1
|
Kayali S, Fantasia S, Gaiani F, Cavallaro LG, de’Angelis GL, Laghi L. NOD2 and Crohn's Disease Clinical Practice: From Epidemiology to Diagnosis and Therapy, Rewired. Inflamm Bowel Dis 2025; 31:552-562. [PMID: 38582044 PMCID: PMC11808579 DOI: 10.1093/ibd/izae075] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2023] [Indexed: 04/08/2024]
Abstract
Crohn's disease (CD) is a chronic inflammatory bowel disease with a multifactorial pathogenesis involving environmental and genetic factors. Since the late 20th century, the discovery of the first susceptibility gene (NOD2, previously referred to as CARD15) for CD has paved the way for further investigations into the correlations between clinical features and genetics, and its potential impact on clinical practice has fueled the research in the last 2 decades. Recent therapeutic advancements involving novel biologic drugs and small molecules have shifted inflammatory bowel disease management from a disease-centered to a patient-centric approach. To date, the role of NOD2 has not been fully understood yet. Recent data suggest that its clinical impact may be greater than currently recognized. This review overviews the most common NOD2 variants' role in real-life clinical practice. These genetic variants increase the risk of developing the disease and can aid in tailoring diagnosis and treatment. They are associated with the stricturing phenotype and ileal involvement and increase the risk of steroid refractoriness. In the meantime, limited and inconclusive evidence exists regarding their predictive role in response to azathioprine, biologic drugs, and small molecules. Eventually, their role in increasing the risk for surgery is evident, especially in those with the L1007fs variant. If further trials will support the initial evidence reported so far, NOD2 genetic variants will emerge as possible candidates for developing precision medicine in CD.
Collapse
Affiliation(s)
- Stefano Kayali
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Stefano Fantasia
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Federica Gaiani
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Gastroenterology and Endoscopy Unit, University Hospital of Parma, Parma, Italy
| | | | | | - Luigi Laghi
- Department of Medicine and Surgery, University of Parma, Parma, Italy
- Laboratory of Molecular Gastroenterology, Humanitas Clinical and Research Centre, Rozzano, Italy
| |
Collapse
|
2
|
Ebrahimi F, Torkian S, Zare-Farashbandi E, Tamizifar B. The Relapse Rate of Inflammatory Bowel Disease (IBD) in Patients Who Discontinue Anti-TNF Therapy: A Systematic Review and Meta-Analysis. IRANIAN JOURNAL OF PUBLIC HEALTH 2024; 53:1976-1991. [PMID: 39429663 PMCID: PMC11490323 DOI: 10.18502/ijph.v53i9.16452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 03/18/2024] [Indexed: 10/22/2024]
Abstract
Background Inflammatory bowel disease (IBD) patients who cease anti-tumor necrosis factor (TNF) therapy are at risk of relapse, which is a matter of concern for the medical community. This study aimed to determine the relapse rate of IBD in patients who cease anti- TNF therapy. Methods A systematic search of international databases (Medline, Web of Sciences, Scopus, and EMBASE) was conducted until Mar 9th, 2022. The random effects model was used to calculate the IBD relapse rate, accompanied by a 95% confidence interval. Results The IBD relapse rate in patients who discontinued anti-TNF therapy was 44%. The pooled IBD-UC and IBD-CD relapse rate in patients who stopped anti-TNF therapy were 43% and 46%, respectively. The studies using infliximab (IFX) showed a pooled IBD relapse rate of 45%, and the IBD relapse rate in the IFX/ADA (Adalimumab) group was 42%. The IBD relapse rate for papers with treatment durations of less than or equal to 12 months was 51%, while for articles with treatment durations of more than 12 months, it was 30%. Conclusion This study emphasizes the need for careful evaluation and monitoring of IBD patients who cease anti-TNF therapy, as well as further investigation of alternative treatments for those who exhibit intolerance or inadequate response to anti-TNF therapy.
Collapse
Affiliation(s)
- Fatemeh Ebrahimi
- Department of Epidemiology & Biostatistics, School of Public Health, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Samaneh Torkian
- Department of Epidemiology, School of Health, Iran University of Medical Sciences, Tehran, Iran
| | - Elahe Zare-Farashbandi
- Clinical Informationist Research Group, Health Information Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Babak Tamizifar
- Isfahan Gastroenterology and Hepatology Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| |
Collapse
|
3
|
Dai C, Wang YN, Tian WN, Huang YH, Jiang M. Long-term clinical outcomes after the discontinuation of anti-TNF agents in patients with inflammatory bowel disease: a meta-analysis. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2023; 115:559-566. [PMID: 37114385 DOI: 10.17235/reed.2023.9537/2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/29/2023]
Abstract
BACKGROUND there are concerns regarding the risk of relapse after discontinuation of anti-tumor necrosis factor (anti-TNF) therapy in patients with inflammatory bowel disease (IBD). A systematic review and meta-analysis were performed to evaluate the risk of relapse after discontinuation of anti-TNF agent in patients, and the response to retreatment with the same anti-TNF agent. METHODS electronic databases were searched to identify relevant studies. Primary outcomes were the pooled percentage of relapses after the withdrawal of anti-TNF agents. Secondary outcomes were the pooled percentage of the response to retreatment with the same anti-TNF agent after relapse. RESULTS thirty-seven studies were included in this meta-analysis. The overall risk of relapse after discontinuation of anti-TNF agent was 43 % for ulcerative colitis (UC) and 43 % for Crohn's disease (CD). In UC, the relapse rate was 37 % at 1-2 year, and 58 % at 3-5 years. In CD, the relapse rate was 38 % at 1-2 year, 53 % at 3-5 years, and 49 % at more than five years. When clinical remission was the only criterion for stopping anti-TNF agent, the relapse rate was 42 % in UC and 45 % in CD, which decreased to 40 % in UC and 36 % in CD when clinical remission and endoscopic healing were required. Retreatment with the same anti-TNF agent induced remission again in 78 % of UC patients and 76 % of CD patients. CONCLUSION our meta-analysis showed that a high proportion of IBD patients will relapse after discontinuation of anti-TNF agent. The response to retreatment with the same anti-TNF agent is generally favorable in patients who relapse.
Collapse
Affiliation(s)
- Cong Dai
- Gastroenterology, First Hospital of China Medical University, china
| | - Yi-Nuo Wang
- Gastroenterology, First Hospital of China Medical University
| | - Wen-Ning Tian
- Gasroenterology, First Hospital of China Medical University
| | - Yu-Hong Huang
- Gastroenterology, First Hospital of China Medical University
| | - Min Jiang
- Gastroenterology, First Hospital of China Medical University
| |
Collapse
|
4
|
Shi G, Li LP, Zhao Q, Wang GY, Lei B, Liu F, Lu GR, Shi WY, Li XL. Value of serum platelet/albumin and C-reactive protein/albumin ratios in evaluating mucosal healing and disease recurrence in patients with Crohn's disease. Shijie Huaren Xiaohua Zazhi 2023; 31:598-604. [DOI: 10.11569/wcjd.v31.i14.598] [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: 06/07/2022] [Revised: 08/04/2022] [Accepted: 03/27/2023] [Indexed: 07/28/2023] Open
Abstract
BACKGROUND At present, the most studied inflammatory markers of Crohn's disease (CD) are C-reactive protein, but CD cannot be predicted by a single index. In recent years, studies have found that the combined application of serum markers can be more accurate for prediction, and platelet/serum albumin (PLT/ALB) and C-reactive protein/serum albumin (CRP/ALB) ratios have high specificity in evaluating inflammatory activity.
AIM To explore the value of serological platelet/albumin and C-reactive protein/albumin ratios in evaluating mucosal healing and disease recurrence in patients with CD.
METHODS Eighty-five patients with CD treated at Xinzhou District People's Hospital from April 2019 to April 2021 were selected. According to the clinical and endoscopic healing criteria, the patients were divided into either a mucosal healing group or a mucosal non-healing group. The general data, serum ALB, PLT, and CRP levels, and PLT/ALB and CRP/ALB ratios were recorded before and after treatment. The correlation between serum indexes and SES-CD score was analyzed to evaluate their value in assessing mucosal healing. The patients were divided into a recurrent group and a non-recurrent group according to whether they relapsed. The value of serum indexes in predicting disease recurrence was assessed.
RESULTS After 6 mo of treatment, the level of ALB in the mucosal healing group (n = 44) was significantly higher than that in the mucosal non-healing group (n = 41), while the levels of PLT, CRP, PLT/ALB ratio, and CRP/ALB ratio significantly decreased (P < 0.05). Serum ALB, PLT, CRP, PLT/ALB ratio, and CRP/ALB ratio were significantly correlated with SES-CD score. The AUC values of ALB, PLT, CRP, CRP/ALB ratio, and PLT/ALB ratio in assessing mucosal healing were 0.712, 0.662, 0.774, 0.776, and 0.719, respectively (all AUC values > 0.5). After treatment, ALB in the recurrent group was significantly lower than that in the non-recurrent group, while the levels of PLT, CRP, PLT/ALB ratio, and CRP/ALB ratio were significantly higher in the recurrent group (P < 0.05). The AUC values of ALB, PLT, CRP, CRP/ALB ratio, and PLT/ALB ratio for predicting disease recurrence were 0.641, 0.628, 0.643, 0.652, and 0.651, respectively (all AUC values > 0.5).
CONCLUSION PLT/ALB and CRP/ALB ratios have high clinical value in evaluating mucosal healing and disease recurrence in patients with CD.
Collapse
Affiliation(s)
- Gan Shi
- Department of Gastroenterology, Xinzhou District People's Hospital, Wuhan 430400, Hubei Province, China
| | - Li-Ping Li
- Department of Gastroenterology, Xinzhou District People's Hospital, Wuhan 430400, Hubei Province, China
| | - Qi Zhao
- Department of Gastroenterology, Xinzhou District People's Hospital, Wuhan 430400, Hubei Province, China
| | - Guan-Yi Wang
- Department of Gastroenterology, Xinzhou District People's Hospital, Wuhan 430400, Hubei Province, China
| | - Bei Lei
- Department of Gastroenterology, Xinzhou District People's Hospital, Wuhan 430400, Hubei Province, China
| | - Fang Liu
- Department of Gastroenterology, Xinzhou District People's Hospital, Wuhan 430400, Hubei Province, China
| | - Guang-Rong Lu
- Department of Gastroenterology, Xinzhou District People's Hospital, Wuhan 430400, Hubei Province, China
| | - Wen-Yao Shi
- Department of Gastroenterology, Xinzhou District People's Hospital, Wuhan 430400, Hubei Province, China
| | - Xiao-Lin Li
- Department of Internal Medicine, Xinzhou District People's Hospital, Wuhan 430400, Hubei Province, China
| |
Collapse
|
5
|
Pauwels RWM, van der Woude CJ, Nieboer D, Steyerberg EW, Casanova MJ, Gisbert JP, Kennedy NA, Lees CW, Louis E, Molnár T, Szántó K, Leo E, Bots S, Downey R, Lukas M, Lin WC, Amiot A, Lu C, Roblin X, Farkas K, Seidelin JB, Duijvestein M, D'Haens GR, de Vries AC. Prediction of Relapse After Anti-Tumor Necrosis Factor Cessation in Crohn's Disease: Individual Participant Data Meta-analysis of 1317 Patients From 14 Studies. Clin Gastroenterol Hepatol 2022; 20:1671-1686.e16. [PMID: 33933376 DOI: 10.1016/j.cgh.2021.03.037] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 03/03/2021] [Accepted: 03/29/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Tools for stratification of relapse risk of Crohn's disease (CD) after anti-tumor necrosis factor (TNF) therapy cessation are needed. We aimed to validate a previously developed prediction model from the diSconTinuation in CrOhn's disease patients in stable Remission on combined therapy with Immunosuppressants (STORI) trial, and to develop an updated model. METHODS Cohort studies were selected that reported on anti-TNF cessation in 30 or more CD patients in remission. Individual participant data were requested for luminal CD patients and anti-TNF treatment duration of 6 months or longer. The discriminative ability (concordance-statistic [C-statistic]) and calibration (agreement between observed and predicted risks) were explored for the STORI model. Next, an updated prognostic model was constructed, with performance assessment by cross-validation. RESULTS This individual participant data meta-analysis included 1317 patients from 14 studies in 11 countries. Relapses after anti-TNF cessation occurred in 632 of 1317 patients after a median of 13 months. The pooled 1-year relapse rate was 38%. The STORI prediction model showed poor discriminative ability (C-statistic, 0.51). The updated model reached a moderate discriminative ability (C-statistic, 0.59), and included clinical symptoms at cessation (hazard ratio [HR], 2.2; 95% CI, 1.2-4), younger age at diagnosis (HR, 1.5 for A1 (age at diagnosis ≤16 years) vs A2 (age at diagnosis 17 - 40 years); 95% CI, 1.11-1.89), no concomitant immunosuppressants (HR, 1.4; 95% CI, 1.18-172), smoking (HR, 1.4; 95% CI, 1.15-1.67), second line anti-TNF (HR, 1.3; 95% CI, 1.01-1.69), upper gastrointestinal tract involvement (HR, 1.3 for L4 vs non-L4; 95% CI, 0.96-1.79), adalimumab (HR, 1.22 vs infliximab; 95% CI, 0.99-1.50), age at cessation (HR, 1.2 per 10 years younger; 95% CI, 1-1.33), C-reactive protein (HR, 1.04 per doubling; 95% CI, 1.00-1.08), and longer disease duration (HR, 1.07 per 5 years; 95% CI, 0.98-1.17). In subanalysis, the discriminative ability of the model improved by adding fecal calprotectin (C-statistic, 0.63). CONCLUSIONS This updated prediction model showed a reasonable discriminative ability, exceeding the performance of a previously published model. It might be useful to guide clinical decisions on anti-TNF therapy cessation in CD patients after further validation.
Collapse
Affiliation(s)
- Renske W M Pauwels
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - C Janneke van der Woude
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Daan Nieboer
- Department of Public Health, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Ewout W Steyerberg
- Department of Public Health, Erasmus University Medical Center, Rotterdam, The Netherlands; Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
| | - María J Casanova
- Department of Gastroenterology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - Javier P Gisbert
- Department of Gastroenterology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - Nick A Kennedy
- Exeter Inflammatory Bowel Disease Research Group, University of Exeter, Exeter, United Kingdom; Department of Gastroenterology and Hepatology, Western General Hospital, Edinburgh, United Kingdom
| | - Charlie W Lees
- Department of Gastroenterology and Hepatology, Western General Hospital, Edinburgh, United Kingdom
| | - Edouard Louis
- Department of Gastroenterology and Hepatology, Centre Hospitalier Universitaire de Liège, Liège, Belgium
| | - Tamás Molnár
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Kata Szántó
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Eduardo Leo
- Department of Digestive Diseases, Hospital Universitario Virgen del Rocío, Seville, Spain
| | - Steven Bots
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Center, Academic Medical Centre, Amsterdam, The Netherlands
| | - Robert Downey
- Department of Gastroenterology and Hepatology, Royal Hallamshire Hospital, Sheffield Teaching Hospitals, National Health Service Foundation Trust, Sheffield, United Kingdom
| | - Milan Lukas
- Inflammatory Bowel Disease Clinical and Research Centre, Iscare a.s, Prague, Czech Republic; Institute of Medical Biochemistry and Laboratory Diagnostics, First Medical Faculty, General Teaching Hospital, Prague, Czech Republic
| | - Wei C Lin
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan
| | - Aurelien Amiot
- Department of Gastroenterology, Assistance Publique-Hôpitaux de Paris, Paris Est Creteil University, Henri Mondor Hospital, Paris Est Creteil University; Department of Gastroenterology, Paris Est-Créteil Val de Marne University, Assistance Publique-Hôpitaux de Paris, Henri Mondor Hospital, Creteil, France
| | - Cathy Lu
- Division of Gastroenterology, Zeidler Ledcor Center, University of Alberta, Edmonton, Alberta, Canada; Division of Gastroenterology, Calgary, Alberta, Canada
| | - Xavier Roblin
- Department of Gastro-Enterology, INSERM CIC 1408, Paris, France; Department of Gastroenterology, University of Saint Etienne, Centre Hospitalier Universitaire Hopital Nord, Saint Etienne, France
| | - Klaudia Farkas
- First Department of Medicine, University of Szeged, Szeged, Hungary
| | - Jakob B Seidelin
- Department of Gastroenterology, Herlev Hospital, Herlev, Denmark
| | - Marjolijn Duijvestein
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Geert R D'Haens
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands
| | - Annemarie C de Vries
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.
| |
Collapse
|
6
|
Abstract
Patients with inflammatory bowel disease (IBD) show large variability in disease course, and also treatment response. The variability in treatment response has led to many initiatives in search of genetic markers to optimize treatment and avoid severe side effects. This has been very successful for thiopurines, one of the drugs used to induce and maintain remission in IBD. However, for the newer treatment options for IBD, like biologicals, the search for genetic predictors has not yielded any candidate biomarkers with clinical utility. In this review, a summary of recent advances in pharmacogenetics focusing on thiopurines and anti-TNF agents is given.
Collapse
Affiliation(s)
- Bianca Jc van den Bosch
- Deparment of Clinical Genetics, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands
| | - Marieke Jh Coenen
- Department of Human Genetics, Radboud Institute for Health Sciences, Radboud University Medical Center, P.O. Box 9101, 6500HB, Nijmegen, The Netherlands
| |
Collapse
|
7
|
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: 164] [Impact Index Per Article: 32.8] [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.
Collapse
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
| |
Collapse
|
8
|
Sakibuzzaman M, Moosa SA, Akhter M, Trisha IH, Talib KA. Identifying the Neurogenetic Framework of Crohn's Disease Through Investigative Analysis of the Nucleotide-binding Oligomerization Domain-containing Protein 2 Gene Mutation. Cureus 2019; 11:e5680. [PMID: 31723489 PMCID: PMC6825438 DOI: 10.7759/cureus.5680] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Accepted: 09/16/2019] [Indexed: 12/16/2022] Open
Abstract
Among several inflammatory bowel diseases, Crohn's disease is associated with inflammation that may take place in any region of the gastrointestinal tract. The inflammatory process is most commonly associated with the ileum, often spreading deep into the bowel tissues, extending into multiple forms, such as strictures and penetrations. Currently, Crohn's disease has no known cure. Various medical and surgical procedures are used to manage the condition. The underlying mechanisms of the disease are yet to be identified, with recent studies suggesting the influence of genetics, environmental factors, and the possible activity of pathogens. Newer studies also offer strong evidence that suggests a relationship between Crohn's disease and the nucleotide-binding oligomerization domain-containing protein 2 (NOD2) gene, also known as inflammatory bowel disease protein 1 (IBD1) or caspase recruitment domain-containing protein 15 (CARD15). NOD2 is responsible for the mechanism in which the immune system identifies foreign microorganisms through the sensing of pathogen-associated molecular patterns in microorganisms. NOD2 can detect intracellular muramyl dipeptide (MDP) in the bacterial wall, thereby causing an inflammatory response. Three major mutations associated with the NOD2 gene are known to have an influence on Crohn's disease (SNP8, SNP12, and SNP13). This article will discuss a number of studies to identify whether there is a relationship between Crohn's disease and the NOD2 gene.
Collapse
Affiliation(s)
- Md Sakibuzzaman
- Internal Medicine, Sir Salimullah Medical College, Dhaka, BGD
| | - Syed Ahmad Moosa
- Family Medicine, Woodhaven Medical Professional Corporation, Queens Village, USA
| | | | | | - Khandokar A Talib
- Medicine, Sylhet Mag Osmani Medical College and Hospital, Sylhet, BGD
| |
Collapse
|
9
|
Gole B, Potočnik U. Pre-Treatment Biomarkers of Anti-Tumour Necrosis Factor Therapy Response in Crohn's Disease-A Systematic Review and Gene Ontology Analysis. Cells 2019; 8:cells8060515. [PMID: 31141991 PMCID: PMC6628089 DOI: 10.3390/cells8060515] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 05/24/2019] [Accepted: 05/25/2019] [Indexed: 12/15/2022] Open
Abstract
The most prominent treatment for the serious cases of Crohn’s disease (CD) are biological tumour necrosis factor (TNF) inhibitors. Unfortunately, therapy nonresponse is still a serious issue in ~1/3 of CD patients. Accurate prediction of responsiveness prior to therapy start would therefore be of great value. Clinical predictors have, however, proved insufficient. Here, we integrate genomic and expression data on potential pre-treatment biomarkers of anti-TNF nonresponse. We show that there is almost no overlap between genomic (annotated with tissue-specific expression quantitative trait loci data) and transcription (RNA and protein data) biomarkers. Furthermore, using interaction networks we demonstrate there is little direct interaction between the proposed biomarkers, though a majority do have common interactors connecting them into networks. Our gene ontology analysis shows that these networks have roles in apoptotic signalling, response to oxidative stress and inflammation pathways. We conclude that a more systematic approach with genome-wide search of genomic and expression biomarkers in the same patients is needed in future studies.
Collapse
Affiliation(s)
- Boris Gole
- Centre for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska ulica 8, SI-2000 Maribor, Slovenia.
| | - Uroš Potočnik
- Centre for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska ulica 8, SI-2000 Maribor, Slovenia.
- Laboratory for Biochemistry, Molecular biology and Genomics, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova ulica 17, SI-2000 Maribor, Slovenia.
| |
Collapse
|
10
|
Gut Microbiota Offers Universal Biomarkers across Ethnicity in Inflammatory Bowel Disease Diagnosis and Infliximab Response Prediction. mSystems 2018; 3:mSystems00188-17. [PMID: 29404425 PMCID: PMC5790872 DOI: 10.1128/msystems.00188-17] [Citation(s) in RCA: 213] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2017] [Accepted: 12/05/2017] [Indexed: 12/14/2022] Open
Abstract
Gut microbiota dysbiosis contributes to the onset and perpetuation of inflammatory bowel disease (IBD). Given that gut microbiotas vary across geography and ethnicity, it remains obscure whether any universal microbial signatures for IBD diagnosis and prognosis evaluation exist irrespective of populations. Here we profiled the fecal microbiota of a series of Chinese IBD patients and combined them with two Western IBD cohorts, PRISM and RISK, for meta-analyses. We found that the gut microbial alteration patterns in IBD are similar among Chinese and Westerners. Our prediction model based on gut microbiome for IBD diagnosis is robust across the cohorts, which showed 87.5% and 79.1% prediction accuracy in Crohn's disease (CD) and ulcerative colitis (UC) patients, respectively. A relative increase in the levels of Actinobacteria and Proteobacteria (Enterobacteriaceae) and a relative decrease in the levels of Firmicutes (Clostridiales) were strongly correlated with IBD severity (P < 0.05). Additionally, restoration of gut microbiota diversity and a significant increase in Clostridiales relative abundance were found in patients responding to infliximab (IFX [Remicade]) treatment compared to those in relapse. Moreover, certain microbes, mainly Clostridiales, predicted the treatment effectiveness with 86.5% accuracy alone and 93.8% accuracy in combination with calprotectin levels and Crohn's disease activity index (CDAI). Taking the results together, we conclude that gut microbiota can offer a set of universal biomarkers for diagnosis, disease activity evaluation, and infliximab treatment response prediction in IBD. IMPORTANCE In the present report, we show that the human fecal microbiota contains promising and universal biomarkers for the noninvasive evaluation of inflammatory bowel disease severity and IFX treatment efficacy, emphasizing the potential ability to mine the gut microbiota as a modality to stratify IBD patients and apply personalized therapy for optimal outcomes.
Collapse
|
11
|
Kupka T, Simova J, Dvorackova J, Martinek L, Motyka O, Uvirova M, Dite P. Crohn's disease - genetic factors and progress of the disease. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2018; 162:139-143. [PMID: 29358789 DOI: 10.5507/bp.2017.058] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Accepted: 12/19/2017] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND AND OBJECTIVES Crohn's disease is a multifactorial inflammatory disease affecting mainly the gastrointestinal tract. The genetic factors that are involved in the disease include mainly three mutations of the gene NOD2/CARD15 (R702W, G908R, 3020insC). The aim of this study was to determine the relationship between the presence of these variants and disease phenotype. MATERIAL AND METHODS 70 patients with Crohn's disease were examined for the presence of the above-mentioned mutations. The researchers used the medical records to retrospectively obtain clinical data and together with the information obtained prospectively according to the protocol they analysed the connection between gene mutations and disease phenotype. RESULTS At least one mutation was found in 22 patients with Crohn's disease (32%), four patients were found to have two different mutations (composed heterozygotes - 6%) and six patients (9%) were homozygotes for the 3020insC gene. No significant differences were found between the groups with wild-type form and the mutated form of the NOD2 / CARD15 gene with respect to age at the time of diagnosis, form of the disease or localization according to the Montreal classification. CONCLUSION Mutations of the NOD2 / CARD15 gene did not significantly affect the frequency of reoperations, homozygotes with 3020insC gene mutations, however, represented a high risk group. The phenotype was not related significantly to the presence of the examined mutations.
Collapse
Affiliation(s)
- Tomas Kupka
- Department of Internal Medicine, University Hospital Ostrava, Czech Republic.,Faculty of Medicine, University of Ostrava, Czech Republic
| | - Jarmila Simova
- Faculty of Medicine, University of Ostrava, Czech Republic.,CGB laborator, a.s., Laboratory of Molecular Genetics and Pathology, Ostrava, Czech Republic
| | - Jana Dvorackova
- Faculty of Medicine, University of Ostrava, Czech Republic.,Institute of Clinical Pathology, University Hospital Ostrava, Czech Republic
| | - Lubomir Martinek
- Faculty of Medicine, University of Ostrava, Czech Republic.,Clinic of Surgery, University Hospital Ostrava, Czech Republic
| | - Oldrich Motyka
- Department of Inorganic Analysis, Centre of Nanotechnology, VSB - Technical University of Ostrava, Czech Republic
| | - Magdalena Uvirova
- Faculty of Medicine, University of Ostrava, Czech Republic.,CGB laborator, a.s., Laboratory of Molecular Genetics and Pathology, Ostrava, Czech Republic
| | - Petr Dite
- Department of Internal Medicine, University Hospital Ostrava, Czech Republic.,Faculty of Medicine, University of Ostrava, Czech Republic
| |
Collapse
|
12
|
Doherty G, Katsanos KH, Burisch J, Allez M, Papamichael K, Stallmach A, Mao R, Berset IP, Gisbert JP, Sebastian S, Kierkus J, Lopetuso L, Szymanska E, Louis E. European Crohn's and Colitis Organisation Topical Review on Treatment Withdrawal ['Exit Strategies'] in Inflammatory Bowel Disease. J Crohns Colitis 2018; 12:17-31. [PMID: 28981623 DOI: 10.1093/ecco-jcc/jjx101] [Citation(s) in RCA: 131] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 07/31/2017] [Indexed: 12/12/2022]
Abstract
Clinically effective therapies now exist for remission maintenance in both ulcerative colitis [UC] and Crohn's Disease [CD]. For each major class of IBD medications [5-aminosalicyclates, immunomodulators, and biologic agents], used alone or in combination, there is a risk of relapse following reduction or cessation of treatment. A consensus expert panel convened by the European Crohn's and Colitis Organisation [ECCO] reviewed the published literature and agreed a series of consensus practice points. The objective of the expert consensus is to provide evidence-based guidance for clinical practice so that physicians can make informed decisions in partnership with their patients. The likelihood of relapse with stopping each class of IBD medication is reviewed. Factors associated with an altered risk of relapse with withdrawal are evaluated, and strategies to monitor and allow early identification of relapse are considered. In general, patients in clinical, biochemical, and endoscopic remission are more likely to remain well when treatments are stopped. Reintroduction of the same treatment is usually, but not always, successful. The decision to stop a treatment needs to be individualized, and shared decision making with the patient should take place.
Collapse
Affiliation(s)
- Glen Doherty
- Centre for Colorectal Disease, St Vincent's University Hospital & University College Dublin, Dublin, Ireland
| | - Konstantinos H Katsanos
- Department of Gastroenterology and Hepatology, University and Medical School of Ioannina, Ioannina, Greece
| | - Johan Burisch
- Department of Gastroenterology, North Zealand University Hospital, Frederikssund, Denmark
| | - Matthieu Allez
- Department of Gastroenterology and Hepatology, Hôpital Saint-Louis, APHP, INSERM UMRS 1160, Université Denis Diderot, Paris, France
| | | | - Andreas Stallmach
- Department of Internal Medicine IV [Gastroenterology, Hepatology and Infectious Disease], University Hospital Jena, Jena, Germany
| | - Ren Mao
- Department of Gastroenterology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ingrid Prytz Berset
- Gastroenterology Department, Alesund Hospital, Helse More Romsdal Hospital Trust, Alesund, Norway
| | - Javier P Gisbert
- Department of Gastroenterology, Hospital Universitario de la Princesa, Instituto de Investigaciun Sanitaria Princesa (IIS-IP) and Centro de Investigaciun Biomédica en Red de Enfermedades Heprticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Shaji Sebastian
- IBD Unit, Department of Gastroenterology, Hull & East Yorkshire Hospitals NHS Trust, Hull, UK
| | - Jaroslaw Kierkus
- Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, Children's Memorial Health Institute, Warsaw, Poland
| | - Loris Lopetuso
- Department of Gastroenterology and Internal Medicine, Catholic University of Rome-A. Gemelli Hospital, Rome, Italy
| | - Edyta Szymanska
- Department of Pediatrics, Nutrition, and Metabolic Disorders, Children's Memorial Health Institute, Warsaw, Poland
| | - Edouard Louis
- Department of Gastroenterology, CHU Liège, Sart Tilman, Liège, Belgium
| |
Collapse
|
13
|
Abstract
Despite the proven efficacy of biological drugs for inflammatory bowel disease, these therapies are costly and do carry some risks, providing incentive for exploring strategies to discontinue therapy in patients with prolonged remission. We presently review multiple cohort studies indicating the overall risk of relapse after stopping an anti-tumor necrosis factor (TNF) in inflammatory bowel disease patients is roughly 40% at 12 months after therapy cessation. Despite methodological differences across studies, it appears that patients without deep remission (ie, patients with endoscopic or biomarker evidence of inflammation) are at increased risk of relapse after stopping anti-TNF, as are those with high-adequate levels of anti-TNF before stopping. In patients who relapse after anti-TNF cessation, retreatment with the same biological seems to reinduce clinical response in most patients. Immunological reasons responsible for this high success rate for retreatment are elucidated, but resorting to retreatment also implies a small but finite risk of a severe flare leading to surgery, which should be borne in mind. Thus, stopping attempts should probably be reserved for patients with low risk for severe outcome should a relapse occur. Proactive endoscopic monitoring after drug cessation is imperative to reduce these risks. The recently introduced concept of treatment-cycles is discussed, along with a pragmatic algorithm of decision tree for therapy discontinuation in the selected appropriate patients.
Collapse
|
14
|
de Bruyn M, Vermeire S. NOD2 and bacterial recognition as therapeutic targets for Crohn’s disease. Expert Opin Ther Targets 2017; 21:1123-1139. [DOI: 10.1080/14728222.2017.1397627] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Magali de Bruyn
- Translational Research in GastroIntestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Translational Research in GastroIntestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium
| |
Collapse
|
15
|
Pharmacogenetic biomarkers of response in Crohn’s disease. THE PHARMACOGENOMICS JOURNAL 2017. [DOI: 10.1038/tpj.2017.27] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
|
16
|
Wang X, Qin L, Cao J, Zhao J. Impact of NOD2/CARD15 polymorphisms on response to monoclonal antibody therapy in Crohn's disease: a systematic review and meta-analysis. Curr Med Res Opin 2016; 32:2007-2012. [PMID: 27533749 DOI: 10.1080/03007995.2016.1226168] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
OBJECTIVE Crohn's disease (CD) is frequently treated with anti-tumor necrosis factor (TNF)α monoclonal antibodies, and NOD2/CARD15 polymorphisms have been reported to predict treatment response. The purpose of this study was to perform a meta-analysis to determine the effect of NOD2/CARD15 polymorphisms on treatment response in patients with CD. METHODS Medline, Cochrane, EMBASE, and Google Scholar databases were searched until 19 December 2015 using the keywords: NOD2, CARD15, polymorphism, Crohn's disease. Randomized controlled trials, prospective, retrospective, and cohort studies of patients with CD who received NOD2/CARD15 genetic analysis and were treated with monoclonal antibodies were included. The primary outcome was treatment response. RESULTS Of 104 records identified, only four studies were relevant and included in the analysis. The four studies included 355 patients with CD, patient age ranged from 35 to 41 years, and the proportion of males ranged from 33% to 38%; however, only two studies reported age and sex data. Patients were treated with adalimumab and/or infliximab. Analysis revealed that NOD2/CARD15 mutations were not significantly associated with response to adalimumab or infliximab treatment (pooled odds ratio [OR] = 1.35, 95% confidence interval [CI]: 0.78 to 2.32, p = .278). CONCLUSIONS NOD2/CARD15 polymorphisms do not predict response to adalimumab and infliximab in patients with CD. However, the number of included studies was small and treatment protocols varied. Further studies are necessary to determine the role of NOD2/CARD15 polymorphisms in patients with CD.
Collapse
Affiliation(s)
- Xiaolei Wang
- a Shanghai Tenth People's Hospital, Tongji University , Shanghai , China
| | - Li Qin
- b Tongji University School of Medicine , Shanghai , China
| | - Jingli Cao
- b Tongji University School of Medicine , Shanghai , China
| | - Jing Zhao
- b Tongji University School of Medicine , Shanghai , China
| |
Collapse
|
17
|
Gisbert JP, Marín AC, Chaparro M. The Risk of Relapse after Anti-TNF Discontinuation in Inflammatory Bowel Disease: Systematic Review and Meta-Analysis. Am J Gastroenterol 2016; 111:632-47. [PMID: 27002797 DOI: 10.1038/ajg.2016.54] [Citation(s) in RCA: 143] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2015] [Accepted: 01/26/2016] [Indexed: 12/11/2022]
Abstract
OBJECTIVES To perform a meta-analysis of the risk of relapse after discontinuation of anti-tumor necrosis factor (anti-TNF) therapy in patients with Crohn's disease (CD) and ulcerative colitis (UC), to evaluate risk factors for relapse, and to assess the response to retreatment with the same anti-TNF. METHODS Studies evaluating the incidence of relapse after anti-TNF discontinuation in patients with CD or UC who reached clinical remission with anti-TNFs were included. Bibliographies up to January 2015 were searched. Frequency of relapse after discontinuation of anti-TNF agents was determined; meta-analyses were performed using the inverse-variance method. RESULTS We included 27 studies (21 infliximab and 6 infliximab/adalimumab). The overall risk of relapse after discontinuation of anti-TNF therapy was 44% for CD (95% confidence interval (CI) 36-51%; I(2)=79%; 912 patients) and 38% for UC (23-52%; I(2)=82%; 266 patients). In CD, the relapse rate was 38% at 6 months after discontinuation (short term), 40% at 12 months (medium term), and 49% at >25 months (long term). In UC, 28% of patients relapsed at 12 months. In CD, when clinical remission was the only criterion for stopping anti-TNF therapy, the relapse rate after 1 year was 42%, which decreased to 26% when endoscopic remission was also required. Retreatment with the same anti-TNF induced remission again in 80% of cases (68-91%). CONCLUSIONS Approximately one-third of patients with inflammatory bowel disease in remission under anti-TNF treatment relapsed 1 year after discontinuation. This proportion increased to half in the long term. In CD patients, the risk of relapse was lower when the criterion for discontinuation was endoscopic remission and not only clinical remission. Response to retreatment with the same anti-TNF agent was favorable.
Collapse
Affiliation(s)
- Javier P Gisbert
- Gastroenterology Unit, Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria Princesa (IIS-IP), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Alicia C Marín
- Gastroenterology Unit, Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria Princesa (IIS-IP), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - María Chaparro
- Gastroenterology Unit, Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria Princesa (IIS-IP), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| |
Collapse
|
18
|
Infliximab for the treatment of Crohn's disease: efficacy and safety in a Chinese single-center retrospective study. Eur J Gastroenterol Hepatol 2015; 27:1270-5. [PMID: 26275085 DOI: 10.1097/meg.0000000000000447] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BACKGROUND AND AIM Information describing the efficacy and safety of infliximab (IFX) for Crohn's disease (CD) in China is limited. The aim of this study was to report response rates, relapse rates after IFX-induced remission, and adverse events, and identify factors associated with relapse in a cohort of CD patients treated with IFX in a Chinese center. PATIENTS AND METHODS Clinical data of CD patients treated with two or more infusions of IFX from July 2010 to February 2013 at Nanfang Hospital (Guangzhou, China) were retrieved and analyzed retrospectively. Primary measurements were clinical response rate and relapse rate during 30 weeks of follow-up. Overall adverse events and risk factors related to IFX were evaluated. RESULTS A total of 70 CD patients were finally included. The clinical response rate was 98.6% at week 2, 97% at week 6, 92.5% at week 14, 84.9% at week 22, and 84.1% at week 30. The remission rate was 55.7% at week 2, 94% at week 6, 92.5% at week 14, 82.7% at week 22, and 77.3% at week 30. Relapse began following the third infusion. The relapse rate was 3.23% at week 6, 6.12% at week 14, 10.53% at week 22, and 8.82% at week 30. Adverse events related to IFX occurred in 32.6% of patients; most were mild and transient. Univariate analysis showed that sex was a significant predictor of clinical relapse. CONCLUSION IFX is an effective and safe treatment for CD in Chinese patients. Sex may be an independent predictor of relapse.
Collapse
|
19
|
Gisbert JP, Marín AC, Chaparro M. Systematic review: factors associated with relapse of inflammatory bowel disease after discontinuation of anti-TNF therapy. Aliment Pharmacol Ther 2015; 42:391-405. [PMID: 26075832 DOI: 10.1111/apt.13276] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2015] [Revised: 04/20/2015] [Accepted: 05/25/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND The discontinuation of anti-tumour necrosis factor (anti-TNF) treatment in inflammatory bowel disease (IBD) patients in remission could be considered. AIM To evaluate the factors associated with relapse of IBD after discontinuation of anti-TNF therapy. METHODS Electronic (PubMed/Embase) and manual search up to January 2015. RESULTS The overall risk of relapse after discontinuation of anti-TNFs (27 studies) was 44% for Crohn's disease (CD; follow-up range: 6-125 months) and 38% for ulcerative colitis (follow-up range: 6-24 months). Several factors were investigated to identify patients who are more likely to achieve long-lasting remission after anti-TNF discontinuation. The factors associated with a higher risk of relapse are younger age, smoking, longer disease duration, and fistulising perianal CD. Laboratory markers such as low haemoglobin levels, high C-reactive protein levels and high faecal calprotectin seem to increase the risk of relapse. On the other hand, low serum anti-TNF levels seem to be associated with a lower risk of flare-up. Mucosal healing seems to decrease the risk of relapse after anti-TNF discontinuation (overall, this risk is 26% at 1 year with mucosal healing and 42% without), although this observation has not been confirmed by some authors. In patients receiving escalated anti-TNF doses or receiving anti-TNFs for the prevention of post-operative CD recurrence, the risk of relapse after discontinuation is high (>75%). Re-administration of the drug in those who relapsed after stopping treatment is effective and safe. CONCLUSIONS A high proportion of patients with IBD relapse after discontinuation of anti-TNF treatment. As available data are insufficient to make strong recommendations on when anti-TNF therapy could be stopped, decisions should be taken on an individual basis.
Collapse
Affiliation(s)
- J P Gisbert
- Gastroenterology Unit, Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria Princesa (IIS-IP), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - A C Marín
- Gastroenterology Unit, Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria Princesa (IIS-IP), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - M Chaparro
- Gastroenterology Unit, Hospital Universitario de La Princesa and Instituto de Investigación Sanitaria Princesa (IIS-IP), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| |
Collapse
|
20
|
Abstract
Ulcerative colitis (UC) and Crohn's disease (CD) are chronic inflammatory disorders, which require long term treatment to achieve remission and to prevent relapses and cancer. While current therapies are effective in most cases, they can have rare but serious side effects and are often associated with high costs. On the other hand, early discontinuation of an effective treatment may lead to a quick relapse and to complications at the restart of therapy. Therefore it is essential to determine the optimal duration of maintenance therapy, but clear guidelines are missing. The most important questions when deciding whether to continue or withdraw therapy in quiescent UC and CD patients are the efficacy of the continuous treatment to maintain remission in the long term, the frequency and severity of side effects, and the chance of relapse after discontinuation of therapy. This review summarizes the current knowledge on these topics with respect to 5-aminosalicylates, thiopurines, methotrexate, and biological therapies and collects information regarding when and in which specific patient groups, in the absence of risk factors, can withdrawal of therapy be considered without a high risk of relapse. Additionally, the particular aspect of colorectal cancer prevention by current therapies will also be discussed.
Collapse
|
21
|
Papamichael K, Vande Casteele N, Gils A, Tops S, Hauenstein S, Singh S, Princen F, Van Assche G, Rutgeerts P, Vermeire S, Ferrante M. Long-term outcome of patients with Crohn's disease who discontinued infliximab therapy upon clinical remission. Clin Gastroenterol Hepatol 2015; 13:1103-10. [PMID: 25478919 DOI: 10.1016/j.cgh.2014.11.026] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Revised: 11/05/2014] [Accepted: 11/19/2014] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS There are limited data on the effects of discontinuing infliximab therapy for Crohn's disease (CD). We investigated the long-term outcome of patients with CD who discontinued infliximab while in clinical remission, and searched for prognostic markers of continued remission after infliximab cessation. METHODS We performed a retrospective, single-center study of 100 patients with CD who discontinued infliximab upon achieving clinical remission; 84 patients continued immunomodulator therapy. Clinical and endoscopic data were retrieved from a medical database in Belgium, and patients were followed up through April 2013 (median, 9.7 y; interquartile range, 8-11.5 y). Sustained clinical remission (SCR) was defined as maintenance of disease remission, without escalation in medical therapy or CD-related surgeries, until the end of the follow-up period. We measured trough concentrations of infliximab, antibodies to microbial antigens, and circulating inflammatory markers in serum samples collected before treatment and at the time of infliximab discontinuation. RESULTS At the end of the follow-up period, 52 patients had SCR. Univariate (log-rank) analysis associated SCR with patient age at diagnosis (≥25 y; P = .012) and disease duration (<1 y; P = .017). Among factors evaluated at the time of infliximab discontinuation, infliximab trough concentrations (<6 μg/mL; P = .031), complete mucosal healing (P = .046), and serum positivity for vascular cell adhesion molecule-1 (>0.67 μg/mL; P = .024) were associated with SCR. In multiple Cox proportional hazards regression analysis, only age at diagnosis of 25 years and older was associated independently with SCR (hazard ratio, 1.83; 95% confidence interval, 1.03-3.25; P = .04). CONCLUSIONS In a large, real-life study, 52% of patients with CD who discontinued infliximab upon achieving clinical remission remained in SCR after a median period of approximately 10 years; Most patients remained on immunomodulator therapy. Although patients with CD have variable responses to infliximab, a subgroup achieved long-term remission after infliximab discontinuation.
Collapse
Affiliation(s)
- Konstantinos Papamichael
- Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, Katholieke Universiteit Leuven, Leuven, Belgium; Department of Gastroenterology, Universitair ziekenhuis Leuven, Leuven, Belgium; Department of Pharmaceutical and Pharmacological Sciences, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Niels Vande Casteele
- Department of Pharmaceutical and Pharmacological Sciences, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Ann Gils
- Department of Pharmaceutical and Pharmacological Sciences, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Sophie Tops
- Department of Pharmaceutical and Pharmacological Sciences, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Scott Hauenstein
- Prometheus Therapeutics and Diagnostics, Laboratories, Inc, San Diego, California
| | - Sharat Singh
- Prometheus Therapeutics and Diagnostics, Laboratories, Inc, San Diego, California
| | - Fred Princen
- Prometheus Therapeutics and Diagnostics, Laboratories, Inc, San Diego, California
| | - Gert Van Assche
- Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, Katholieke Universiteit Leuven, Leuven, Belgium; Department of Gastroenterology, Universitair ziekenhuis Leuven, Leuven, Belgium
| | - Paul Rutgeerts
- Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, Katholieke Universiteit Leuven, Leuven, Belgium; Department of Gastroenterology, Universitair ziekenhuis Leuven, Leuven, Belgium
| | - Severine Vermeire
- Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, Katholieke Universiteit Leuven, Leuven, Belgium; Department of Gastroenterology, Universitair ziekenhuis Leuven, Leuven, Belgium
| | - Marc Ferrante
- Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders, Katholieke Universiteit Leuven, Leuven, Belgium; Department of Gastroenterology, Universitair ziekenhuis Leuven, Leuven, Belgium.
| |
Collapse
|
22
|
Papamichael K, Vermeire S. Withdrawal of anti-tumour necrosis factor α therapy in inflammatory bowel disease. World J Gastroenterol 2015; 21:4773-4778. [PMID: 25944990 PMCID: PMC4408449 DOI: 10.3748/wjg.v21.i16.4773] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Revised: 01/07/2015] [Accepted: 02/11/2015] [Indexed: 02/06/2023] Open
Abstract
Anti-tumour necrosis factor α (anti-TNFα) therapy is an established treatment in inflammatory bowel disease. However, this treatment is associated with high costs and the possibility of severe adverse events representing a true challenge for patients, clinicians and health care systems. Consequently, a crucial question is raised namely if therapy can be stopped once remission is achieved and if so, how and in whom. Additionally, in a real-life clinical setting, discontinuation may also be considered for other reasons such as the patient’s preference, pregnancy, social reasons as moving to countries or continents with less access, or different local policy or reimbursement. In contrast to initiation of anti-TNFα therapy guidelines regarding stopping of this treatment are missing. As a result, the decision of discontinuation is still a challenging aspect in the use of anti-TNFα therapy. Currently this is typically based on an estimated, case-by-case, benefit-risk ratio. This editorial is intended to provide an overview of recent data on this topic and shed light on the proposed drug withdrawal strategies.
Collapse
|
23
|
Abstract
Pattern recognition receptors are essential mediators of host defense and inflammation in the gastrointestinal system. Recent data have revealed that toll-like receptors and nucleotide-binding domain and leucine-rich repeat-containing proteins (NLRs) function to maintain homeostasis between the host microbiome and mucosal immunity. The NLR proteins are a diverse class of cytoplasmic pattern recognition receptors. In humans, only about half of the identified NLRs have been adequately characterized. The majority of well-characterized NLRs participate in the formation of a multiprotein complex, termed the inflammasome, which is responsible for the maturation of interleukin-1β and interleukin-18. However, recent observations have also uncovered the presence of a novel subgroup of NLRs that function as positive or negative regulators of inflammation through modulating critical signaling pathways, including NF-κB. Dysregulation of specific NLRs from both proinflammatory and inhibitory subgroups have been associated with the development of inflammatory bowel disease (IBD) in genetically susceptible human populations. Our own preliminary retrospective data mining efforts have identified a diverse range of NLRs that are significantly altered at the messenger RNA level in colons from patients with IBD. Likewise, studies using genetically modified mouse strains have revealed that multiple NLR family members have the potential to dramatically modulate the immune response during IBD. Targeting NLR signaling represents a promising and novel therapeutic strategy. However, significant effort is necessary to translate the current understanding of NLR biology into effective therapies.
Collapse
|
24
|
Bhullar M, Macrae F, Brown G, Smith M, Sharpe K. Prediction of Crohn’s disease aggression through NOD2/ CARD15 gene sequencing in an Australian cohort. World J Gastroenterol 2014; 20:5008-5016. [PMID: 24803813 PMCID: PMC4009534 DOI: 10.3748/wjg.v20.i17.5008] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2013] [Revised: 08/04/2013] [Accepted: 09/17/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the association between mutations in oligomerisation domain 2/caspase recruitment domains 15 (NOD2/CARD15) and the natural history of Crohn’s disease (CD) to identify patients who would benefit from early aggressive medical intervention.
METHODS: We recruited thirty consecutive unrelated CD patients with a history of ileo-caecal or small bowel resection during the period 1980-2000; Fifteen patients of these had post-operative relapse that required further surgery and fifteen did not. Full sequencing of the NOD2/CARD15 gene using dHPLC for exons 3, 5, 7, 10 and 12 and direct sequencing for exons 2, 4, 6, 8, 9 and 11 was conducted. CD patients categorized as carrying variants were anyone with at least 1 variant of the NOD2/CARD15 gene.
RESULTS: About 13.3% of the cohort (four patients) carried at least one mutant allele of 3020insC of the NOD2/CARD15 gene. There were 20 males and 10 females with a mean age of 43.3 years (range 25-69 years). The mean follow up was 199.6 mo and a median of 189.5 mo. Sixteen sequence variations within the NOD2/CARD15 gene were identified, with 9 of them occurring with an allele frequency of greater than 10 %. In this study, there was a trend to suggest that patients with the 3020insC mutation have a higher frequency of operations compared to those without the mutation. Patients with the 3020insC mutation had a significantly shorter time between the diagnosis of CD and initial surgery. This study included Australian patients of ethnically heterogenous background unlike previous studies conducted in different countries.
CONCLUSION: These findings suggest that patients carrying NOD2/CARD15 mutations follow a rapid and more aggressive form of Crohn’s disease showing a trend for multiple surgical interventions and significantly shorter time to early surgery.
Collapse
|