis. However, up to one-third of treated patients show primary nonresponse (PNR) to anti-TNF-α therapies, and 23%-50% of IBD patients experience loss of response (LOR) to these biologics during subsequent treatment. There is still no recognized predictor for evaluating the efficacy of anti-TNF drugs. This review summarizes the existing predictors of PNR and LOR to anti-TNF in IBD patients. Most predictors remain controversial, and only previous surgical history, disease manifestations, drug concentrations, antidrug antibodies, serum albumin, some biologic markers, and some genetic markers may be potentially predictive. In addition, we also discuss the next steps of treatment for patients with PNR or LOR to TNF antagonists. Therapeutic drug monitoring plays an important role in treatment selection. Dose escalation, combination therapy, switching to a different anti-TNF drug, or switching to a biologic with a different mechanism of action can be selected based on the concentration of the drug and/or antidrug antibodies.
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Affiliation(s)
- Liang-Fang Wang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Ping-Run Chen
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Si-Ke He
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Shi-Hao Duan
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yan Zhang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
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Coufal S, Kverka M, Kreisinger J, Thon T, Rob F, Kolar M, Reiss Z, Schierova D, Kostovcikova K, Roubalova R, Bajer L, Jackova Z, Mihula M, Drastich P, Tresnak Hercogova J, Novakova M, Vasatko M, Lukas M, Tlaskalova-Hogenova H, Jiraskova Zakostelska Z. Serum TGF- β1 and CD14 Predicts Response to Anti-TNF- α Therapy in IBD. J Immunol Res 2023; 2023:1535484. [PMID: 37383609 PMCID: PMC10299888 DOI: 10.1155/2023/1535484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 05/12/2023] [Accepted: 05/22/2023] [Indexed: 06/30/2023] Open
Abstract
Background Tumor necrosis factor-alpha (TNF-α) agonists revolutionized therapeutic algorithms in inflammatory bowel disease (IBD) management. However, approximately every third IBD patient does not respond to this therapy in the long term, which delays efficient control of the intestinal inflammation. Methods We analyzed the power of serum biomarkers to predict the failure of anti-TNF-α. We collected serum of 38 IBD patients at therapy prescription and 38 weeks later and analyzed them with relation to therapy response (no-, partial-, and full response). We used enzyme-linked immunosorbent assay to quantify 16 biomarkers related to gut barrier (intestinal fatty acid-binding protein, liver fatty acid-binding protein, trefoil factor 3, and interleukin (IL)-33), microbial translocation, immune system regulation (TNF-α, CD14, lipopolysaccharide-binding protein, mannan-binding lectin, IL-18, transforming growth factor-β1 (TGF-β1), osteoprotegerin (OPG), insulin-like growth factor 2 (IGF-2), endocrine-gland-derived vascular endothelial growth factor), and matrix metalloproteinase system (MMP-9, MMP-14, and tissue inhibitors of metalloproteinase-1). Results We found that future full-responders have different biomarker profiles than non-responders, while partial-responders cannot be distinguished from either group. When future non-responders were compared to responders, their baseline contained significantly more TGF-β1, less CD14, and increased level of MMP-9, and concentration of these factors could predict non-responders with high accuracy (AUC = 0.938). Interestingly, during the 38 weeks, levels of MMP-9 decreased in all patients, irrespective of the outcome, while OPG, IGF-2, and TGF-β1 were higher in non-responders compared to full-responders both at the beginning and the end of the treatment. Conclusions The TGF-β1 and CD14 can distinguish non-responders from responders. The changes in biomarker dynamics during the therapy suggest that growth factors (such as OPG, IGF-2, and TGF-β) are not markedly influenced by the treatment and that anti-TNF-α therapy decreases MMP-9 without influencing the treatment outcome.
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Affiliation(s)
- Stepan Coufal
- Laboratory of Cellular and Molecular Immunology, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Miloslav Kverka
- Laboratory of Cellular and Molecular Immunology, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Jakub Kreisinger
- Laboratory of Animal Evolutionary Biology, Faculty of Science, Department of Zoology, Charles University, Prague, Czech Republic
| | - Tomas Thon
- Laboratory of Cellular and Molecular Immunology, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Filip Rob
- Second Faculty of Medicine, University Hospital Bulovka, Dermatovenerology Department, Charles University, Prague, Czech Republic
| | - Martin Kolar
- ISCARE a.s., IBD Clinical and Research Centre, Prague, Czech Republic
| | - Zuzana Reiss
- Laboratory of Cellular and Molecular Immunology, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Dagmar Schierova
- Laboratory of Cellular and Molecular Immunology, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Klara Kostovcikova
- Laboratory of Cellular and Molecular Immunology, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Radka Roubalova
- Laboratory of Cellular and Molecular Immunology, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Lukas Bajer
- Laboratory of Cellular and Molecular Immunology, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic
- Department of Gastroenterology and Hepatology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Zuzana Jackova
- Laboratory of Cellular and Molecular Immunology, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Martin Mihula
- Laboratory of Cellular and Molecular Immunology, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Pavel Drastich
- Department of Gastroenterology and Hepatology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Jana Tresnak Hercogova
- Second Faculty of Medicine, University Hospital Bulovka, Dermatovenerology Department, Charles University, Prague, Czech Republic
- Dermatology Prof. Hercogova, Center for Biological Therapy, Prague, Czech Republic
| | - Michaela Novakova
- Second Faculty of Medicine, University Hospital Bulovka, Dermatovenerology Department, Charles University, Prague, Czech Republic
| | - Martin Vasatko
- ISCARE a.s., IBD Clinical and Research Centre, Prague, Czech Republic
| | - Milan Lukas
- ISCARE a.s., IBD Clinical and Research Centre, Prague, Czech Republic
- Institute of Medical Biochemistry and Laboratory Diagnostics, General University Hospital and First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Helena Tlaskalova-Hogenova
- Laboratory of Cellular and Molecular Immunology, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic
| | - Zuzana Jiraskova Zakostelska
- Laboratory of Cellular and Molecular Immunology, Institute of Microbiology of the Czech Academy of Sciences, Prague, Czech Republic
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Sharma TT, Rabizadeh RR, Prabhakar VS, Bury MI, Sharma AK. Evolving Experimental Platforms to Evaluate Ulcerative Colitis. Adv Biol (Weinh) 2022; 6:e2200018. [PMID: 35866469 DOI: 10.1002/adbi.202200018] [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: 02/26/2022] [Revised: 05/06/2022] [Indexed: 01/28/2023]
Abstract
Ulcerative colitis (UC) is a multifactorial disease defined by chronic intestinal inflammation with idiopathic origins. It has a predilection to affect the mucosal lining of the large intestines and rectum. Management of UC depends upon numerous factors that include disease pathogenesis and severity that are maintained via medical or surgical means. Chronic inflammation that is left untreated or managed poorly from a clinical stance can result in intestinal ulceration accompanied by resulting physiological dysfunction. End-stage UC is mediated by surgical intervention with the resection of diseased tissue. This can lead to numerous health-related quality of life issues but is considered a curative approach. Regimens to treat UC are ever evolving and find their basis within various platforms to evaluate and treat UC. Numerous modeling systems have been examined to delineate potential mechanisms of action. However, UC is a heterogenous disease spanning unknown genetic origins coupled with environmental factors that can influence disease outcomes and related treatment procedures. Unfortunately, there is no one-size-fits-all model to fully assess all facets of UC. Within the context of this review article, the utility of various approaches that have been employed to gain insight into different aspects of UC will be investigated.
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Affiliation(s)
- Tiffany T Sharma
- Lurie Children's Hospital, Division of Pediatric Urology, Chicago, IL, 60611, USA.,Stanley Manne Children's Research Institute, Chicago, IL, 60611, USA
| | - Rebecca R Rabizadeh
- Lurie Children's Hospital, Division of Pediatric Urology, Chicago, IL, 60611, USA
| | - Vibhav S Prabhakar
- Lurie Children's Hospital, Division of Pediatric Urology, Chicago, IL, 60611, USA
| | - Matthew I Bury
- Lurie Children's Hospital, Division of Pediatric Urology, Chicago, IL, 60611, USA
| | - Arun K Sharma
- Lurie Children's Hospital, Division of Pediatric Urology, Chicago, IL, 60611, USA.,Stanley Manne Children's Research Institute, Chicago, IL, 60611, USA.,Feinberg School of Medicine, Department of Urology, Northwestern University, Chicago, IL, 60611, USA.,McCormick School of Engineering, Department of Biomedical Engineering, Northwestern University, Evanston, IL, 60208, USA.,Center for Advanced Regenerative Engineering (CARE), Northwestern University, Evanston, IL, 60208, USA.,Simpson Querrey Institute (SQI), Northwestern University, Chicago, IL, 60611, USA
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Kempski J, Huber S. [Role of the gut microbiome in the pathogenesis and treatment of inflammatory bowel diseases]. INNERE MEDIZIN (HEIDELBERG, GERMANY) 2022; 63:1022-1027. [PMID: 36044059 DOI: 10.1007/s00108-022-01396-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 08/22/2022] [Indexed: 06/15/2023]
Abstract
Inflammatory bowel diseases (IBD) are systemic diseases that mainly manifest in the gastrointestinal tract. Due to chronically impaired intestinal homeostasis, they often require permanent and in some cases systemic therapy. The exact causes of IBD are largely unknown. It is postulated that these complex diseases arise in genetically susceptible individuals through a misdirected immune response, promoted by barrier defects, environmental toxins, and the gut microbiome. In this regard, the importance of the microbiome and its pathogenic changes (dysbiosis) in the pathogenesis of IBD is increasingly coming into focus. This review article presents the current state of research on the role of the microbiome in the development of IBD. Therapeutic approaches aimed at correcting intestinal dysbiosis are also discussed.
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Affiliation(s)
- Jan Kempski
- I. Medizinische Klinik und Poliklinik, Zentrum für Innere Medizin, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Deutschland
| | - Samuel Huber
- I. Medizinische Klinik und Poliklinik, Zentrum für Innere Medizin, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Deutschland.
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Celani LMS, Egito EST, Azevedo ÍM, Oliveira CN, Dourado D, Medeiros AC. Treatment of colitis by oral negatively charged nanostructured curcumin in rats. Acta Cir Bras 2022; 37:e370602. [PMID: 35976279 PMCID: PMC9377652 DOI: 10.1590/acb370602] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 04/08/2022] [Accepted: 05/03/2022] [Indexed: 12/05/2022] Open
Abstract
PURPOSE To examine the effects of a negatively charged nanostructured curcumin microemulsion in experimental ulcerative colitis (UC) in rats. METHODS Four percent acetic acid was used to induce UC. The animals were treated for seven days and randomly assigned to four groups: normal control (NC), colitis/normal saline (COL/NS), colitis/curcumin (COL/CUR), and colitis/mesalazine (COL/MES). The nanostructured curcumin was formulated with a negative zeta potential (-16.70 ± 1.66 mV). Dosage of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin 1-β (IL-1β), interleukin 6 (IL-6), and antioxidant enzymes (catalase, superoxide dismutase, and glutathione peroxidase), macro and microscopic evaluation of the colon tissue were analyzed. RESULTS The COL/CUR group had a higher level of antioxidant enzymes compared to the COL/MESgroup. The levels of TNF-α, IL-1β and IL-6 were significantly lower in the colonic tissue of the COL/CUR group rats, when compared to the COL/NS and COL/MES groups (p < 0.001). The presence of ulcers in the colonic mucosa in rats of the COL/NSgroup was significantly higher than in the COL/MES group (p < 0.001). In the NC and COL/CUR groups, there were no ulcers in the colonic mucosa. CONCLUSIONS The nanostructured microemulsion of curcumin, used orally, positively influenced the results of the treatment of UC in rats. The data also suggests that nanostructured curcumin with negative zeta potential is a promising phytopharmaceutical oral delivery system for UC therapy. Further research needs to be done to better understand the mechanisms of the negatively charged nanostructured curcumin microemulsion in UC therapy.
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Affiliation(s)
- Lívia Medeiros Soares Celani
- Fellow master degree. Universidade Federal do Rio Grande do Norte – Postgraduate Program in Health Sciences – Natal (RN), Brazil
| | - Eryvaldo Sócrates Tabosa Egito
- PhD, full professor, chairman. Universidade Federal do Rio Grande do Norte – Laboratory of Dispersed Systems – Natal (RN), Brazil
| | | | - Cláudia Nunes Oliveira
- PhD. Universidade Federal do Rio Grande do Norte – Pathology Department – Health Sciences – Natal (RN), Brazil
| | - Douglas Dourado
- Fellow PhD degree. Universidade Federal do Rio Grande do Norte – Postgraduate Program in Health Sciences – Natal (RN), Brazil
| | - Aldo Cunha Medeiros
- PhD, full professor, chairman. Universidade Federal do Rio Grande do Norte – Nucleus of Experimental Surgery – Natal (RN), Brazil
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Park SH, Park SH. Personalized medicine in inflammatory bowel disease: Perspectives on Asia. J Gastroenterol Hepatol 2022; 37:1434-1445. [PMID: 35726657 DOI: 10.1111/jgh.15919] [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: 03/29/2022] [Revised: 06/10/2022] [Accepted: 06/18/2022] [Indexed: 12/09/2022]
Abstract
Inflammatory bowel diseases are chronic, relapsing inflammatory disorders of the gastrointestinal tract with variable disease courses and complications, which in some cases can result in significant morbidities and disabilities. Etiologies remain unclear due to complex interactions between genetic and environmental factors. Considering the heterogeneity of inflammatory bowel diseases, personalized approaches in diagnosing and managing affected patients would be beneficial in maximizing treatment efficacies and minimizing adverse events. Personalized medicine may also help to stratify patients with a high risk of progression and inflammatory bowel disease-related complications and identify sub-phenotypic mechanisms to facilitate drug discovery and the development of new treatments. In Asia, with a rapidly increasing incidence and prevalence of inflammatory bowel diseases, studies have shown that patients of Asian ethnicity differ from their Western counterparts in terms of genetic and clinical aspects of inflammatory bowel diseases. Therefore, personalized medicine may differ for patients of Asian ethnicity with inflammatory bowel diseases. We reviewed and summarized current evidence concerning personalized medicine for the diagnosis and management of patients with inflammatory bowel diseases and its possible role from an Asian perspective.
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Affiliation(s)
- Su Hyun Park
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
| | - Sang Hyoung Park
- Department of Gastroenterology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, South Korea
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7
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Pu D, Zhang Z, Feng B. Alterations and Potential Applications of Gut Microbiota in Biological Therapy for Inflammatory Bowel Diseases. Front Pharmacol 2022; 13:906419. [PMID: 35734396 PMCID: PMC9207480 DOI: 10.3389/fphar.2022.906419] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 04/26/2022] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is a chronic immune-mediated inflammatory disorder of the gastrointestinal tract that is closely associated with dysbiosis of the intestinal microbiota. Currently, biologic agents are the mainstream therapies for IBD. With the increasing incidence of IBD, limitations of biologic agents have gradually emerged during treatment. Recent studies have indicated that gut microbiota is highly correlated with the efficacy of biologic agents. This review focuses on alterations in both the components and metabolites of gut microbiota during biological therapy for IBD, systematically summarises the specific gut microbiota closely related to the clinical efficacy, and compares current predictive models for the efficacy of biologics, further highlighting the predictive value of intestinal microbiota. Based on the mechanistic analysis of faecal microbiota transplantation (FMT) and biologic agents, a new therapeutic strategy, comprising a combination of FMT and biologics, has been proposed as a promising treatment for IBD with improved efficacy.
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Affiliation(s)
| | - Zhe Zhang
- *Correspondence: Zhe Zhang, ; Baisui Feng,
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Amani B, Zareei S, Amani B, Zareei M, Zareei N, Shabestan R, Akbarzadeh A. Artesunate, imatinib, and infliximab in COVID‐19: A rapid review and meta‐analysis of current evidence. Immun Inflamm Dis 2022; 10:e628. [PMID: 35634954 PMCID: PMC9092000 DOI: 10.1002/iid3.628] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 03/26/2022] [Accepted: 03/29/2022] [Indexed: 11/26/2022] Open
Abstract
Background and Objective Despite the pervasive vaccination program against coronavirus disease 2019 (COVID‐19), people who got fully vaccinated are still contaminated by severe acute respiratory syndrome coronavirus 2, making an effective and safe therapeutic intervention a crucial need for the patients' survival. The purpose of the present study is to seek available evidence for the efficacy and safety of three promising medications artesunate, imatinib, and infliximab against COVID‐19. Methods A literature search was conducted in PubMed, Cochrane Library, medRxive, and Google Scholar, and the relevant articles published up to January 2022 were found. Furthermore, the clinical trial databases were screened for finding more citations. Data analysis was carried out applying The Cochrane Collaboration tool and Newcastle–Ottawa scale to assess the included studies. Meta‐analysis was performed using RevMan 5.4.1. Results Five published studies were identified as eligible. Meta‐analysis showed that there was no significant difference between the infliximab and control groups in terms of mortality rate (risk ratio [RR]: 0.65; confidence interval [CI] 95%: 0.40–1.07; p = .09). However, a significant difference was observed between the two groups for the hospital discharge (RR: 1.37; CI 95%: 1.04–1.80; p = .03). No remarkable clinical benefit was observed for using imatinib in COVID‐19 patients. Artesunate showed significant improvement in patients with COVID‐19. Conclusion In the present, limited evidence exists for the efficacy and safety of artesunate, imatinib, and infliximab in patients with COVID‐19. The findings of WHO's Solidarity international trial will provide further information regarding these therapeutic interventions.
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Affiliation(s)
- Bahman Amani
- Department of Health Management and Economics, School of Public Health Tehran University of Medical Sciences Tehran Iran
| | - Sara Zareei
- Department of Cell & Molecular Biology, Faculty of Biological Sciences Kharazmi University Tehran Iran
| | - Behnam Amani
- Department of Health Management and Economics, School of Public Health Tehran University of Medical Sciences Tehran Iran
| | - Mahsa Zareei
- Department of Health Services Management, School of Health Management and Information Sciences Iran University of Medical Sciences Tehran Iran
| | - Neda Zareei
- Shiraz Transplant Research Center Shiraz University of Medical Sciences Shiraz Iran
| | - Rouhollah Shabestan
- Department of Biostatistics and Epidemiology, School of Public Health Tehran University of Medical Sciences Tehran Iran
| | - Arash Akbarzadeh
- Department of Biostatistics and Epidemiology, School of Public Health Tehran University of Medical Sciences Tehran Iran
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Zhang CB, Tang J, Wang XD, Lyu KS, Huang M, Gao X. Multi-alleles predict primary non-response to infliximab therapy in Crohn's disease. Gastroenterol Rep (Oxf) 2021; 9:427-434. [PMID: 34733528 PMCID: PMC8560039 DOI: 10.1093/gastro/goaa070] [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: 04/06/2020] [Revised: 06/18/2020] [Accepted: 07/28/2020] [Indexed: 11/12/2022] Open
Abstract
Background Infliximab (IFX) is the first-line treatment for patients with Crohn's disease (CD) and is noted for its relatively high cost. The therapeutic efficacy of IFX has noticeable individual differences. Known single-gene polymorphisms (SNPs) are inadequate for predicting non-response to IFX. In this study, we aimed to identify new genetic factors associated with IFX-therapy failure and to predict non-response to IFX by developing a multivariate predictive model. Methods In this retrospective study, we collected and analysed the data of Chinese patients with CD who received IFX therapy at one hospital between June 2013 and June 2019. Primary non-response (PNR) and non-durable response (NDR) were evaluated using a simple endoscopic score for CD (SES-CD). A total of 125 SNPs within 44 genes were genotyped. A multivariate logistic-regression model was established to predict non-response to IFX. An area-under-the-receiver-operating-characteristics curve (AUROC) was applied to evaluate the predictive model performance. Results Forty-two of 206 (20.4%) patients experienced PNR and 15 of 159 (9.4%) patients experienced NDR. Nine SNPs were associated with PNR (P < 0.05). A PNR predictive model was established, incorporating 2-week high-sensitivity C-reactive protein (hs-CRP), rs61886887, rs61740234, rs357291, rs2269330, and rs111504845, and the AUROC on training and testing data sets were 0.818 (P < 0.001) and 0.888 (P < 0.001), respectively. At week 14, hs-CRP levels ≥ 2.25 mg/L were significantly associated with NDR (AUROC = 0.815, P < 0.001). PNR-associated SNPs were not mutually associated with NDR, suggesting distinct mechanisms between PNR and NDR. Conclusion Genetic polymorphisms are significantly associated with response to IFX among Chinese CD patients.
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Affiliation(s)
- Cai-Bin Zhang
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Jian Tang
- Department of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Xue-Ding Wang
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Kun-Sheng Lyu
- Southern China Center for Statistical Science School of Mathematics, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Min Huang
- Institute of Clinical Pharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Xiang Gao
- Department of Gastroenterology, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China.,Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
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Lee JY, Oh K, Hong HS, Kim K, Hong SW, Park JH, Hwang SW, Yang DH, Ye BD, Byeon JS, Myung SJ, Yang SK, Lee HS, Jo KW, Park SH. Risk and characteristics of tuberculosis after anti-tumor necrosis factor therapy for inflammatory bowel disease: a hospital-based cohort study from Korea. BMC Gastroenterol 2021; 21:390. [PMID: 34670529 PMCID: PMC8527666 DOI: 10.1186/s12876-021-01973-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 10/07/2021] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Anti-tumor necrosis factor (TNF) treatment for inflammatory bowel disease (IBD) increases the risk of tuberculosis (TB) infection. In the present study, we analyzed the clinical characteristics and risks of TB in Korean patients with IBD who received anti-TNF treatment. METHODS The study included patients with IBD who were treated using anti-TNF agents between January 2001 and June 2018 at the Asan Medical Center. Overall, 1434 patients with ulcerative colitis or Crohn's disease were enrolled. We calculated the incidence of active TB infection after anti-TNF treatment and compared the clinical characteristics of the TB group with those of the non-TB group. RESULTS Twenty-one patients (1.46%) developed active TB infection, and the incidence rate of active TB was 366.73 per 100,000 person-years. In total, 198 patients (14.9%) were positive for latent tuberculosis infection (LTBI), of whom only eight (4%) did not complete LTBI treatment. The age at which the anti-TNF therapy was started was significantly higher in the TB group than in the non-TB group (HR 1.041, 95% CI 1.014-1.069, p = 0.002), and as age increased, so did the incidence rate of active TB infection (linearity p < 0.001). There was no significant difference in the incidence rate of LTBI between the TB and non-TB groups (HR 0.896, 95% CI 0.262-3.066, p = 0.862). CONCLUSIONS In patients with IBD, the incidence rate of TB increased with age at anti-TNF therapy initiation. Active treatment of LTBI may lower the incidence of TB in patients with IBD who are to undergo anti-TNF therapy.
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Affiliation(s)
- Jae Yong Lee
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Kyunghwan Oh
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Hee Seung Hong
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Kyuwon Kim
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Seung Wook Hong
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Jin Hwa Park
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Sung Wook Hwang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Dong-Hoon Yang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Byong Duk Ye
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Jeong-Sik Byeon
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Seung-Jae Myung
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Suk-Kyun Yang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Ho-Su Lee
- Department of Biochemistry, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea
| | - Kyung-Wook Jo
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea.
| | - Sang Hyoung Park
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Korea.
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11
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Lee JM, Wei SC, Lee KM, Ye BD, Mao R, Kim HS, Park SJ, Park SH, Oh EH, Im JP, Jang BI, Kim DB, Takeuchi K. Clinical Course of Hepatitis B Viral Infection in Patients Undergoing Anti-Tumor Necrosis Factor α Therapy for Inflammatory Bowel Disease. Gut Liver 2021; 16:396-403. [PMID: 34593670 PMCID: PMC9099383 DOI: 10.5009/gnl210081] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 06/17/2021] [Accepted: 06/29/2021] [Indexed: 11/17/2022] Open
Abstract
Background/Aims Little is known about the clinical course of hepatitis B virus (HBV)-infected patients undergoing anti-tumor necrosis factor α (TNF-α) therapy for inflammatory bowel disease (IBD). We aimed to investigate the clinical course of HBV infection and IBD and to analyze liver dysfunction risks in patients undergoing anti-TNF-α therapy. Methods This retrospective multinational study involved multiple centers in Korea, China, Taiwan, and Japan. We enrolled IBD patients with chronic or resolved HBV infection, who received anti-TNF-α therapy. The patients’ medical records were reviewed, and data were collected using a web-based case report form. Results Overall, 191 patients (77 ulcerative colitis and 114 Crohn’s disease) were included, 28.3% of whom received prophylactic antivirals. During a median follow-up duration of 32.4 months, 7.3% of patients experienced liver dysfunction due to HBV reactivation. Among patients with chronic HBV infection, the proportion experiencing liver dysfunction was significantly higher in the non-prophylaxis group (26% vs 8%, p=0.02). Liver dysfunction occurred in one patient with resolved HBV infection. Antiviral prophylaxis was independently associated with an 84% reduction in liver dysfunction risk in patients with chronic HBV infection (odds ratio, 0.16; 95% confidence interval, 0.04 to 0.66; p=0.01). The clinical course of IBD was not associated with liver dysfunction or the administration of antiviral prophylaxis. Conclusions Liver dysfunction due to HBV reactivation can occur in HBV-infected IBD patients treated with anti-TNF-α agents. Careful monitoring is needed in these patients, and antivirals should be administered, especially to those with chronic HBV infection.
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Affiliation(s)
- Ji Min Lee
- Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Shu-Chen Wei
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Kang-Moon Lee
- Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Byong Duk Ye
- Department of Gastroenterology and Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Ren Mao
- Department of Internal Medicine, First Affiliated Hospital, Sun Yat-sen University, Shanghai, China, Korea
| | - Hyun-Soo Kim
- Department of Internal Medicine and Institute of Lifelong Health, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Soo Jung Park
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Hyoung Park
- Department of Gastroenterology and Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Eun Hye Oh
- Department of Gastroenterology and Inflammatory Bowel Disease Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.,Department of Gastroenterology, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Jong Pil Im
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Byung Ik Jang
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Dae Bum Kim
- Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ken Takeuchi
- Department of Internal Medicine, Toho University Sakura Medical Center, Sakura, Japan
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12
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Yueying C, Jing F, Tian Y, Yuqi Q, Jun S. Bioelectrical impedance analysis-based nomogram construction for predicting secondary loss of response to infliximab in bio-naïve Crohn's disease patients. Biomed Pharmacother 2021; 142:112076. [PMID: 34449314 DOI: 10.1016/j.biopha.2021.112076] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 08/13/2021] [Accepted: 08/17/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Infliximab is emerging as the first-line therapy for Crohn's disease (CD); however, the rate of secondary loss of response (SLR) can exceed 50%. This study aimed to construct a nomogram based on bioelectrical impedance analysis (BIA) indexes and laboratory markers to predict SLR to infliximab in biologically naïve CD patients. METHODS Data of 136 biologically naïve CD patients treated between September 2019 and March 2021 were retrospectively retrieved. BIA-based body composition parameters and laboratory markers were obtained before the infliximab therapy. Predictor selection was conducted using the least absolute shrinkage and selection operator (LASSO) and univariate logistic regression. The nomogram was developed using multivariable logistic regression, and internal validation was made by ten-fold cross-validation. RESULTS SLR occurred in 51% of the CD patients during 54 weeks. The nomogram predictors included hemoglobin, albumin, serum iron, and BIA scores. The nomogram showed significant discrimination (area under the curve [AUC], 0.920; 95% confidence interval, 0.873-0.967) and calibration (mean error = 0.012). Decision curve analysis (DCA) indicated that the nomogram provided net clinical benefit when the risk probability was between 2% and 83%. Internal validation assessment of the nomogram robustness found an AUC of 0.904 and an accuracy of 0.841. CONCLUSIONS This BIA-based body composition parameters- and laboratory markers-based novel nomogram could act as a predictive tool to evaluate SLR to infliximab therapy, crucial for optimizing treatment strategies and switching biologics in CD.
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Affiliation(s)
- Chen Yueying
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, 160# Pu Jian Ave, Shanghai 200127, China; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160# Pu Jian Ave, Shanghai 200127, China; Shanghai Institute of Digestive Disease, 160# Pu Jian Ave, Shanghai 200127, China
| | - Feng Jing
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, 160# Pu Jian Ave, Shanghai 200127, China; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160# Pu Jian Ave, Shanghai 200127, China; Shanghai Institute of Digestive Disease, 160# Pu Jian Ave, Shanghai 200127, China
| | - Yang Tian
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, 160# Pu Jian Ave, Shanghai 200127, China; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160# Pu Jian Ave, Shanghai 200127, China; Shanghai Institute of Digestive Disease, 160# Pu Jian Ave, Shanghai 200127, China
| | - Qiao Yuqi
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, 160# Pu Jian Ave, Shanghai 200127, China; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160# Pu Jian Ave, Shanghai 200127, China; Shanghai Institute of Digestive Disease, 160# Pu Jian Ave, Shanghai 200127, China.
| | - Shen Jun
- Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Inflammatory Bowel Disease Research Center, 160# Pu Jian Ave, Shanghai 200127, China; Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160# Pu Jian Ave, Shanghai 200127, China; Shanghai Institute of Digestive Disease, 160# Pu Jian Ave, Shanghai 200127, China.
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13
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Shin SY, Park SJ, Kim Y, Im JP, Kim HJ, Lee KM, Kim JW, Jung SA, Lee J, Kang SB, Shin SJ, Kim ES, Kim YS, Kim TO, Kim HS, Park DI, Kim HK, Kim ES, Kim YH, Kim DH, Teng D, Kim JH, Kim W, Choi CH. Clinical outcomes and predictors of response for adalimumab in patients with moderately to severely active ulcerative colitis: a KASID prospective multicenter cohort study. Intest Res 2021; 20:350-360. [PMID: 34289648 PMCID: PMC9344242 DOI: 10.5217/ir.2021.00049] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 06/09/2021] [Indexed: 12/02/2022] Open
Abstract
Background/Aims This study assessed the efficacy and safety of adalimumab (ADA) and explored predictors of response in Korean patients with ulcerative colitis (UC). Methods A prospective, observational, multicenter study was conducted over 56 weeks in adult patients with moderately to severely active UC who received ADA. Clinical response, remission, and mucosal healing were assessed using the Mayo score. Results A total of 146 patients were enrolled from 17 academic hospitals. Clinical response rates were 52.1% and 37.7% and clinical remission rates were 24.0% and 22.0% at weeks 8 and 56, respectively. Mucosal healing rates were 39.0% and 30.1% at weeks 8 and 56, respectively. Prior use of anti-tumor necrosis factor-α (anti-TNF-α) did not affect clinical and endoscopic responses. The ADA drug level was significantly higher in patients with better outcomes at week 8 (P<0.05). In patients with lower endoscopic activity, higher body mass index, and higher serum albumin levels at baseline, the clinical response rate was higher at week 8. In patients with lower Mayo scores and C-reactive protein levels, clinical responses, and mucosal healing at week 8, the clinical response rate was higher at week 56. Serious adverse drug reactions were identified in 2.8% of patients. Conclusions ADA is effective and safe for induction and maintenance in Korean patients with UC, regardless of prior anti-TNF-α therapy. The ADA drug level is associated with the efficacy of induction therapy. Patients with better short-term outcomes were predictive of those with an improved long-term response.
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Affiliation(s)
- Seung Yong Shin
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Soo Jung Park
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Young Kim
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Jong Pil Im
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Hyo Jong Kim
- Department of Gastroenterology, Kyung Hee University Hospital, Seoul, Korea
| | - Kang-Moon Lee
- Department of Gastroenterology, The Catholic University of Korea St. Vincent's Hospital, Suwon, Korea
| | - Ji Won Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.,Department of Gastroenterology, SMG-SNU Boramae Medical Center, Seoul, Korea
| | - Sung-Ae Jung
- Department of Gastroenterology, Ewha Womans University College of Medicine, Seoul, Korea
| | - Jun Lee
- Department of Internal Medicine, Chosun University College of Medicine, Gwangju, Korea
| | - Sang-Bum Kang
- Department of Internal Medicine, Daejeon St. Mary's Hospital, The Catholic University of Korea College of Medicine, Daejeon, Korea
| | - Sung Jae Shin
- Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea
| | - Eun Sun Kim
- Department of Gastroenterology, Korea University Anam Hospital, Seoul, Korea
| | - You Sun Kim
- Department of Gastroenterology, Inje University Seoul Paik Hospital, Seoul, Korea
| | - Tae Oh Kim
- Department of Gastroenterology, Inje University Haeundae Paik Hospital, Busan, Korea
| | - Hyun-Soo Kim
- Department of Gastroenterology, Chonnam National University Hospital, Gwangju, Korea
| | - Dong Il Park
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyung Kil Kim
- Department of Gastroenterology, Inha University Hospital, Incheon, Korea
| | - Eun Soo Kim
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Young-Ho Kim
- Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | | | | | - Jong-Hwa Kim
- Department of Microbiology, Chung-Ang University College of Medicine, Seoul, Korea
| | - Wonyong Kim
- Department of Microbiology, Chung-Ang University College of Medicine, Seoul, Korea
| | - Chang Hwan Choi
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
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14
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Ye BD, Cheon JH, Song KH, Kim JS, Kim YH, Yoon H, Lee KM, Kang SB, Jang BI, Park JJ, Kim TO, Lee DW, Foo CY, Shin JE, Park DI. The real-world outcomes of vedolizumab in patients with ulcerative colitis in Korea: a multicenter retrospective study. Therap Adv Gastroenterol 2021; 14:17562848211024769. [PMID: 34285716 PMCID: PMC8261845 DOI: 10.1177/17562848211024769] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Accepted: 05/25/2021] [Indexed: 02/04/2023] Open
Abstract
AIM This study examined the real-world effectiveness and safety outcomes of vedolizumab in ulcerative colitis (UC) patients who had failed anti-tumor necrosis factor (anti-TNF) therapy in Korea. METHODS A retrospective chart review study was conducted in adults with moderate to severely active UC who had failed anti-TNF agents and subsequently received vedolizumab. Clinical response and clinical remission at week 6 and 14 after vedolizumab initiation was evaluated. Safety outcomes were also reported. Outcome rates were compared with a matched sub-cohort derived from the open-label sub-cohort of the GEMINI 1 trial using the optimal matching method. RESULTS A total of 105 patients (mean age, 45.3 years; 63.8% male) were included. At week 6, 55.8% (n = 43/77) achieved a clinical response and 18.2% (n = 14/77) achieved clinical remission. At week 14, 73.2% (n = 52/71) achieved a clinical response and 39.4% (n = 28/71) achieved clinical remission. When non-response imputation was used, the clinical response rate at week 6 and week 14 were 40.1% (n = 43/105) and 49.5% (n = 52/105) respectively. Of the 105 patients, 16 (15.2%) experienced at least one adverse event. The matched analysis showed that the clinical response rate at week 6 was higher in the matched sub-cohort of this study (24/47, 51.1%) versus the matched sub-cohort from the GEMINI 1 open-label cohort (12/47, 34.3%, p = 0.019). The clinical remission rates at week 6 were similar (7/47, 14.9% versus 9/47, 19.1%, p = 0.785). CONCLUSIONS In the real-world setting, vedolizumab is effective and well tolerated within the first 14 weeks of use in Korea. The proportion of patients experiencing clinical response and clinical remission at 6 and 14 weeks appeared to be largely consistent with that observed in real-world studies from other regions and populations.
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Affiliation(s)
| | - Jae Hee Cheon
- Division of Gastroenterology, Department of
Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Ki Hwan Song
- Department of Surgery, KOO Hospital, Daegu,
Korea
| | - Joo Sung Kim
- Department of Internal Medicine and Liver
Research Institute, Seoul National University College of Medicine, Seoul,
Korea
| | - Young-Ho Kim
- Division of Gastroenterology, Department of
Medicine, Samsung Medical Center, Sungkyunkwan University School of
Medicine, Seoul, Korea
| | - Hyuk Yoon
- Division of Gastroenterology, Department of
Internal Medicine, Seoul National University Bundang Hospital, Seongnam,
Korea
| | - Kang-Moon Lee
- Department of Internal Medicine, St. Vincent’s
Hospital, College of Medicine, The Catholic University of Korea, Suwon,
Korea
| | - Sang-Bum Kang
- Division of Gastroenterology, Departments of
Internal Medicine, Daejeon St. Mary’s Hospital, College of Medicine, The
Catholic University of Korea, Daejeon, Korea
| | - Byung Ik Jang
- Division of Gastroenterology and Hepatology,
Department of Internal Medicine, Yeungnam University College of Medicine,
Daegu, Korea
| | - Jae Jun Park
- Division of Gastroenterology, Department of
Internal Medicine, Severance Hospital, Yonsei University College of
Medicine, Seoul, Korea
| | - Tae Oh Kim
- Division of Gastroenterology, Department of
Internal Medicine, Haeundae Paik Hospital, Inje University College of
Medicine, Busan, Korea
| | - Dae-Wook Lee
- Takeda Pharmaceutical Ltd, Medical Affairs,
Asia-Pacific Region, Singapore
| | | | - Jeong Eun Shin
- Division of Gastroenterology, Department of
Internal Medicine, Dankook University College of Medicine, Cheonan,
Korea
| | - Dong Il Park
- Division of Gastroenterology, Department of
Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School
of Medicine, Seoul, Korea
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15
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Treatments of inflammatory bowel disease toward personalized medicine. Arch Pharm Res 2021; 44:293-309. [PMID: 33763844 DOI: 10.1007/s12272-021-01318-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 03/06/2021] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a chronic inflammatory disease characterized by intestinal inflammation and epithelial injury. For the treatment of IBD, 5-aminosalicylic acids, corticosteroids, immunomodulators, and biologic agents targeting tumor necrosis factor (TNF)-α, α4β7-integrin, and interleukin (IL)-12/23 have been widely used. Especially, anti-TNF-α antibodies are the first biologic agents that presently remain at the forefront. However, 10-30% of patients resist biologic agents, including anti-TNF-α agents (primary non-responder; PNR), and 20-50% of primary responders develop treatment resistance within one year (secondary loss of response; SLR). Nonetheless, the etiologies of PNR and SLR are not clearly understood, and predictors of response to biologic agents are also not defined yet. Numerous studies are being performed to discover prediction markers of the response to biologic agents, and this review will introduce currently available therapeutic options for IBD, biologics under investigation, and recent studies exploring various predictive factors related to PNR and SLR.
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16
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Atreya R, Neurath MF, Siegmund B. Personalizing Treatment in IBD: Hype or Reality in 2020? Can We Predict Response to Anti-TNF? Front Med (Lausanne) 2020; 7:517. [PMID: 32984386 PMCID: PMC7492550 DOI: 10.3389/fmed.2020.00517] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 07/27/2020] [Indexed: 12/12/2022] Open
Abstract
The advent of anti-TNF agents as the first approved targeted therapy in the treatment of inflammatory bowel disease (IBD) patients has made a major impact on our existing therapeutic algorithms. They have not only been approved for induction and maintenance treatment in IBD patients, but have also enabled us to define and achieve novel therapeutic outcomes, such as combination of clinical symptom control and endoscopic remission, as well as mucosal healing. Nevertheless, approximately one third of treated patients do not respond to initiated anti-TNF therapy and these treatments are associated with sometimes severe systemic side-effects. There is therefore the currently unmet clinical need do establish predictive markers of response to identify the subgroup of IBD patients, that have a heightened probability of response. There have so far been approaches from different fields of IBD research, to descry markers that would empower us to apply TNF-inhibitors in a more rational manner. These markers encompass findings from disease-related and clinical factors, pharmacokinetics, biochemical markers, blood and stool derived parameters, pharmacogenomics, microbial species, metabolic compounds, and mucosal factors. Furthermore, changes in the intestinal immune cell composition in response to therapeutic pressure of anti-TNF treatment have recently been implicated in the process of molecular resistance to these drugs. Insights into factors that determine resistance to anti-TNF therapy give reasonable hope, that a more targeted approach can then be utilized in these non-responders. Here, IL-23 could be identified as one of the key factors determining resistance to TNF-inhibitors. Growing insights into the molecular mechanism of action of TNF-inhibitors might also enable us to derive critical molecular markers that not only mediate the clinical effects of anti-TNF therapy, but which level of expression might also correlate with its therapeutic efficacy. In this narrative review, we present an overview of currently identified possible predictive markers for successful anti-TNF therapy and discuss identified molecular pathways that drive resistance to these substances. We will also point out the necessity and difficulty of developing and validating a diagnostic marker concerning clinically relevant outcome parameters, before they can finally enter daily clinical practice and enable a more personalized therapeutic approach.
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Affiliation(s)
- Raja Atreya
- Department of Medicine, Medical Clinic 1, University Hospital Erlangen, University of Erlangen-Nürnberg Erlangen, Erlangen, Germany.,Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany.,The Transregio 241 IBDome Consortium, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine, Medical Clinic 1, University Hospital Erlangen, University of Erlangen-Nürnberg Erlangen, Erlangen, Germany.,Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Britta Siegmund
- The Transregio 241 IBDome Consortium, Berlin, Germany.,Medizinische Klinik m. S. Gastroenterologie, Infektiologie und Rheumatologie, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.,Berlin Institute of Health, Berlin, Germany
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17
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Oh SJ, Shin GY, Soh H, Lee JG, Im JP, Eun CS, Lee KM, Park DI, Han DS, Kim HJ, Lee CK. Long-term outcomes of infliximab in a real-world multicenter cohort of patients with acute severe ulcerative colitis. Intest Res 2020; 19:323-331. [PMID: 32806875 PMCID: PMC8322032 DOI: 10.5217/ir.2020.00039] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 06/03/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/AIMS Infliximab (IFX) has proven effective as rescue therapy in steroid-refractory acute severe ulcerative colitis (ASUC), however, the long-term real-world data are scarce. Our study aimed to assess the long-term treatment outcomes of IFX in a real-life cohort. METHODS We established a multicenter retrospective cohort of hospitalized patients with ASUC, who met Truelove and Witt's criteria and received intravenous corticosteroid (IVCS) or IFX during index hospitalization between 2006 and 2016 in 5 university hospitals in Korea. The cohort was systematically followed up until colectomy, death or last follow-up visit. RESULTS A total of 296 patients were followed up for a mean of 68.9 ± 44.0 months. During index hospitalization, 49 patients were treated with IFX; as rescue therapy for IVCS failure in 37 and as first-line medical therapy for ASUC in 12. All patients treated with IFX avoided colectomy during index hospitalization. The cumulative rates of rehospitalization and colectomy were 20.4% and 6.1% at 3 months and 39.6% and 18.8% at the end of follow-up, respectively. Patients treated with IFX presented with significantly shorter colectomy-free survival than IVCS responders (P= 0.04, log-rank test). Both cytomegalovirus colitis and Clostridioides difficile infection (CDI) were the significant predictors of colectomy in the overall study cohort (hazard ratios of 6.57 and 4.61, respectively). There were no fatalities. CONCLUSIONS Our real-world cohort study demonstrated that IFX is an effective therapeutic option in Korean patients with ASUC, irrespective of IFX indication. Aggressive vigilance for cytomegalovirus colitis and CDI is warranted for hospitalized patients with ASUC.
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Affiliation(s)
- Shin Ju Oh
- Center for Crohn's and Colitis, Department of Gastroenterology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, Korea
| | - Ga Young Shin
- Center for Crohn's and Colitis, Department of Gastroenterology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, Korea
| | - Hosim Soh
- Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Jae Gon Lee
- Department of Gastroenterology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
| | - Jong Pil Im
- Department of Internal Medicine and Liver Research Institute, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Chang Soo Eun
- Department of Gastroenterology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
| | - Kang-Moon Lee
- Department of Internal Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Suwon, Korea
| | - Dong Il Park
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Dong Soo Han
- Department of Gastroenterology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
| | - Hyo Jong Kim
- Center for Crohn's and Colitis, Department of Gastroenterology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, Korea
| | - Chang Kyun Lee
- Center for Crohn's and Colitis, Department of Gastroenterology, Kyung Hee University Hospital, Kyung Hee University College of Medicine, Seoul, Korea
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18
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O'Connell J, Keohane S, McGreal-Bellone A, McDonagh P, Naimimohasses S, Kennedy U, Dunne C, Hartery K, Larkin J, MacCarthy F, Meaney J, McKiernan S, Norris S, O'Toole D, Kevans D. Characteristics and outcomes of acute colitis diagnosed on cross-sectional imaging presenting via the emergency department in an Irish academic medical centre. Ir J Med Sci 2020; 189:1115-1121. [PMID: 31925651 DOI: 10.1007/s11845-019-02162-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 12/03/2019] [Indexed: 11/28/2022]
Abstract
BACKGROUND AND AIMS A significant proportion of patients presenting to the Emergency Department with gastrointestinal symptoms that result in cross-sectional imaging receive a radiological diagnosis of colitis. We aimed to review the characteristics, outcomes, and final diagnoses of new emergency department presentations with colitis diagnosed on cross-sectional imaging. METHODS A radiology database was interrogated to identify patients admitted from the Emergency Department of St James's Hospital whose cross-sectional imaging demonstrated colitis. Baseline demographic data, information on inpatient investigations, final diagnoses, and outcomes were recorded. Adverse outcomes were defined as a requirement for surgery, intensive care unit (ICU) stay, or mortality RESULTS: A total of 118 patients, 67% female, were identified with a median age of 64 years (range 16.9-101.2). Median (range) admission duration was 10 days (1-241). Final colitis diagnoses were infectious (28%), undefined (27%), reactive (18%), inflammatory bowel disease (11%), ischaemic (9%), chemotherapy-associated (3%), diverticular (3%), and medication-associated (1%). Colonic perforation, colectomy, and mortality occurred in 1%, 5%, and 13% of the cohort respectively. On univariate analysis, low haemoglobin, low albumin, high lactate, and male gender were associated with adverse outcomes with the following odds ratios (OR) and 95% confidence intervals (95%CI) were low haemoglobin 1.49 [1.15-1.92] P = 0.002, low albumin 1.16 [1.07-1.25] P = 0.0002, lactate 1.65 [1.13-2.42] P = 0.009, and male gender 3.09 [1.23-7.77] P = 0.019. On multivariate analysis, male gender was associated with adverse outcomes. CONCLUSION Patients presenting to the Emergency Department with a colitis, requiring an abdominal CT are a heterogenous group with a proportion having concomitant intra-abdominal pathology resulting in critical illness. Hence their is a significant morbidity and mortality observed in this cohort which should not be extrapolated to a general population of patients presenting with colitis. In this cohort of patients, anaemia, hypoalbuminaemia, and elevated lactate in patients presenting to the ED with acute colitis are significantly associated with adverse outcomes. Early recognition of these prognostic factors may identify the cohort of patients who are best managed in a high-dependency setting.
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Affiliation(s)
- J O'Connell
- Department of Gastroenterology, St James's Hospital, Dublin, Ireland.
| | - S Keohane
- Department of Gastroenterology, St James's Hospital, Dublin, Ireland
| | - A McGreal-Bellone
- Department of Gastroenterology, St James's Hospital, Dublin, Ireland
| | - P McDonagh
- Department of Gastroenterology, St James's Hospital, Dublin, Ireland
| | - S Naimimohasses
- Department of Gastroenterology, St James's Hospital, Dublin, Ireland
| | - U Kennedy
- Department of Gastroenterology, St James's Hospital, Dublin, Ireland
| | - C Dunne
- Department of Gastroenterology, St James's Hospital, Dublin, Ireland
- Department of Colorectal Surgery, St James's Hospital, Dublin, Ireland
| | - K Hartery
- Department of Gastroenterology, St James's Hospital, Dublin, Ireland
- Department of Colorectal Surgery, St James's Hospital, Dublin, Ireland
| | - J Larkin
- Department of Colorectal Surgery, St James's Hospital, Dublin, Ireland
- Department of Diagnostic Imaging, St James's Hospital, Dublin, Ireland
| | - F MacCarthy
- Department of Gastroenterology, St James's Hospital, Dublin, Ireland
- Department of Colorectal Surgery, St James's Hospital, Dublin, Ireland
| | - J Meaney
- Department of Colorectal Surgery, St James's Hospital, Dublin, Ireland
| | - S McKiernan
- Department of Gastroenterology, St James's Hospital, Dublin, Ireland
- Department of Colorectal Surgery, St James's Hospital, Dublin, Ireland
| | - S Norris
- Department of Gastroenterology, St James's Hospital, Dublin, Ireland
- Department of Colorectal Surgery, St James's Hospital, Dublin, Ireland
| | - D O'Toole
- Department of Gastroenterology, St James's Hospital, Dublin, Ireland
- Department of Colorectal Surgery, St James's Hospital, Dublin, Ireland
| | - D Kevans
- Department of Gastroenterology, St James's Hospital, Dublin, Ireland
- Department of Colorectal Surgery, St James's Hospital, Dublin, Ireland
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Gisbert JP, Chaparro M. Predictors of Primary Response to Biologic Treatment [Anti-TNF, Vedolizumab, and Ustekinumab] in Patients With Inflammatory Bowel Disease: From Basic Science to Clinical Practice. J Crohns Colitis 2020; 14:694-709. [PMID: 31777929 DOI: 10.1093/ecco-jcc/jjz195] [Citation(s) in RCA: 177] [Impact Index Per Article: 35.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Inflammatory bowel diseases [IBD]-ulcerative colitis and Crohn's disease-are commonly treated with biologic drugs. However, only approximately two-thirds of patients have an initial response to these therapies. Personalised medicine has the potential to optimise efficacy, decrease the risk of adverse drug events, and reduce costs by establishing the most suitable therapy for a selected patient. AIM The present study reviews the potential predictors of short-term primary response to biologic treatment, including not only anti-tumour necrosis factor [TNF] agents [such as infliximab, adalimumab, certolizumab, and golimumab] but also vedolizumab and ustekinumab. METHODS We performed a systematic bibliographical search to identify studies investigating predictive factors of response to biologic therapy. RESULTS For anti-TNF agents, most of the evaluated factors have not demonstrated usefulness, and many others are still controversial. Thus, only a few factors may have a potential role in the prediction of the response, including disease behaviour/phenotype, disease severity, C-reactive protein, albumin, cytokine expression in serum, previous anti-TNF therapy, some proteomic markers, and some colorectal mucosa markers. For vedolizumab, the availability of useful predictive markers seems to be even lower, with only some factors showing a limited value, such as the expression of α4β7 integrin in blood, the faecal microbiota, some proteomic markers, and some colorectal mucosa markers. Finally, in the case of ustekinumab, no predictive factor has been reported yet to be helpful in clinical practice. CONCLUSION In summary, currently no single marker fulfils all criteria for being an appropriate prognostic indicator of response to any biologic treatment in IBD.
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Affiliation(s)
- Javier P Gisbert
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa [IIS-IP], Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Madrid, Spain
| | - María Chaparro
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa [IIS-IP], Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Madrid, Spain
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20
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Biologic Use Patterns and Predictors for Non-persistence and Switching of Biologics in Patients with Inflammatory Bowel Disease: A Nationwide Population-Based Study. Dig Dis Sci 2020; 65:1436-1444. [PMID: 31677070 DOI: 10.1007/s10620-019-05867-1] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Accepted: 09/26/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND Data on real-life patterns of biologic use for inflammatory bowel disease (IBD) are scarce. AIMS We aimed to examine the patterns of biologic use and the factors associated with non-persistence and switching of biologics in Korean IBD patients. METHODS Using National Health Insurance claims, we collected data on patients who were diagnosed with IBD and exposed to biologics between 2010 and 2016. RESULTS Among 1838 patients with Crohn's disease (CD), 1237 and 601 started with infliximab and adalimumab, respectively. Among 1125 patients with ulcerative colitis (UC), 774, 294, and 57 initiated infliximab, adalimumab, and golimumab, respectively. Rates of non-persistence and switching were higher in UC than in CD. One- and 3-year non-persistence rates were 14.2% and 26.5% in CD and 35.4% and 53.4% in UC, respectively. One- and 3-year switching rates were 3.7% and 10.1% in CD and 15.6% and 22.0% in UC, respectively. In both CD and UC, infliximab and adalimumab initiators showed similar persistence rates, whereas adalimumab initiators had a higher risk of switching than infliximab initiators. In UC, golimumab initiators had a higher risk of non-persistence and switching than infliximab initiators. Steroid use at biologic initiation was associated with an increased risk of non-persistence and switching in both CD and UC. UC patients who started biologic treatment at tertiary hospitals were more likely to continue treatment than those who started at general hospitals/community hospitals/clinics. CONCLUSIONS In real-world clinical practice settings, discontinuation of biologics occurred frequently in IBD patients, and switching of biologics was common in UC patients.
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21
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Chen P, Zhou G, Lin J, Li L, Zeng Z, Chen M, Zhang S. Serum Biomarkers for Inflammatory Bowel Disease. Front Med (Lausanne) 2020; 7:123. [PMID: 32391365 PMCID: PMC7188783 DOI: 10.3389/fmed.2020.00123] [Citation(s) in RCA: 105] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Accepted: 03/20/2020] [Indexed: 12/12/2022] Open
Abstract
Background: Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic, inflammatory disorder of the gastrointestinal tract. As the novel therapeutic goal and biologicals are widely recognized, accurate assessment of disease and prediction of therapeutic response have become a crucial challenge in clinical practice. Also, because of the continuously rising incidence, convenient and economical methods of diagnosis and clinical assessment are urgently needed. Recently, serum biomarkers have made a great progress and become a focus in IBD study because they are non-invasive, convenient, and relatively inexpensive than are markers in biopsy tissue, stool, breath, and other body fluids. Aims: To review the available data on serological biomarkers for IBD. Methods: We searched PubMed using predefined key words on relevant literatures of serum biomarkers regarding diagnosis, evaluation of therapeutic efficacy, surveillance of disease activity, and assessment of prognosis for IBD. Results: We reviewed serological biomarkers that are well-established and widely used (e.g., C-reactive protein), newly discovered biomarkers (e.g., cytokines, antibodies, and non-coding RNAs), and also recently advancements in serological biomarkers (e.g., metabolomics and proteomics) that are used in different aspects of IBD management. Conclusions: With such a wealth of researches, to date, there are still no ideal serum biomarkers for IBD. Serum profiling and non-coding RNAs are just starting to blossom but reveal great promise for future clinical practice. Combining different biomarkers can be valuable in improving performance of disease evaluation.
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Affiliation(s)
- Peng Chen
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Gaoshi Zhou
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Jingxia Lin
- Division of Blood Transfusion, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Li Li
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhirong Zeng
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Minhu Chen
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shenghong Zhang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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22
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Trough Levels of Infliximab at Week 6 Are Predictive of Remission at Week 14 in Pediatric Crohn's Disease. J Pediatr Gastroenterol Nutr 2020; 70:310-317. [PMID: 31651668 DOI: 10.1097/mpg.0000000000002536] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVE Infliximab (IFX) is a frequent therapeutic option for Crohn disease (CD) patients. Early detection of responders to IFX is critical for the management of CD in order to avoid long-term exposure to the drug without benefit. This retrospective study aimed at analysing which early parameters recorded during the induction period are able to predict response to IFX during the maintenance period in pediatric CD. PATIENTS AND METHODS Medical records of all CD patients ages from 2 to 18 years who received IFX at a tertiary IBD center were retrospectively analyzed. Children were classified in 3 groups according to their response at week 14 (W14) remission, clinical response or , no response. The factors recorded at W0, W2, and W6, which were associated with remission at W14 were analyzed using a logistic regression. RESULTS Among the 111 patients included, 74.8% patients were responders to IFX at W14, including 38.7% in clinical remission and 36% with partial clinical response. Clinical remission at W14 was associated with normal growth (P < 0.01), and normal albuminemia (P = 0.01) at baseline, It was also associated with trough levels to IFX >8.3 μg/ml at week 6 (P < 0.01). CONCLUSION Trough levels to IFX >8.3 μg/ml at week 6 are predictive of remission at W14 for luminal disease.
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23
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Kim NH, Lee JH, Hong SN, Yoon H, Kang HW, Lee SH, Im JP, Cha JM, Eun CS, Kim JW, Choi CH, Park DI. Long-term efficacy and safety of CT-P13, a biosimilar of infliximab, in patients with inflammatory bowel disease: A retrospective multicenter study. J Gastroenterol Hepatol 2019; 34:1523-1532. [PMID: 30828891 DOI: 10.1111/jgh.14645] [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: 11/05/2018] [Revised: 02/05/2019] [Accepted: 02/26/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIM A biosimilar of infliximab, CT-P13 (Remsima®) has the potential to reduce treatment costs and enhance access to biological therapy for inflammatory bowel disease (IBD) patients. However, long-term clinical data on its use for IBD treatment are currently sparse. We aimed to investigate the long-term efficacy and safety of CT-P13 therapy in a large, real-life IBD cohort. METHODS A total of 368 IBD patients (227 with Crohn's disease [CD] and 141 with ulcerative colitis [UC]) treated with CT-P13 at 16 referral hospitals in Korea between July 2012 and December 2017 were retrospectively analyzed. RESULTS The cumulative retention rates at years 1, 3, and 5 were 86.1%, 68.5%, and 58.7% and 69.7%, 46.0%, and 26.7% in anti-tumor necrosis factor (TNF)-naïve CD and UC patients, respectively. The clinical response and remission rates at week 14 and at years 1, 3, and 5 were 94.3%, 92.7%, 76.8%, and 17.6% and 78.6%, 82.4%, 72.2%, and 17.6% in anti-TNF-naïve CD and 85.6%, 80.0%, 55.2%, and 6.7% and 42.6%, 59.8%, 44.2%, and 6.7% in anti-TNF-naïve UC patients, respectively. Among patients who switched from the biologic originator to CT-P13, the cumulative retention rates at years 1, 3, and 5 were 88.5%, 66.1%, and 44.8% in CD, and 73.9%, 42.5%, and 42.5% in UC patients, respectively. Significant improvements in disease activity scores were accompanied by marked reductions in inflammatory marker levels, and no unexpected adverse events including death or malignancy occurred during the study period. CONCLUSIONS Long-term treatment with CT-P13 is effective in inducing and maintaining disease improvement and is well-tolerated in patients with IBD. CT-P13 may be a promising treatment option for IBD.
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Affiliation(s)
- Nam Hee Kim
- Preventive Healthcare Center, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ji Hyun Lee
- Digestive Endoscopic Center, Seoul Song Do Colorectal Hospital, Seoul, Korea
| | - Sung Noh Hong
- Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hyuk Yoon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Hyoun Woo Kang
- Department of Internal Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, Korea
| | - Suck-Ho Lee
- Digestive Endoscopic Center, Esoo Hospital, Cheonan-si, Korea
| | - Jong Pil Im
- Division of Gastroenterology, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Jae Myung Cha
- Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, Korea
| | - Chang Soo Eun
- Department of Internal Medicine, Hanyang University Guri Hospital, Guri, Korea
| | - Ji Won Kim
- Department of Internal Medicine, SMG-SNU Boramae Medical Center, SNUH College of Medicine, Seoul, Korea
| | - Chang Hwan Choi
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Dong Il Park
- Division of Gastroenterology, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
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A Review on the Use of Anti-TNF in Children and Adolescents with Inflammatory Bowel Disease. Int J Mol Sci 2019; 20:ijms20102529. [PMID: 31126015 PMCID: PMC6566820 DOI: 10.3390/ijms20102529] [Citation(s) in RCA: 85] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 05/14/2019] [Accepted: 05/20/2019] [Indexed: 02/07/2023] Open
Abstract
Inflammatory bowel disease (IBD) presents with disabling symptoms and may lead to insufficient growth and late pubertal development in cases of disease onset during childhood or adolescence. During the last decade, the role of anti-tumor necrosis factor (TNF) in the treatment of paediatric-onset IBD has gained more ground. The number of biologicals presently available for children and adolescents with IBD has increased, biosimilars have become available, and practices in adult gastroenterology with regards to anti-TNF have changed. The aim of this study is to review the current evidence on the indications, judicious use, effectiveness and safety of anti-TNF agents in paediatric IBD. A PubMed literature search was performed and included articles published after 2000 using the following terms: child or paediatric, Crohn, ulcerative colitis, inflammatory bowel disease, anti-TNF, TNF alpha inhibitor, infliximab, adalimumab, golimumab and biological. Anti-TNF agents, specifically infliximab and adalimumab, have proven to be effective in moderate and severe paediatric IBD. Therapeutic drug monitoring increases therapy effectiveness and safety. Clinical predictors for anti-TNF response are currently of limited value because of the variation in outcome definitions and follow-ups. Future research should comprise large cohorts and clinical trials comparing groups according to their risk profile in order to provide personalized therapeutic strategies.
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Atreya R, Neurath MF. Mechanisms of molecular resistance and predictors of response to biological therapy in inflammatory bowel disease. Lancet Gastroenterol Hepatol 2019; 3:790-802. [PMID: 30353856 DOI: 10.1016/s2468-1253(18)30265-6] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 07/25/2018] [Accepted: 07/27/2018] [Indexed: 02/07/2023]
Abstract
Biological therapy has led to marked improvements in treatment of patients with inflammatory bowel disease, and an increasing number of drugs has been approved for treatment. However, only a subgroup of patients responds to therapy, highlighting the need to identify biomarkers for therapeutic response to allow personalised medicine in inflammatory bowel disease. Potential markers of response to biological therapy have been identified; however, studies also suggest that changes in the composition of immune cell infiltrates in response to therapeutic pressure lead to molecular resistance to these drugs. For instance, the cytokine interleukin 23 has been identified as a driver of evasion of apoptosis in response to anti-tumour necrosis factor drugs in patients with Crohn's disease, leading to expansion of apoptosis-resistant T cells and drug resistance. In this Review, we examine the concept of molecular resistance to biological therapy and discuss implications for future therapy.
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Affiliation(s)
- Raja Atreya
- Department of Medicine 1, University Hospital Erlangen, and Ludwig Demling Endoscopy Center of Excellence, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine 1, University Hospital Erlangen, and Ludwig Demling Endoscopy Center of Excellence, University of Erlangen-Nuremberg, Erlangen, Germany.
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26
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Lee JM, Kim YJ, Lee KM, Yoon H, Lee BI, Kim DB, Kang D. Long-term clinical outcome after infliximab discontinuation in patients with inflammatory bowel disease. Scand J Gastroenterol 2019; 53:1280-1285. [PMID: 30351977 DOI: 10.1080/00365521.2018.1524024] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES We investigated the long-term clinical outcome and risk factors for clinical relapse in inflammatory bowel disease (IBD) patients after stopping infliximab (IFX). MATERIALS AND METHODS We retrospectively reviewed the medical records of IBD patients who were treated with IFX in four university hospitals in South Korea. Among them, patients who discontinued scheduled IFX therapy with a favorable disease course were enrolled. Clinical relapse was defined as an increase in disease activity, addition of new drugs, or abdominal surgery. RESULTS In total, 28 ulcerative colitis (UC) patients and 17 Crohn's disease (CD) patients were enrolled. The median duration of follow-up after discontinuation was 41 months (range: 8-109 months) in UC patients and 141 months (range: 66-262 months) in CD patients. The cumulative probability of relapse at 12 months was 32.1% in UC patients and 30.7% in CD patients. Fewer IFX infusions and a shorter duration of mesalamine treatment after IFX discontinuation were risk factors for relapse after IFX discontinuation in UC patients (p = .04 and .01, respectively). In CD patients, a higher erythrocyte sedimentation rate and CRP at IFX discontinuation and a shorter duration of azathioprine treatment after IFX discontinuation were risk factors for relapse (p = .03, .03 and .01, respectively). CONCLUSIONS Approximately 30% of IBD patients who responded to IFX therapy experienced relapse within 1 year after discontinuation. We identified several risk factors for relapse. Further studies should identify factors predictive of the disease course after discontinuing IFX maintenance therapy.
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Affiliation(s)
- Ji Min Lee
- a Department of Internal Medicine , St. Vincent's Hospital, College of Medicine, The Catholic University of Korea , Seoul , Korea
| | - Yoon Jae Kim
- b Department of Internal Medicine , Gachon University, Gil Medical Center , Incheon , Korea
| | - Kang-Moon Lee
- a Department of Internal Medicine , St. Vincent's Hospital, College of Medicine, The Catholic University of Korea , Seoul , Korea
| | - Hyuk Yoon
- c Department of Internal Medicine , Seoul National University Bundang Hospital , Seongnam , Gyeonggi-do , Korea
| | - Bo-In Lee
- d Department of Internal Medicine , Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea , Seoul , Korea
| | - Dae Bum Kim
- a Department of Internal Medicine , St. Vincent's Hospital, College of Medicine, The Catholic University of Korea , Seoul , Korea
| | - Donghoon Kang
- d Department of Internal Medicine , Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea , Seoul , Korea
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Stevens TW, Matheeuwsen M, Lönnkvist MH, Parker CE, Wildenberg ME, Gecse KB, D'Haens GR. Systematic review: predictive biomarkers of therapeutic response in inflammatory bowel disease-personalised medicine in its infancy. Aliment Pharmacol Ther 2018; 48:1213-1231. [PMID: 30378142 DOI: 10.1111/apt.15033] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 07/19/2018] [Accepted: 09/29/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is characterised by substantial heterogeneity in treatment response. With an expanding number of therapeutic agents, identifying optimal treatment at the patient level remains a major challenge. AIM To systematically review the available literature on predictive biomarkers of therapeutic response in IBD. METHODS An electronic literature search was performed on 30 January 2018 using MEDLINE, EMBASE and the Cochrane Library. Retrospective, prospective, uncontrolled and controlled studies reporting on biomarkers predicting therapeutic response in paediatric and adult IBD populations were eligible for inclusion. The methodological quality of the included studies was assessed using the QUIPS tool. Due to anticipated heterogeneity and limited data, a qualitative, rather than quantitative, assessment was planned. RESULTS Of the 10 638 citations identified, 92 articles met the inclusion criteria. Several potential DNA, mRNA and protein markers were evaluated as predictive biomarkers. Most studies focused on predicting response to anti-TNF agents. Substantial between-study heterogeneity was identified with respect to both the biomarkers studied and the definition of response. None of the included studies received a low risk of bias rating for all six domains. Currently, none of the biomarkers is sufficiently predictive for clinical use. CONCLUSIONS The search for predictive biomarkers is still in its infancy and current evidence is limited. Future research efforts should take into account the high patient heterogeneity within prospective trials with objective response assessment. Predictive models will most likely comprise a combination of several molecular markers from integrated omics-levels and clinical characteristics.
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Affiliation(s)
- Toer W Stevens
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Mijntje Matheeuwsen
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Maria H Lönnkvist
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | | | - Manon E Wildenberg
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.,Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, Amsterdam, The Netherlands
| | - Krisztina B Gecse
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Geert R D'Haens
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
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Zhang H, Zeng Z, Mukherjee A, Shen B. Molecular diagnosis and classification of inflammatory bowel disease. Expert Rev Mol Diagn 2018; 18:867-886. [PMID: 30152711 DOI: 10.1080/14737159.2018.1516549] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Traditional diagnosis and classification of inflammatory bowel diseases (IBDs) have been based on clinical evaluation, laboratory testing, endoscopy, imaging, and histological examinations. With the advancement of medical technology, an increasing number of molecular surrogates are playing a key role in diagnosis, differential diagnosis, assessment of disease activity, prediction of clinical course, and therapeutic response of IBD. Areas covered: The authors review roles of both existing and emerging surrogates including genetic, serological, histologic, and fecal markers in diagnosis and classification of IBD. Comparisons in advantages and disadvantages of different markers have also been discussed. In addition, this review underscores controversial and unclear aspects which need further study. Expert commentary: IBD is characteristic of chronicity, relapse-remission and destructiveness. It is of great importance for clinicians to make an accurate diagnosis and classification. Current and new molecular markers perform well with acceptable sensitivity and specificity. The use of molecular markers in clinical practice needs to be further explored and then generalized. More work is warranted to identify novel useful markers and elucidate how to apply them together with current markers in clinical settings.
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Affiliation(s)
- Hu Zhang
- a Center for Inflammatory Bowel Disease & Department of Gastroenterology , West China Hospital, Sichuan University , Chengdu , China
| | - Zhen Zeng
- a Center for Inflammatory Bowel Disease & Department of Gastroenterology , West China Hospital, Sichuan University , Chengdu , China
| | - Arjudeb Mukherjee
- b West China School of Medicine , Sichuan University , Chengdu , China
| | - Bo Shen
- c Center for Inflammatory Bowel Disease, Digestive Disease and Surgery Institute, The Cleveland Clinic Foundation , Cleveland , Ohio , USA
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29
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Golimumab effectiveness and safety in clinical practice for moderately active ulcerative colitis. Eur J Gastroenterol Hepatol 2018; 30:1019-1026. [PMID: 29878945 DOI: 10.1097/meg.0000000000001177] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIMS Golimumab (GLB) is an antitumour necrosis factor-α (anti-TNF) therapy that has shown efficacy as induction and maintenance therapy for ulcerative colitis (UC). We aimed to describe the outcome of GLB therapy for UC in a real-world clinical practice. PATIENTS AND METHODS Consecutive patients receiving GLB for UC in six Irish Academic Medical Centres were identified. The primary study endpoint was the 6-month corticosteroid-free remission rate. The secondary endpoints included the 3-month clinical response, time free of GLB discontinuation and adverse events. RESULTS Seventy-two patients were identified [57% men; median (range) age of 41.4 years (20.3-76.8); disease duration 6.6 years (0-29.9); follow-up 8.7 months (0.4-39.2)]. Sixty-four percent of patients were anti-TNF naive. The 3-month clinical response and the 6-month corticosteroid-free remission rates were 55 and 39%, respectively. Forty-four percent of patients discontinued GLB during the follow-up, median (95% confidence interval) time to GLB discontinuation 18.7 months (9.2-28.1). A C-reactive protein more than 5 mg/l at baseline was associated with failure to achieve 6-month corticosteroid-free remission and a shorter time to GLB discontinuation, odds ratio 0.2 (0.1-0.7), P=0.008, and hazard ratio (95% confidence interval) 2.8 (1.3-5.7), P=0.007, respectively. Adverse events occurred in 7% of patients (n=5), all of which were minor and self-limiting. CONCLUSION These real-world clinical data suggest that GLB is an effective and safe therapy for a UC cohort with significant previous anti-TNF exposure. An elevated baseline C-reactive protein, likely reflective of increased inflammatory burden, is associated with a reduced likelihood of a successful outcome of GLB therapy.
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Burke KE, Khalili H, Garber JJ, Haritunians T, McGovern DPB, Xavier RJ, Ananthakrishnan AN. Genetic Markers Predict Primary Nonresponse and Durable Response to Anti-Tumor Necrosis Factor Therapy in Ulcerative Colitis. Inflamm Bowel Dis 2018; 24:1840-1848. [PMID: 29718226 PMCID: PMC6128143 DOI: 10.1093/ibd/izy083] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Despite a high nonresponse rate, predictors of response to anti-tumor necrosis factor (anti-TNF) therapy in ulcerative colitis (UC) remain limited. We aim to determine clinical and genetic predictors of primary nonresponse (PNR) and durable response (DR) to anti-TNF therapy in a large prospective UC cohort. METHODS Using the Illumina Immunochip, candidate polymorphisms associated with clinical outcomes of PNR and DR were separately evaluated and combined into weighted genetic risk scores. Combined genetic and clinical multivariable models for PNR and DR were compared with clinical predictive models using area under the receiver operating characteristic (AUROC) curves. Models were internally (DR) or externally (PNR) validated. Multivariable logistic regression was utilized to assess the association of genetic risk scores with infliximab levels and antibodies. RESULTS Of 231 patients, 28 (12%) experienced PNR and 120 (52%) experienced DR. There was no significant difference in clinical features between primary nonresponders and responders. Eight alleles were associated with PNR. A combined clinical-genetic model (AUROC, 0.87) more accurately predicted PNR compared with a clinical-only model (AUROC, 0.57; P < 0.0001). In an external cohort of 131 patients, increasing tertiles of PNR genetic risk score correlated with increased risk of PNR (P = 0.052). Twelve candidate loci were associated with DR. Genetic risk score quartiles for DR demonstrated a strong dose-response relationship in predicting treatment duration. Genetic risk scores for PNR and DR were not associated with infliximab levels or antibody formation. CONCLUSION Genetic polymorphisms enhance prediction of PNR and DR to anti-TNF therapy in patients with UC.
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Affiliation(s)
- Kristin E Burke
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts,Harvard Medical School, Boston, Massachusetts
| | - Hamed Khalili
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts,Harvard Medical School, Boston, Massachusetts
| | - John J Garber
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts,Harvard Medical School, Boston, Massachusetts
| | - Talin Haritunians
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Dermot P B McGovern
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Ramnik J Xavier
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts,Harvard Medical School, Boston, Massachusetts
| | - Ashwin N Ananthakrishnan
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts,Harvard Medical School, Boston, Massachusetts,Address correspondence to: Ashwin N. Ananthakrishnan, Massachusetts General Hospital Crohn’s and Colitis Center, 165 Cambridge Street, Boston, MA 02114 ()
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CRP/Albumin Ratio: An Early Predictor of Steroid Responsiveness in Acute Severe Ulcerative Colitis. J Clin Gastroenterol 2018; 52:e48-e52. [PMID: 28737646 DOI: 10.1097/mcg.0000000000000884] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
INTRODUCTION Identifying hospitalized patients with acute severe ulcerative colitis (ASUC) who will be refractory to corticosteroid therapy and require rescue therapy remains difficult. Hypoalbuminemia worsens with time during hospitalization and is associated with rapid clearance of and reduced response to infliximab (IFX) rescue. Early use of rescue therapy may therefore be more effective. Simple clinical and laboratory predictors of corticosteroid responsiveness would facilitate earlier use of rescue therapy. MATERIALS AND METHODS Retrospective study of a prospectively maintained database of 3600 patients attending a single center was conducted. Patients with histologically confirmed ulcerative colitis admitted with ASUC over a 5-year period from January 2010 to December 2014 were identified. All patients initially received intravenous corticosteroids. Patient demographics were collected; C-reactive protein (CRP) and albumin levels were recorded at baseline and during admission. Receiver operating characteristic statistics were used to determine the optimal stool frequency, CRP, albumin, and CRP/albumin ratio (CAR) to predict steroid response. RESULTS A total of 124 ASUC patients were admitted during a 5-year period. Median follow-up was 2.3 years. A total of 62 patients (50%) were steroid responsive, 55 patients (44%) received rescue IFX, 22 patients (18%) required colectomy within 30 days of admission, whereas a further 14 (11%) required colectomy during follow-up. By receiver operating characteristic statistics, day 3 CAR was a more accurate marker of steroid responsiveness than day 3 CRP or day 3 albumin alone [area under curve=0.75 (P<0.001)]. The optimal CAR to predict response to steroids on day 3 was 0.85 (sensitivity 70%, specificity 76%). When combined with D3 stool frequency, specificity improved to 83%. If at day 3, CAR was >0.85 and stool frequency was >3, the relative risk of steroid nonresponse was significantly raised at 3.9 (95% confidence interval, 2.1-7.2). CONCLUSIONS Raised D3 CAR is an early predictor of steroid-refractory ASUC. When combined with D3 stool frequency, its predictive ability improves. In patients with predicted steroid nonresponse, early introduction of rescue IFX at this stage may be more effective, before serum albumin falls profoundly.
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Nishida Y, Hosomi S, Watanabe K, Watanabe K, Yukawa T, Otani K, Nagami Y, Tanaka F, Taira K, Kamata N, Yamagami H, Tanigawa T, Watanabe T, Fujiwara Y. Serum interleukin-6 level is associated with response to infliximab in ulcerative colitis. Scand J Gastroenterol 2018; 53:579-585. [PMID: 29171305 DOI: 10.1080/00365521.2017.1403647] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES Infliximab is effective in patients with ulcerative colitis (UC); however, one-third of patients do not respond and require additional therapies such as other biologic agents. Therefore, the aim of this study was to analyze the association between pro-inflammatory molecules and clinical efficacy to elucidate possible mechanisms for the non-response to infliximab to aid in treatment selection. MATERIALS AND METHOD Patients with moderate-to-severe active UC receiving infliximab in our hospital between 2010 and 2016 for whom pre-treatment serum samples were available were retrospectively evaluated. We analyzed the association between serum interleukin (IL)-6, tumor necrosis factor-α (TNF-α) and soluble mucosal vascular addressin cell adhesion molecule-1 (sMAdCAM-1) and the clinical efficacy of infliximab. The primary endpoint was clinical response at the end of the induction period. RESULTS Forty-one patients were included in this study. After induction therapy, 27 patients (65.9%) showed a clinical response. Serum IL-6 levels were significantly lower in responders than in non-responders (p = .012), whereas no significant differences were noted in other factors including sMAdCAM-1 and TNF-α. Multivariate analysis identified that serum IL-6 level (odds ratio = 0.72; 95% confidence interval, 0.54-0.96; p = .027) was independently associated with response to infliximab. CONCLUSIONS Serum IL-6 level is associated with response to infliximab in UC. Elevated concentrations of IL-6 may provide insight to the mechanism of non-response to infliximab.
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Affiliation(s)
- Yu Nishida
- a Department of Gastroenterology , Osaka City University Graduate School of Medicine , Osaka , Japan
| | - Shuhei Hosomi
- a Department of Gastroenterology , Osaka City University Graduate School of Medicine , Osaka , Japan
| | - Kenji Watanabe
- a Department of Gastroenterology , Osaka City University Graduate School of Medicine , Osaka , Japan.,b Department of Intestinal Inflammation Research , Hyogo College of Medicine , Hyogo , Japan
| | - Kimihiko Watanabe
- a Department of Gastroenterology , Osaka City University Graduate School of Medicine , Osaka , Japan
| | - Tomomi Yukawa
- a Department of Gastroenterology , Osaka City University Graduate School of Medicine , Osaka , Japan
| | - Koji Otani
- a Department of Gastroenterology , Osaka City University Graduate School of Medicine , Osaka , Japan
| | - Yasuaki Nagami
- a Department of Gastroenterology , Osaka City University Graduate School of Medicine , Osaka , Japan
| | - Fumio Tanaka
- a Department of Gastroenterology , Osaka City University Graduate School of Medicine , Osaka , Japan
| | - Koichi Taira
- a Department of Gastroenterology , Osaka City University Graduate School of Medicine , Osaka , Japan
| | - Noriko Kamata
- a Department of Gastroenterology , Osaka City University Graduate School of Medicine , Osaka , Japan
| | - Hirokazu Yamagami
- a Department of Gastroenterology , Osaka City University Graduate School of Medicine , Osaka , Japan
| | - Tetsuya Tanigawa
- a Department of Gastroenterology , Osaka City University Graduate School of Medicine , Osaka , Japan
| | - Toshio Watanabe
- a Department of Gastroenterology , Osaka City University Graduate School of Medicine , Osaka , Japan
| | - Yasuhiro Fujiwara
- a Department of Gastroenterology , Osaka City University Graduate School of Medicine , Osaka , Japan
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Asensio-Sánchez VM, Díaz-Cabanas L, Martín-Prieto A, Haro-Álvarez B. Asymptomatic choroidal tubercle in a patient with Crohn's disease on adalimumab treatment. ARCHIVOS DE LA SOCIEDAD ESPANOLA DE OFTALMOLOGIA 2018; 93:147-150. [PMID: 28743416 DOI: 10.1016/j.oftal.2017.06.009] [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: 03/25/2017] [Revised: 05/27/2017] [Accepted: 06/21/2017] [Indexed: 06/07/2023]
Abstract
INTRODUCTION Adalimumab, an anti-tumour necrosis factor alpha therapy for active Crohn's disease (CD), is associated with increased risks of tuberculosis infection. CASE REPORT The case is presented of a 48 year-old male with active CD on treatment with adalimumab. After three months, he developed a miliary pulmonary tuberculosis infection, with a solitary non-reactive choroidal tubercle temporal-superior to the optic disc being found in an ophthalmological study. Fluorescein angiography showed late hyperfluorescence in a staining pattern. Optic coherence tomography showed a flat mass without serous retinal detachment. The choroidal tubercle slowly regressed with antituberculosis therapy. DISCUSSION Choroidal tubercles with no vitreo-retinal symptomatology can be present in patients with CD and on treatment with adalimumab.
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Affiliation(s)
- V M Asensio-Sánchez
- Servicio de Oftalmología, Hospital Clínico Universitario, Valladolid, España.
| | - L Díaz-Cabanas
- Servicio de Oftalmología, Hospital Clínico Universitario, Valladolid, España
| | - A Martín-Prieto
- Servicio de Oftalmología, Hospital Clínico Universitario, Valladolid, España
| | - B Haro-Álvarez
- Servicio de Oftalmología, Hospital Clínico Universitario, Valladolid, España
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Sami Ullah KR, Xiong YL, Miao YL, Ummair S, Dai W. Thalidomide and thalidomide analogues in treatment of patients with inflammatory bowel disease: Meta-analysis. World J Meta-Anal 2017; 5:124-131. [DOI: 10.13105/wjma.v5.i5.124] [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: 01/21/2017] [Revised: 05/05/2017] [Accepted: 07/03/2017] [Indexed: 02/05/2023] Open
Abstract
AIM To examine the efficacy and safety of thalidomide and thalidomide analogues in induction and maintenance of remission in patients with inflammatory bowel disease (IBD).
METHODS A literature search was performed in the following databases: PubMed, EMBASE, Web of Science, Ovid and the Cochrane Library, and Chinese databases such as the China National Knowledge Infrastructure, China Science and Technology Journal Database (VIP), Wanfang Data. The randomized controlled analysis was performed to assess the effects of thalidomide therapy on inflammatory bowel disease for patients who did show good response with other therapies.
RESULTS Three studies (n = 212) met the inclusion criteria were used in this Meta-analysis. No difference was found between thalidomide/thalidomide analogues and placebo in the induction of remission (RR = 1.36, 95%CI: 0.83-2.22, P = 0.22), the induction of clinical response (RR = 1.14, 95%CI: 0.75-1.72, P = 0.54) and the induction of adverse events (RR = 1.41, 95%CI: 0.99-2.02, P = 0.06).
CONCLUSION Currently, there is not enough evidence to support use of thalidomide or its analogue for the treatment in patients of any age with IBD. However, it warrants a reanalysis when more data become available.
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Affiliation(s)
- Khan Rana Sami Ullah
- Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Disease, Kunming 650032, Yunnan Province, China
| | - Yu-Lin Xiong
- Library of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Ying-Lei Miao
- Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Disease, Kunming 650032, Yunnan Province, China
| | - Saeed Ummair
- Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Kunming 650032, Yunnan Province, China
| | - Wei Dai
- Department of Gastroenterology, First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Disease, Kunming 650032, Yunnan Province, China
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Lopetuso LR, Gerardi V, Papa V, Scaldaferri F, Rapaccini GL, Gasbarrini A, Papa A. Can We Predict the Efficacy of Anti-TNF-α Agents? Int J Mol Sci 2017; 18:ijms18091973. [PMID: 28906475 PMCID: PMC5618622 DOI: 10.3390/ijms18091973] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 09/05/2017] [Accepted: 09/11/2017] [Indexed: 12/21/2022] Open
Abstract
The use of biologic agents, particularly anti-tumor necrosis factor (TNF)-α, has revolutionized the treatment of inflammatory bowel diseases (IBD), modifying their natural history. Several data on the efficacy of these agents in inducing and maintaining clinical remission have been accumulated over the past two decades: their use avoid the need for steroids therapy, promote mucosal healing, reduce hospitalizations and surgeries and therefore dramatically improve the quality of life of IBD patients. However, primary non-response to these agents or loss of response over time mainly due to immunogenicity or treatment-related side-effects are a frequent concern in IBD patients. Thus, the identification of predicting factors of efficacy is crucial to allow clinicians to efficiently use these therapies, avoiding them when they are ineffective and eventually shifting towards alternative biological therapies with the end goal of optimizing the cost-effectiveness ratio. In this review, we aim to identify the predictive factors of short- and long-term benefits of anti-TNF-α therapy in IBD patients. In particular, multiple patient-, disease- and treatment-related factors have been evaluated.
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Affiliation(s)
- Loris Riccardo Lopetuso
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Gemelli, Catholic University of Rome, 00168 Rome, Italy; (L.R.L.); (V.G.); (F.S.); (G.L.R.); (A.G.)
| | - Viviana Gerardi
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Gemelli, Catholic University of Rome, 00168 Rome, Italy; (L.R.L.); (V.G.); (F.S.); (G.L.R.); (A.G.)
| | - Valerio Papa
- Digestive Surgery Department, Fondazione Policlinico Gemelli, Catholic University of Rome, 00168 Rome, Italy;
| | - Franco Scaldaferri
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Gemelli, Catholic University of Rome, 00168 Rome, Italy; (L.R.L.); (V.G.); (F.S.); (G.L.R.); (A.G.)
| | - Gian Lodovico Rapaccini
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Gemelli, Catholic University of Rome, 00168 Rome, Italy; (L.R.L.); (V.G.); (F.S.); (G.L.R.); (A.G.)
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Gemelli, Catholic University of Rome, 00168 Rome, Italy; (L.R.L.); (V.G.); (F.S.); (G.L.R.); (A.G.)
| | - Alfredo Papa
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Gemelli, Catholic University of Rome, 00168 Rome, Italy; (L.R.L.); (V.G.); (F.S.); (G.L.R.); (A.G.)
- Correspondence: ; Tel.: +39-06-3503310
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Seo H, Chang K, Lee SH, Song EM, Kim GU, Seo M, Lee HS, Hwang SW, Yang DH, Kim KJ, Ye BD, Byeon JS, Myung SJ, Yang SK, Park SH. Long-term outcomes of infliximab treatment and predictors of response in 195 patients with ulcerative colitis: a hospital-based cohort study from Korea. Scand J Gastroenterol 2017; 52:857-863. [PMID: 28502189 DOI: 10.1080/00365521.2017.1323229] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Large-scale studies regarding the long-term efficacy of infliximab (IFX) treatment in non-Caucasian patients with ulcerative colitis (UC) are lacking. STUDY We analyzed the long-term outcomes of IFX in 195 Korean UC patients who received scheduled IFX treatments at Asan Medical Center. IFX failure was defined as IFX discontinuation due to colectomy or non-response to IFX, and additionally UC-related hospitalization or a need for rescue corticosteroids during the course of IFX. RESULTS Between December 2006 and October 2016, a total of 3101 infusions of IFX were administered to 195 patients over a median period of 21 months. At the end of the follow-up, 86 patients (44.1%) were still receiving IFX without failure. IFX was stopped in 73 (37.4%) patients due to colectomy (23 patients, 11.8%), non-response to IFX (35 patients, 17.9%) or other reasons such as adverse events or patients' preferences (15 patients, 7.7%). An additional 36 (18.5%) patients experienced IFX failure during follow-up due to a need for rescue corticosteroids (13 patients, 6.7%), UC-related hospitalization (8 patients, 4.1%), or both (15 patients, 7.7%). The survival free of IFX failure was 58.1% at 1 year, 50.7% at 3 years and 44.8% at 5 years. In a multivariate regression analysis, cytomegalovirus colitis within 3 months before IFX initiation was a predictor of IFX failure (hazard ratio 1.57; 95% confidence interval 1.04-2.37; p = .032). CONCLUSIONS The long-term efficacy of IFX in a large, real-life cohort of Korean UC patients appears to be comparable to that in previously published Western studies.
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Affiliation(s)
- Hyungil Seo
- a Department of Gastroenterology , University of Ulsan College of Medicine, Asan Medical Center , Seoul , Korea
| | - Kiju Chang
- a Department of Gastroenterology , University of Ulsan College of Medicine, Asan Medical Center , Seoul , Korea
| | - Sun-Ho Lee
- a Department of Gastroenterology , University of Ulsan College of Medicine, Asan Medical Center , Seoul , Korea
| | - Eun-Mi Song
- a Department of Gastroenterology , University of Ulsan College of Medicine, Asan Medical Center , Seoul , Korea
| | - Gwang-Un Kim
- a Department of Gastroenterology , University of Ulsan College of Medicine, Asan Medical Center , Seoul , Korea
| | - Myeongsook Seo
- a Department of Gastroenterology , University of Ulsan College of Medicine, Asan Medical Center , Seoul , Korea
| | - Ho-Su Lee
- b Health Screening and Promotion Center , University of Ulsan College of Medicine, Asan Medical Center , Seoul , Korea
| | - Sung-Wook Hwang
- a Department of Gastroenterology , University of Ulsan College of Medicine, Asan Medical Center , Seoul , Korea
- c Inflammatory Bowel Disease Center , University of Ulsan College of Medicine, Asan Medical Center , Seoul , Korea
| | - Dong-Hoon Yang
- a Department of Gastroenterology , University of Ulsan College of Medicine, Asan Medical Center , Seoul , Korea
| | - Kyung-Jo Kim
- a Department of Gastroenterology , University of Ulsan College of Medicine, Asan Medical Center , Seoul , Korea
- c Inflammatory Bowel Disease Center , University of Ulsan College of Medicine, Asan Medical Center , Seoul , Korea
| | - Byong Duk Ye
- a Department of Gastroenterology , University of Ulsan College of Medicine, Asan Medical Center , Seoul , Korea
- c Inflammatory Bowel Disease Center , University of Ulsan College of Medicine, Asan Medical Center , Seoul , Korea
| | - Jeong-Sik Byeon
- a Department of Gastroenterology , University of Ulsan College of Medicine, Asan Medical Center , Seoul , Korea
| | - Seung-Jae Myung
- a Department of Gastroenterology , University of Ulsan College of Medicine, Asan Medical Center , Seoul , Korea
| | - Suk-Kyun Yang
- a Department of Gastroenterology , University of Ulsan College of Medicine, Asan Medical Center , Seoul , Korea
- c Inflammatory Bowel Disease Center , University of Ulsan College of Medicine, Asan Medical Center , Seoul , Korea
| | - Sang Hyoung Park
- a Department of Gastroenterology , University of Ulsan College of Medicine, Asan Medical Center , Seoul , Korea
- c Inflammatory Bowel Disease Center , University of Ulsan College of Medicine, Asan Medical Center , Seoul , Korea
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Li Y, Shu HJ, Lu H, Yang H, Li J, Tan B, Qian JM. Long-term risk of infection in patients with Crohn's disease on anti-TNF treatment: A prospective single-center cohort study in China. J Dig Dis 2017. [PMID: 28644565 DOI: 10.1111/1751-2980.12499] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The aim of this study was to explore the long-term risk of infection in patients with Crohn's disease (CD) on infliximab (IFX) therapy. METHODS All CD patients treated with IFX were recruited from January 2008 to December 2015. Their characteristics and infectious events during IFX therapy were prospectively collected, and the risk of infection was evaluated using Cox regression. RESULTS Seventy CD patients receiving IFX were consecutively recruited. During a median of 15 months, 15 patients experienced 17 infectious events which occurred within a median of 21 weeks after the initiation of IFX therapy. Of 17 infectious events, eight were viral infections, six were bacterial infections, and the others were fungal infections. IFX was discontinued in 6 (40.0%) out of 15 cases due to infections. Compared with those without infections, patients with infectious events were more likely of Montreal B1 (inflammatory) behavior, with concomitant use of systemic corticosteroids when infliximab was started but less mucosal healing when infections occurred (P < 0.05). By Cox hazard ratio (HR) analysis, patients with B1 behavior had a higher risk of developing infections than those with B3 (fistulizing) behavior (HR 4.897, P = 0.010). Successful corticosteroid withdrawal (HR 0.275, P = 0.035) or mucosal healing (HR 0.155, P = 0.002) were associated with a lower risk of infections. CONCLUSIONS Long-term use of IFX in CD patients has a high risk of infections. Failure in mucosal healing and increased concomitant use of systemic corticosteroids are independent risk factors of infections during IFX therapy.
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Affiliation(s)
- Yue Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Hui Jun Shu
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Hong Lu
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Hong Yang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Ji Li
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Bei Tan
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jia Ming Qian
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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Kim ES, Kim KO, Jang BI, Lee CK, Kim HJ, Lee KM, Kim YS, Eun CS, Jung SA, Yang SK, Lee J, Kim TO, Jung Y, Seo GS, Yoon SM. Factors Contributing to the Preference of Korean Patients with Crohn's Disease When Selecting an Anti-Tumor Necrosis Factor Agent (CHOICE Study). Gut Liver 2017; 10:391-8. [PMID: 26347512 PMCID: PMC4849692 DOI: 10.5009/gnl15126] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Background/Aims Two comparable anti-tumor necrosis factor (TNF) agents with different routes of administration (intravenous [iv] infliximab [IFX] vs subcutaneous [sc] adalimumab [ADA]) are available for patients with Crohn’s disease (CD) in Korea. This study aimed to identify the preferences of Korean CD patients for a specific anti-TNF agent and the factors contributing to the decision. Methods A prospective survey was performed among anti-TNF-naive CD patients in 10 tertiary referral hospitals. A 16-item questionnaire addressed patient preferences and the factors contributing to the decision in favor of a particular anti-TNF agent. A logistic regression was conducted to assess predictive factors for ADA preference. Results Overall, 189 patients (139 males; mean age, 32.47±11.71 years) completed the questionnaire. IFX and ADA were preferred by 63.5% (120/189) and 36.5% (69/189) of patients, respectively. The most influential reason for choosing IFX was ‘doctor’s presence’ (68.3%, 82/120), and ADA was “easy to use” (34.8%, 24/69). Amid various clinicodemographic data, having a >60-minute travel time to the hospital was a significant independent predictive factor for ADA preference. Conclusions A large number of anti-TNF-naive Korean patients with CD preferred anti-TNFs with an iv route of administration. The reassuring effect of a doctor’s presence might be the main contributing factor for this decision.
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Affiliation(s)
- Eun Soo Kim
- Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Korea
| | - Kyeong Ok Kim
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Byung Ik Jang
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Chang Kyun Lee
- Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea
| | - Hyo Jong Kim
- Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea
| | - Kang-Moon Lee
- Department of Internal Medicine, The Catholic University of Korea College of Medicine, Suwon, Korea
| | - You Sun Kim
- Department of Internal Medicine, Inje University College of Medicine, Seoul, Korea
| | - Chang Soo Eun
- Department of Internal Medicine, Hanyang University College of Medicine, Guri, Korea
| | - Sung-Ae Jung
- Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Korea
| | - Suk-Kyun Yang
- Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Korea
| | - Jun Lee
- Department of Internal Medicine, Chosun University School of Medicine, Gwangju, Korea
| | - Tae-Oh Kim
- Department of Internal Medicine, Inje University College of Medicine, Busan, Korea
| | - Yunho Jung
- Department of Internal Medicine, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Geom Seog Seo
- Department of Internal Medicine, Wonkwang University School of Medicine, Iksan, Korea
| | - Soon Man Yoon
- Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Korea
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Cheon JH. Understanding the complications of anti-tumor necrosis factor therapy in East Asian patients with inflammatory bowel disease. J Gastroenterol Hepatol 2017; 32:769-777. [PMID: 27723166 DOI: 10.1111/jgh.13612] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/02/2016] [Indexed: 02/06/2023]
Abstract
Remarkable advances have been made in the treatment of inflammatory bowel disease since the introduction of anti-tumor necrosis factor-α agents, especially for patients who are refractory to or cannot tolerate conventional therapies. Currently, infliximab, adalimumab, and golimumab are available in the East Asian medical market, and these agents have been shown to be effective for inducing and maintaining long-term remission of inflammatory bowel disease. Despite their clinical benefits, anti-tumor necrosis factor therapy can also lead to increased vulnerability to infections, development of autoimmune diseases and malignancy, and decreased immunogenicity of vaccinations. Because infectious diseases, such as tuberculosis, hepatitis, and influenza, remain major health problems in East Asia, more cautious use of biologics is needed. To further improve treatment efficacy and safety, close monitoring of inflammation, regular surveillance for malignancy, and regularly scheduled vaccinations are needed. Treatment strategies for biologics should be customized to meet the needs of different patients.
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Affiliation(s)
- Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
- Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
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Abstract
BACKGROUND Biological therapies represent a fundamental innovation for the management of inflammatory bowel diseases (IBD). However, many biological originators have reached, or are about to reach, patent expiry and long-term therapy costs have become progressively unsustainable. CT-P13, a biosimilar of the anti-tumor necrosis factor (anti-TNF) monoclonal antibody infliximab, might represent a significant alternative to its originator, with the potential to decrease medical care costs and, therefore, become available to a large number of patients. OBJECTIVES In this systematic review, we analyzed the data from available clinical trials that recently investigated the validity of indication extrapolation of CT-P13 for the treatment of IBD in naïve patients and in patients who switched from its originator infliximab, focusing on clinical efficacy, safety and immunogenicity. METHODS A detailed literature search was developed a priori to identify articles that investigated the validity of indication extrapolation of CT-P13 for the treatment of IBD in TNF inhibitor treatment-naïve patients and in patients who switched from the originator infliximab. This was applied to Ovid MEDLINE, In-Process and Other Non-Indexed Citations, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus for content from 2012 to September 2016. RESULTS We based our review on the available data from 11 studies that included a total of 1007 IBD patients: 570 patients suffering from Crohn's disease (294 switched and 276 naïve), 435 patients suffering from ulcerative colitis (127 switched and 308 naïve), and two IBD unclassified patients (switched). Overall, no significant difference in efficacy and safety between the originator infliximab and its biosimilar CT-P13 was observed. When assessing the safety of CT-P13, we found that 9.2% of patients experienced adverse effects (4.1% infusion-related reactions and 4.3% infections). CONCLUSION The analyzed studies did not report a significant difference in terms of efficacy, safety and immunogenicity when comparing the clinical experience with CT-P13 with the available literature data on the originator treatment in IBD. However, some debate is ongoing regarding interchangeability and immunogenicity.
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Nuki Y, Esaki M, Asano K, Maehata Y, Umeno J, Moriyama T, Nakamura S, Matsumoto T, Kitazono T. Comparison of the therapeutic efficacy and safety between tacrolimus and infliximab for moderate-to-severe ulcerative colitis: a single center experience. Scand J Gastroenterol 2016; 51:700-5. [PMID: 26818468 DOI: 10.3109/00365521.2016.1138239] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Both tacrolimus (Tac) and infliximab (IFX) are effective for moderate-to-severe ulcerative colitis (UC). The aim of this study was to compare the therapeutic efficacy and safety of both drugs. MATERIALS AND METHODS We performed a retrospective analysis of 46 patients with moderate-to-severe UC who were treated either by Tac (n = 21) or IFX (n = 25). We compared the remission and response rates for 10 weeks between the two groups. In patients who achieved a clinical response, the subsequent relapse rate was compared. The overall adverse events were also compared between the two groups. RESULTS The remission and response rates at week 10 did not differ between patients treated with Tac (67% and 86%, respectively) and patients treated with IFX (76% and 92%, respectively). Among 41 patients showing a clinical response, eight of 23 patients treated with IFX and eight of 18 patients treated with Tac showed a subsequent relapse. The risk of relapse was not different between the two groups. While no serious adverse events were observed, the incidence of adverse events was higher in patients treated with Tac than in those treated with IFX. CONCLUSION Tac and IFX may be equally efficacious for the induction and maintenance of remission in patients with UC while minor adverse events are more frequent with the former treatment.
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Affiliation(s)
- Yoichiro Nuki
- a Department of Medicine and Clinical Science, Graduate School of Medical Sciences , Kyushu University , Fukuoka , Japan
| | - Motohiro Esaki
- a Department of Medicine and Clinical Science, Graduate School of Medical Sciences , Kyushu University , Fukuoka , Japan
| | - Kouichi Asano
- a Department of Medicine and Clinical Science, Graduate School of Medical Sciences , Kyushu University , Fukuoka , Japan ;,b Department of Endoscopic Diagnostics and Therapeutics , Kyushu University Hospital , Fukuoka , Japan
| | - Yuji Maehata
- a Department of Medicine and Clinical Science, Graduate School of Medical Sciences , Kyushu University , Fukuoka , Japan
| | - Junji Umeno
- a Department of Medicine and Clinical Science, Graduate School of Medical Sciences , Kyushu University , Fukuoka , Japan
| | - Tomohiko Moriyama
- a Department of Medicine and Clinical Science, Graduate School of Medical Sciences , Kyushu University , Fukuoka , Japan
| | - Shotaro Nakamura
- c Division of Gastroenterology and Hepatology, Department of Internal Medicine , Iwate Medical University , Morioka , Japan
| | - Takayuki Matsumoto
- c Division of Gastroenterology and Hepatology, Department of Internal Medicine , Iwate Medical University , Morioka , Japan
| | - Takanari Kitazono
- a Department of Medicine and Clinical Science, Graduate School of Medical Sciences , Kyushu University , Fukuoka , Japan
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Farkas K, Rutka M, Golovics PA, Végh Z, Lovász BD, Nyári T, Gecse KB, Kolar M, Bortlik M, Duricova D, Machkova N, Hruba V, Lukas M, Mitrova K, Malickova K, Bálint A, Nagy F, Bor R, Milassin Á, Szepes Z, Palatka K, Lakatos PL, Lukas M, Molnár T. Efficacy of Infliximab Biosimilar CT-P13 Induction Therapy on Mucosal Healing in Ulcerative Colitis. J Crohns Colitis 2016; 10:1273-1278. [PMID: 27106537 DOI: 10.1093/ecco-jcc/jjw085] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Accepted: 03/29/2016] [Indexed: 12/22/2022]
Abstract
INTRODUCTION CT-P13 is the first biosimilar to infliximab that has been approved for the same indications as its originator infliximab. No data are available on the effect of infliximab biosimilar on mucosal healing. The aim of this study was to evaluate the efficacy of CT-P13 induction therapy on mucosal healing in patients with ulcerative colitis [UC]. PATIENTS AND METHODS UC patients, who received CT-P13 therapy from its local introduction at three Hungarian and one Czech inflammatory bowel disease centres, were prospectively enrolled. Sigmoidoscopy was performed after the end of the induction therapy at week 14. Mucosal healing was defined as Mayo endoscopic subscore 0 or 1. Complete mucosal healing was defined as Mayo endoscopic subscore 0. Trough level of CT-P13 was measured at week 14. RESULTS Sixty-three UC patients who underwent CT-P13 induction therapy were enrolled in the study. Indication for the therapy was acute, severe flare up and chronic, refractory activity in 24 and 39 patients, respectively. Cumulative clinical response and steroid-free remission at week 14 were achieved in 82.5% and 47.6% of the patients, respectively. Sigmoidoscopy revealed steroid-free mucosal healing in 47.6% of the patients, and complete mucosal healing was present in 27%. Mayo endoscopic subscore decreased significantly at week 14 compared to baseline. Trough levels of infliximab correlated with mucosal healing. CONCLUSION This is, to our knowledge, the first study examining the efficacy of CT-P13 induction therapy on mucosal healing in UC. The results indicate that mucosal healing is achieved in two-thirds of UC patients by the end of the induction treatment with CT-P13.
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Affiliation(s)
- Klaudia Farkas
- 1 Department of Medicine, University of Szeged, Szeged, Hungary
| | - Mariann Rutka
- 1 Department of Medicine, University of Szeged, Szeged, Hungary
| | - Petra A Golovics
- 1 Department of Medicine, Semmelweis University, Budapest, Hungary
| | - Zsuzsanna Végh
- 1 Department of Medicine, Semmelweis University, Budapest, Hungary
| | - Barbara D Lovász
- 1 Department of Medicine, Semmelweis University, Budapest, Hungary
| | - Tibor Nyári
- Department of Medical Physics and Informatics, University of Szeged, Szeged, Hungary
| | | | - Martin Kolar
- IBD Clinical and Research Centre, Iscare a.s., Prague, Czech Republic
- 1 Medical Faculty, Charles University, Prague, Czech Republic
| | - Martin Bortlik
- IBD Clinical and Research Centre, Iscare a.s., Prague, Czech Republic
- Department of Internal Medicine, Military Hospital, Charles University, Prague, Czech Republic
| | - Dana Duricova
- IBD Clinical and Research Centre, Iscare a.s., Prague, Czech Republic
- Institute of Pharmacology, 1 Medical Faculty, Charles University, Prague, Czech Republic
| | - Nadezda Machkova
- IBD Clinical and Research Centre, Iscare a.s., Prague, Czech Republic
| | - Veronika Hruba
- IBD Clinical and Research Centre, Iscare a.s., Prague, Czech Republic
| | - Martin Lukas
- IBD Clinical and Research Centre, Iscare a.s., Prague, Czech Republic
| | - Katarina Mitrova
- IBD Clinical and Research Centre, Iscare a.s., Prague, Czech Republic
- Department of Paediatrics, Faculty Hospital Motol, 2 Medical Faculty, Charles University, Prague, Czech Republic
| | - Karin Malickova
- Institute of Medical Biochemistry and Laboratory Diagnostics, 1 Medical Faculty and General Teaching Hospital, Charles University, Prague, Czech Republic
| | - Anita Bálint
- 1 Department of Medicine, University of Szeged, Szeged, Hungary
| | - Ferenc Nagy
- 1 Department of Medicine, University of Szeged, Szeged, Hungary
| | - Renáta Bor
- 1 Department of Medicine, University of Szeged, Szeged, Hungary
| | - Ágnes Milassin
- 1 Department of Medicine, University of Szeged, Szeged, Hungary
| | - Zoltán Szepes
- 1 Department of Medicine, University of Szeged, Szeged, Hungary
| | - Károly Palatka
- 2 Department of Medicine, University of Debrecen, Debrecen, Hungary
| | - Péter L Lakatos
- 1 Department of Medicine, Semmelweis University, Budapest, Hungary
| | - Milan Lukas
- IBD Clinical and Research Centre, Iscare a.s., Prague, Czech Republic
- Institute of Medical Biochemistry and Laboratory Diagnostics, 1 Medical Faculty and General Teaching Hospital, Charles University, Prague, Czech Republic
| | - Tamás Molnár
- 1 Department of Medicine, University of Szeged, Szeged, Hungary
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Kim JH, Cheon JH, Park Y, Lee HJ, Park SJ, Kim TI, Kim WH. Effect of mucosal healing (Mayo 0) on clinical relapse in patients with ulcerative colitis in clinical remission. Scand J Gastroenterol 2016; 51:1069-1074. [PMID: 26895215 DOI: 10.3109/00365521.2016.1150503] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Revised: 01/19/2016] [Accepted: 02/01/2016] [Indexed: 02/04/2023]
Abstract
OBJECTIVE The aim of this study was to identify the effect of mucosal healing (MH) on clinical relapse in patients with ulcerative colitis (UC) who are in clinical remission, with special reference to Mayo endoscopic subscore 0. METHODS Between November 2005 and December 2013, medical records from a total of 215 patients with UC who underwent colonoscopic examination at the time of clinical remission were retrospectively reviewed. Endoscopic MH was defined as a '0 point' of Mayo endoscopic subscore (Mayo 0). Patients were categorized into two groups according to Mayo endoscopic subscore and then analyzed. RESULTS The baseline characteristics of both groups (MH vs. no-MH), including age at diagnosis, gender, and initial clinical and colonoscopic findings, were not significantly different. The median follow-up duration was 80 (12-118) months. Factors predictive of longer clinical remission duration were age ≥30 years at diagnosis (≥30 years vs. <30 years; hazard ratio [HR] 3.16, 95% CI 1.88-5.30, p < 0.001), shorter interval between diagnosis and clinical remission (<15 months vs. ≥15 months; HR 1.93, 95% CI 1.13-3.28, p = 0.015), and presence of MH at clinical remission (HR 1.95, 95% CI 1.15-3.32, p = 0.014). With a Cox regression model, patients with MH at clinical remission were more likely to have longer duration of clinical remission than patients without MH. CONCLUSION The achievement of MH, Mayo 0 in particular, in patients with UC who are in clinical remission is important in predicting a favorable disease course prognosis.
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Affiliation(s)
- Jae Hyun Kim
- a Department of Internal Medicine and Institute of Gastroenterology , Yonsei University College of Medicine , Seoul , Korea
| | - Jae Hee Cheon
- a Department of Internal Medicine and Institute of Gastroenterology , Yonsei University College of Medicine , Seoul , Korea
| | - Yehyun Park
- a Department of Internal Medicine and Institute of Gastroenterology , Yonsei University College of Medicine , Seoul , Korea
| | - Hyun Jung Lee
- a Department of Internal Medicine and Institute of Gastroenterology , Yonsei University College of Medicine , Seoul , Korea
| | - Soo Jung Park
- a Department of Internal Medicine and Institute of Gastroenterology , Yonsei University College of Medicine , Seoul , Korea
| | - Tae Il Kim
- a Department of Internal Medicine and Institute of Gastroenterology , Yonsei University College of Medicine , Seoul , Korea
| | - Won Ho Kim
- a Department of Internal Medicine and Institute of Gastroenterology , Yonsei University College of Medicine , Seoul , Korea
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Fernández-Salazar L, Muñoz F, Barrio J, Muñoz C, Pajares R, Rivero M, Prieto V, Legido J, Bouhmidi A, Herranz M, Fernández N, Sánchez-Ocaña R, Joao D, Santos F. Infliximab in ulcerative colitis: real-life analysis of factors predicting treatment discontinuation due to lack of response or colectomy: ECIA (ACAD Colitis and Infliximab Study). Scand J Gastroenterol 2016. [PMID: 26200929 DOI: 10.3109/00365521.2015.1070900] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE To describe clinical practice with infliximab (IFX) in ulcerative colitis (UC); identification of predictive factors for IFX treatment discontinuation due to insufficient response and for colectomy. MATERIAL AND METHODS Retrospective, multicentric and observational study including every UC IFX-treated patient in 10 Spanish hospitals. Variables analyzed: epidemiological data; variables for poor prognosis; IFX prior treatments; characteristics of the IFX treatment; time from the UC diagnosis to induction with IFX; time from induction to colectomy or until data collection. Predictive and protective factors for IFX discontinuation due to lack of response and for colectomy were analyzed with binary logistic regression and Cox analysis. RESULTS Follow-up time from induction with IFX to the collection of data or colectomy: 36.7 ± 25.7 months. Prior treatment with immunomodulator medications (IMM): 79%; IFX + immunosuppressant therapy: 77%; discontinuation of IFX: 26%, colectomy 16%. Independent predictive or protective factors for IFX discontinuation: IMM resistance (OR: 2.9, p = 0.022, 95% CI: 1.2-7.2), prior use of leukocytapheresis (OR: 3.3, p = 0.024, 95% CI: 1.1-9.4), IFX + IMM therapy (OR: 0.3, p = 0.022, 95% CI: 0.1-0.9, and HR: 0.4, p = 0.006, 95% CI: 0.2-0.8) and corticosteroid use in induction (HR: 1.9, p = 0.049, 95% CI: 1.0-3.8). Independent predictive or protective factors for colectomy: Use of leukocytapheresis (OR: 3.0, p = 0.036, 95% CI: 1.1-8.4), IFX + IMM therapy (OR: 0.3, p = 0.022, 95% CI: 0.1-0.8, and HR: 0.3, p = 0.011, 95% CI: 0.1-0.8) and severe cortico-resistant flare-up (HR: 2.5, p = 0.032, 95% CI: 1.1-5.9). CONCLUSIONS Prior use of IMM and leukocytapheresis, the use of corticosteroids in induction and a severe cortico-resistant flare predict a worse response to IFX and the need for colectomy. Combination therapy is a protective factor for both.
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Affiliation(s)
| | - Fernando Muñoz
- b 2 Gastroenterology Unit, Complejo Asistencial Universitario , León, Spain
| | - Jesús Barrio
- c 3 Gastroenterology Unit, Hospital Universitario Río Hortega , Valladolid, Spain
| | - Concepción Muñoz
- d 4 Gastroenterology Unit, Hospital Virgen de la Salud , Toledo, Spain
| | - Ramón Pajares
- e 5 Gastroenterology Unit, Hospital Infanta Sofía, San Sebastián de los Reyes , Madrid, Spain
| | - Montserrat Rivero
- f 6 Gastroenterology Unit, Hospital Universitario Marqués de Valdecilla , Santander, Spain
| | - Vanessa Prieto
- g 7 Gastroenterology Unit, Complejo Asistencial Universitario , Salamanca, Spain
| | - Jesús Legido
- h 8 Gastroenterology Unit, Complejo Asistencial , Segovia, Spain
| | - Abdel Bouhmidi
- i 9 Gastroenterology Unit, Hospital Santa Bárbara de Puertollano , Ciudad Real, Spain
| | - Maite Herranz
- j 10 Gastroenterology Unit, Complejo Asistencial , Ávila, Spain
| | - Nereida Fernández
- b 2 Gastroenterology Unit, Complejo Asistencial Universitario , León, Spain
| | - Ramón Sánchez-Ocaña
- c 3 Gastroenterology Unit, Hospital Universitario Río Hortega , Valladolid, Spain
| | - Diana Joao
- b 2 Gastroenterology Unit, Complejo Asistencial Universitario , León, Spain
| | - Fernando Santos
- c 3 Gastroenterology Unit, Hospital Universitario Río Hortega , Valladolid, Spain
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García-Bosch O, Aceituno M, Ordás I, Etchevers J, Sans M, Feu F, Panés J, Ricart E. Long-Term Follow-Up of Patients Treated with Infliximab for Ulcerative Colitis: Predictive Factors of Response-An Observational Study. Dig Dis Sci 2016; 61:2051-9. [PMID: 26921082 DOI: 10.1007/s10620-016-4089-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Accepted: 02/15/2016] [Indexed: 01/14/2023]
Abstract
AIM To evaluate the early and long-term efficacy of infliximab in ulcerative colitis and to determine predictors of response and colectomy. METHODS This is an ambidirectional cohort study in a tertiary referral center including patients who started infliximab within 2005 and 2008 and monitored until 2014. Efficacy was evaluated by partial Mayo scores at weeks 2, 4, 8, 30, and 54. Long-term treatment maintenance with infliximab and colectomy requirements were recorded. RESULTS Fifty-three patients were included with a median follow-up of 69.5 months. Clinical remission at the time point assessments was 40.8, 47.2, 54.7, 54.7, and 49.1 %. At the time of maximal follow-up, the proportion of patients under infliximab maintenance was 24.5 %. A higher level of albumin (OR 1.4, CI 95 % 1.06-1.8; p = 0.017) was predictive of a higher remission rate at week 8. Concomitant immunomodulators beyond 6 months were predictive of infliximab's long-term maintenance (OR 15.8, CI 95 % 1.8-135.4; p = 0.012). Colectomy was required in 41.5 %. Factors associated with a higher rate of colectomy at week 54 were previous treatment with cyclosporine (OR 3.4, CI 95 % 1.2-9.7; p = 0.012), absence of response at week 8 (OR 10.3, CI 95 % 3.3-31.7; p < 0.001), and not receiving concomitant immunomodulators (OR 4.1, CI 95 % 1.8-9; p = 0.002). Colectomy rates within the first 54 weeks were closely dependent on the number of variables present: none (0 %), 1 (26.3 %), 2 (71.4 %), or 3 (100 %) of them (log rank <0.0001). CONCLUSIONS Low albumin, previous treatment with cyclosporine, absence of a concomitant immunomodulator, and lack of response at week 8 negatively affected the efficacy of infliximab in ulcerative colitis.
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Affiliation(s)
- Orlando García-Bosch
- Department of Gastroenterology, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Carrer Villarroel, 170, 08036, Barcelona, Spain. .,Department of Digestive Diseases, Hospital de Sant Joan Despí Moisès Broggi, Sant Joan Despí, Carrer Jacint Verdaguer, 90, 08906, Barcelona, Spain.
| | - Montserrat Aceituno
- Department of Gastroenterology, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Carrer Villarroel, 170, 08036, Barcelona, Spain.,Department of Digestive Diseases, Hospital Mútua de Terrassa, Plaça Doctor Robert, 5, 08221, Terrassa, Spain
| | - Ingrid Ordás
- Department of Gastroenterology, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Carrer Villarroel, 170, 08036, Barcelona, Spain
| | - Josefina Etchevers
- Department of Gastroenterology, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Carrer Villarroel, 170, 08036, Barcelona, Spain
| | - Miquel Sans
- Department of Gastroenterology, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Carrer Villarroel, 170, 08036, Barcelona, Spain
| | - Faust Feu
- Department of Gastroenterology, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Carrer Villarroel, 170, 08036, Barcelona, Spain
| | - Julián Panés
- Department of Gastroenterology, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Carrer Villarroel, 170, 08036, Barcelona, Spain
| | - Elena Ricart
- Department of Gastroenterology, Hospital Clínic de Barcelona, IDIBAPS, CIBERehd, Carrer Villarroel, 170, 08036, Barcelona, Spain
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Lee JW, Choi CH, Park JH, Kim JW, Kang SB, Koo JS, Kim YH, Kim YS, Joo YE, Chang SK. Clinical features of active tuberculosis that developed during anti-tumor necrosis factor therapy in patients with inflammatory bowel disease. Intest Res 2016; 14:146-51. [PMID: 27175115 PMCID: PMC4863048 DOI: 10.5217/ir.2016.14.2.146] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Revised: 03/20/2016] [Accepted: 03/21/2016] [Indexed: 12/27/2022] Open
Abstract
Background/Aims Anti-tumor necrosis factor (TNF) therapy for active ulcerative colitis (UC) and Crohn's disease (CD) is associated with increased risks of tuberculosis (TB) infection. We analyzed the incidence and clinical features of Korean patients with inflammatory bowel disease (IBD) who developed active TB during anti-TNF therapy. Methods Ten cases of active TB developed in patients treated with infliximab (n=592) or adalimumab (n=229) for UC (n=160) or CD (n=661) were reviewed. We analyzed demographics, interval between start of anti-TNF therapy and active TB development, tests for latent TB infection (LTBI), concomitant medications, and the details of diagnosis and treatments for TB. Results The incidence of active TB was 1.2% (10/821): 1.5% (9/592) and 0.4% (1/229) in patients receiving infliximab and adalimumab, respectively. The median time to the development of active TB after initiation of anti-TNF therapy was three months (range: 2–36). Three patients had past histories of treatment for TB. Positive findings in a TB skin test (TST) and/or interferon gamma releasing assay (IGRA) were observed in three patients, and two of them received anti-TB prophylaxis. Two patients were negative by both TST and IGRA. The most common site of active TB was the lungs, and the active TB was cured in all patients. Conclusions Active TB can develop during anti-TNF therapy in IBD patients without LTBI, and even in those with histories of TB treatment or LTBI prophylaxis. Physicians should be aware of the potential for TB development during anti-TNF therapy, especially in countries with a high prevalence of TB.
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Affiliation(s)
- Jang Wook Lee
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Chang Hwan Choi
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Ji Hoon Park
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Jeong Wook Kim
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
| | - Sang Bum Kang
- Department of Internal Medicine, The Catholic University of Korea College of Medicine, Daejeon, Korea
| | - Ja Seol Koo
- Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea
| | - Young-Ho Kim
- Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - You Sun Kim
- Department of Internal Medicine, Inje University College of Medicine, Seoul, Korea
| | - Young Eun Joo
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Sae Kyung Chang
- Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea
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Long-term infliximab therapy is needed for sustained steroid-free remission in patients with ulcerative colitis. Dig Liver Dis 2016; 48:208-9. [PMID: 26614643 DOI: 10.1016/j.dld.2015.10.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2015] [Revised: 10/13/2015] [Accepted: 10/20/2015] [Indexed: 12/11/2022]
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Kobayashi T, Suzuki Y, Motoya S, Hirai F, Ogata H, Ito H, Sato N, Ozaki K, Watanabe M, Hibi T. First trough level of infliximab at week 2 predicts future outcomes of induction therapy in ulcerative colitis-results from a multicenter prospective randomized controlled trial and its post hoc analysis. J Gastroenterol 2016; 51:241-51. [PMID: 26162647 PMCID: PMC4766223 DOI: 10.1007/s00535-015-1102-z] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Accepted: 06/25/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND Infliximab (IFX) is one of the treatments of choice for corticosteroid-refractory and corticosteroid-dependent ulcerative colitis (UC). A high serum trough level of IFX (TL) is reported to be associated with sustained efficacy during maintenance treatment. As part of a phase 3 randomized controlled trial of IFX in UC, we assessed the predictive value of the first TL at week 2 for short- and long-term response. METHODS Patients received intravenous IFX 5 mg/kg or placebo at weeks 0, 2, and 6. Patients with evidence of a response by week 8 continued treatment at weeks 14 and 22. TL was measured by enzyme-linked immunosorbent assay. Post hoc analysis was then performed for TL and clinical outcomes. RESULTS Clinical response rate at week 8, the primary end point, was significantly higher in the IFX group than placebo (p = 0.005). The incidence of adverse events between groups was similar. Week 2 TL was significantly associated with a 14-week clinical activity index (CAI) remission. In multiple logistic regression analysis, the week 2 TL-to-CAI ratio (TL/CAI, odds ratio 8.07; 95% confidence interval 2.84-27.07, p < 0.001) was an independent factor correlating with 14-week CAI remission. The week 2 TL and TL/CAI were also significantly associated with 30-week mucosal healing. CONCLUSIONS IFX was confirmed to be effective and safe in this population. Our results suggest that the first TL at week 2, in combination with clinical evaluation, is useful for predicting both short- and long-term outcomes, allowing an earlier decision between continuing IFX or switching to other options.
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Affiliation(s)
- Taku Kobayashi
| | - Yasuo Suzuki
| | - Satoshi Motoya
| | - Fumihito Hirai
| | - Haruhiko Ogata
| | - Hiroaki Ito
| | - Noriko Sato
| | | | - Mamoru Watanabe
| | - Toshifumi Hibi
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Abstract
BACKGROUND Vedolizumab (VDZ) demonstrated efficacy in Crohn's disease (CD) and ulcerative colitis (UC) in the GEMINI trials. Our aim was to evaluate the efficacy of VDZ at week 14 in inflammatory bowel disease in a multicenter cohort of patients. METHODS Patients at Massachusetts General Hospital and Brigham and Women's Hospital were considered for inclusion. VDZ (300 mg) was administered at weeks 0, 2, 6, and 14. Efficacy was assessed using the Harvey-Bradshaw index for CD, the simple clinical colitis activity index for UC and physician assessment, along with C-reactive protein and decrease of corticosteroid therapy. Clinical response was defined as decrease in Harvey-Bradshaw index ≥3 and simple clinical colitis activity index ≥3 and remission as Harvey-Bradshaw index ≤4, simple clinical colitis activity index ≤2 and physician assessment of response and remission. RESULTS Our study included 172 patients (107 CD, 59 UC, 6 inflammatory bowel disease-unclassified, men 48.3%, mean age 40 years and disease duration 14 years). Fourteen patients had ostomy and 9 ileoanal pouch, and only 35.5% fulfilled eligibility for the GEMINI trials. Previous treatment failures with ≥ 2 anti-TNFs occurred in 70.9%, one-third were on an immunomodulator and 46% systemic steroids at baseline. In CD, 48.9% and 23.9% and in UC, 53.9% and 29.3% had clinical response and clinical remission at week 14, respectively. Adverse events occurred in 10.5%. CONCLUSIONS VDZ is safe and well tolerated in refractory inflammatory bowel disease patients in a clinical practice with efficacy in UC and CD with responses similar to what was seen in clinical trials.
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Jung YS, Park DI, Kim YH, Lee JH, Seo PJ, Cheon JH, Kang HW, Kim JW. Efficacy and safety of CT-P13, a biosimilar of infliximab, in patients with inflammatory bowel disease: A retrospective multicenter study. J Gastroenterol Hepatol 2015; 30:1705-12. [PMID: 25974251 DOI: 10.1111/jgh.12997] [Citation(s) in RCA: 115] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/30/2015] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIM The biosimilar of infliximab, CT-P13, has recently been shown to be equivalent to infliximab in both efficacy and safety in the treatment of rheumatologic diseases. However, no data are available with respect to the drug's efficacy in patients with inflammatory bowel disease (IBD). We aimed to assess the efficacy and safety of CT-P13 in IBD patients METHODS This was a retrospective multicenter study including both anti-tumor necrosis factor (TNF) naïve patients and patients who switched from the biologic originator to CT-P13. RESULTS In anti-TNF naïve Crohn's disease (CD) patients (n = 32), clinical response and remission rates were 90.6% and 68.8% at week 2, 90.6% and 84.4% at week 8, 95.5% and 77.3% at week 30, and 87.5% and 75.0% at week 54, respectively. In anti-TNF naïve ulcerative colitis (UC) patients (n = 42), clinical response and remission rates were 76.2% and 19.0% at week 2, 81.0% and 38.1% at week 8, 91.3% and 47.8% at week 30, and 100% and 50.0% at week 54, respectively, while mucosal healing rates were 58.3% at week 8, 66.7% at week 30, and 66.7% at week 54. The efficacy of CT-P13 was maintained in 92.6% (25/27) of CD patients and in 66.7% (6/9) of UC patients after switching from its originator. Adverse events related to CT-P13 occurred in 11.8% of UC patients. CONCLUSIONS CT-P13 appears to have comparable efficacy, safety, and interchangeability with its originator in the treatment of IBD. Further prospective studies with long-term follow-up periods will be needed to confirm the biosimilarity of CT-P13.
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Affiliation(s)
- Yoon Suk Jung
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Dong Il Park
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young Ho Kim
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ji Hyun Lee
- Digestive Endoscopic Center, Seoul Song Do Colorectal Hospital, Seoul, Korea
| | - Pyoung Ju Seo
- Digestive Endoscopic Center, Seoul Song Do Colorectal Hospital, Seoul, Korea
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea
| | - Hyoun Woo Kang
- Department of Internal Medicine, College of Medicine, Dongguk University Ilsan Hospital, Goyang, Korea
| | - Ji Won Kim
- Department of Internal Medicine, Seoul National University Boramae Hospital, Seoul, Korea
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