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Dolinger MT, Aronskyy I, Spencer EA, Pittman N, Dubinsky MC. Early intestinal ultrasound response to biologic and small molecule therapy is accurate to predict treat-to-target endoscopic outcomes in children with ulcerative colitis: results from the prospective super sonic-UC study. J Crohns Colitis 2025; 19:jjaf075. [PMID: 40312920 DOI: 10.1093/ecco-jcc/jjaf075] [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: 01/15/2025] [Indexed: 05/03/2025]
Abstract
BACKGROUND AND AIMS Stride-II recommends monitoring early biomarker targets to achieve treat-to-target (T2T) endoscopic remission (ER) in ulcerative colitis (UC). Predictive capabilities of intestinal ultrasound (IUS) for ER remain unknown. We evaluated IUS response to predict ER in children with UC. METHODS Prospective longitudinal cohort study of children with UC (Mayo endoscopic score [MES ≥2) starting advanced therapy undergoing IUS (including Milan Ultrasound Criteria [MUC], Civitelli Ulcerative Colitis Index, and International Bowel Ultrasound Group Segmental Activity Score), fecal calprotectin (FC), C-reactive protein (CRP), and Pediatric Ulcerative Colitis Activity Index at baseline, week 8, and T2T. Primary outcome was accuracy to predict T2T ER (MES = 0) for change in bowel wall thickness (BWT) from baseline to week 8, and absolute BWT at week 8. Logistic regression with forward selection determined an optimal prediction model for endoscopic outcomes. RESULTS Of 42 children, 21 (50%) achieved ER. Week 8 BWT ≤ 2.7 mm (OR 6.4 [95% CI, 1.8-27.0], P = .007), MUC < 6.0 (OR 5.7 [95% CI, 1.5-25.3], P = .015), and FC ≤ 177 (OR 4.5 [95% CI, 1.1-23.6], P = .049) were associated with ER. CONCLUSIONS Combining noninvasive biomarkers of BWT and the MUC on IUS, and FC, is a feasible tight control monitoring strategy in children with UC that is predictive of endoscopic outcomes. Larger, multicenter validation studies are needed to understand how an IUS and FC monitoring strategy may improve outcomes in children with UC.
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Affiliation(s)
- Michael Todd Dolinger
- Division of Pediatric Gastroenterology, Susan and Leonard Feinstein Inflammatory Bowel Disease Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Illya Aronskyy
- Division of Pediatric Gastroenterology, Susan and Leonard Feinstein Inflammatory Bowel Disease Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Elizabeth A Spencer
- Division of Pediatric Gastroenterology, Susan and Leonard Feinstein Inflammatory Bowel Disease Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Nanci Pittman
- Division of Pediatric Gastroenterology, Susan and Leonard Feinstein Inflammatory Bowel Disease Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Marla C Dubinsky
- Division of Pediatric Gastroenterology, Susan and Leonard Feinstein Inflammatory Bowel Disease Center, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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Zheng J, Zheng D, Fan Z, Li L, Chen R, Zhang S. Developing and Externally Validating a Simple Index Based on the Nonlinear Relationship of Fecal Calprotectin and Long-Term Outcomes in Ulcerative Colitis. J Inflamm Res 2024; 17:11247-11256. [PMID: 39717662 PMCID: PMC11665438 DOI: 10.2147/jir.s497655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Accepted: 12/14/2024] [Indexed: 12/25/2024] Open
Abstract
Background The possible nonlinear association with therapeutic outcomes in ulcerative colitis may contribute to the inconclusive cutoff values of fecal calprotectin (FC). We aimed to explore the nonlinear association between FC levels and long-term therapeutic outcomes in patients with ulcerative colitis and establish a clinically applicable FC index. Methods We included patients treated with vedolizumab or adalimumab from the VARSITY (n=661) and GEMINI 1 (n=620) studies as discovery and validation cohorts, respectively. The primary outcome was endoscopic remission at week 52 (Mayo Endoscopic Score 0). Restricted cubic splines were used to model nonlinearity between FC and long-term outcomes. Cutoff values were determined using piecewise regression to establish the FC index. Multivariable logistic regression and receiver operating characteristic curve analyses were performed to assess its predictive value. Results A nonlinear approximate enantiomorphic "J-shaped" association was observed between post-induction FC levels and long-term outcomes. Cutoff values of 180, 500, and 1300 μg/g were selected to construct the FC index; a higher index was significantly associated with a poorer outcome (P for trend <0.05). Furthermore, the FC index had an area under the receiver operating characteristic curve of 0.7095 [95% CI: 0.6621-0.7569], 0.6856 [95% CI: 0.6427-0.7284], 0.7527 [95% CI: 0.7084-0,7971], and 0.7630 [95% CI: 0.7110-0.8150] in predicting long-term endoscopic remission, clinical remission, histological remission, and disease clearance, respectively, approximately comparable to continuous FC, and superior to dichotomous FC. Conclusion The FC index is a promising indicator of therapeutic outcomes and may guide clinicians' therapeutic decisions.
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Affiliation(s)
- Jieqi Zheng
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Danping Zheng
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China
| | - Zinan Fan
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, People’s Republic of China
| | - Li Li
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China
| | - Rirong Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China
| | - Shenghong Zhang
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People’s Republic of China
- Guangxi Hospital Division of The First Affiliated Hospital, Sun Yat-Sen University, Nanning, People’s Republic of China
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Ricart E, Bastida G, Carpio D, Ceballos D, Ginard D, Marín-Jimenéz I, Menchén L, Muñoz F, González-Lama Y. Clinical Approach to STRIDE-II in Real-Life Settings: Analysis and Practical Recommendations. CROHN'S & COLITIS 360 2024; 6:otae055. [PMID: 39445340 PMCID: PMC11497081 DOI: 10.1093/crocol/otae055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Indexed: 10/25/2024] Open
Abstract
Background We aimed to (1) analyze the applicability of the updated Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE-II) recommendations in real-world clinical practice, (2) identify barriers to their implementation, and (3) propose practical measures to overcome these obstacles. Methods This qualitative study was based on a survey, a literature review, and expert opinions. Nine inflammatory bowel disease (IBD) experts identified 7 areas likely to be controversial or potential implementation barriers in daily clinical practice: endoscopy, histology, ultrasound, quality of life, biomarkers, symptom control, and patient-reported outcomes (PROs). Based on this, a survey was carried out among educational course participants. The experts discussed the literature review and survey results and proposed several statements and practical actions. Results A total of 55 gastroenterologists answered the survey. The reported difficulty level in reaching STRIDE-II treatment goals in clinical practice was high. Only 22% of participants performed clinical remission assessments using clinical indexes and PROs. Seventy percent of responders did not use fecal calprotectin cutoffs and considered changes from the previous levels instead. Mucosal healing as a long-term therapeutic goal was considered necessary to be individualized in specific patient subgroups (eg, elderly/fragile patients, multiple treatment failures, and last-line therapies). Other barriers, like the lack of access to imaging techniques or insufficient knowledge and skills among healthcare professionals, were detected. The experts suggested adding less stringent treatment goals and measurements, patient stratification, local adaptations, educational activities, and research. Conclusions STRIDE-II recommendations face various implementation barriers needing careful evaluation in order to enhance their adoption in clinical practice, and ultimately improve outcomes in IBD patients.
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Affiliation(s)
- Elena Ricart
- Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Clinic Barcelona, IDIBAPS, CIBEREHD, Barcelona 08036, Spain
| | - Guillermo Bastida
- Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia 46026, Spain
| | - Daniel Carpio
- Gastroenterology Department, Complexo Hospitalario Universitario de Pontevedra, Instituto de Investigación Sanitaria Galicia Sur (IISGS), Pontevedra 36071, Spain
| | - Daniel Ceballos
- Gastroenterology Department, Hospital Universitario Doctor Negrin, Las Palmas de Gran Canaria 35010, Spain
| | - Daniel Ginard
- Gastroenterology Department, Hospital Universitario Son Espases, Palma de Mallorca 07120, Spain
| | - Ignacio Marín-Jimenéz
- Gastroenterology Department, Departamento de Medicina, Facultad de Medicina, Universidad Complutense de Madrid, Hospital Universitario Gregorio Marañón-Instituto de Investigación Sanitaria Gregorio Marañón, Madrid 28007, Spain
| | - Luis Menchén
- Gastroenterology Department, Departamento de Medicina, Facultad de Medicina, Universidad Complutense de Madrid, Hospital Universitario Gregorio Marañón-Instituto de Investigación Sanitaria Gregorio Marañón, Madrid 28007, Spain
| | - Fernando Muñoz
- Gastroenterology Department, Hospital Universitario de Salamanca, Salamanca 37007, Spain
| | - Yago González-Lama
- Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Universitario 12 de Octubre, Madrid 28041, Spain
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Herrlinger KR, Stange EF. To STRIDE or not to STRIDE: a critique of "treat to target" in ulcerative colitis. Expert Rev Gastroenterol Hepatol 2024; 18:493-504. [PMID: 39193775 DOI: 10.1080/17474124.2024.2397654] [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: 07/03/2024] [Accepted: 08/24/2024] [Indexed: 08/29/2024]
Abstract
INTRODUCTION The STRIDE consensus intends to complement the clinical endpoint with an endoscopic endpoint of mucosal healing and others as treatment targets in ulcerative colitis. If these targets are not reached, STRIDE requires dose or timing adjustments or switching the medication. This narrative review provides a critique of this concept. AREAS COVERED We analyze and discuss the limitations of current endpoints as targets, their currently limited achievability, and the lacking evidence from controlled trials relating to 'treat to target.' The relevant publications in PubMed were identified in a literature review with the key word 'ulcerative colitis.' EXPERT OPINION In ulcerative colitis, the standard clinical target is measured traditionally by the MAYO-score, but in variable combinations of patient and physician reported outcomes as well as also different definitions of the endoscopic part. Only a score of 0 is more stringent than clinical remission but is only achieved by a minority of patients in first and even less in second line therapy. The concept is not based on clear evidence that patients indeed benefit from appropriate escalation of treatment. Until the STRIDE approach is proven to be superior to standard treatment focusing on clinical well-being, the field should remain reluctant.
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Affiliation(s)
| | - Eduard F Stange
- Innere Medizin I, UniversitätsklinikTübingen, Tübingen, Germany
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5
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D'Amico F, Magro F, Dignass A, Al Awadhi S, Gutierrez Casbas A, Queiroz NSF, Rydzewska G, Duk Ye B, Ran Z, Hart A, Jairath V, Fiorino G, Peyrin-Biroulet L, Danese S. Practical management of mild-to-moderate ulcerative colitis: an international expert consensus. Expert Rev Gastroenterol Hepatol 2024; 18:421-430. [PMID: 39225555 DOI: 10.1080/17474124.2024.2397650] [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: 07/01/2024] [Accepted: 08/24/2024] [Indexed: 09/04/2024]
Abstract
INTRODUCTION Although there are well-defined guidelines for the management of mild-to-moderate ulcerative colitis (UC), there are still unmet needs. For this reason, we conducted an international expert consensus to standardize the management of patients with mild-to-moderate UC and provide practical guidance to clinicians. AREAS COVERED Based on Delphi methodology, 15 statements were approved after two rounds of voting, addressing several aspects of disease management from sequencing to treatment duration, from monitoring to optimization techniques and safety profile. EXPERT OPINION Growing knowledge of mild-to-moderate UC has led to the development of new ambitious outcomes such as histological remission and disease clearance. Furthermore, noninvasive tools for patient monitoring such as fecal calprotectin and intestinal ultrasound are now available. Their implementation in clinical practice will allow clinicians to tightly monitor disease activity and promptly adapt treatment, avoiding complications and disease progression and targeting better disease control.
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Affiliation(s)
- Ferdinando D'Amico
- Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, Milan, Italy
| | - Fernando Magro
- CINTESIS@RISE, Faculty of Medicine, The University of Porto, Porto, Portugal
| | - Axel Dignass
- Department of Medicine I, Agaplesion Markus Hospital, Goethe University, Frankfurt/Main, Germany
| | | | - Ana Gutierrez Casbas
- Department of Gastroenterology, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, España
- Department of Gastroenterology, Hospital General Universitario de Alicante, Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, España
| | | | - Grażyna Rydzewska
- Department of Gastroenterology and Internal Medicine, National Medical Institute of Ministry of Interior and Administration, Warsaw, Poland
| | - Byong Duk Ye
- Department of Gastroenterology and Inflammatory Bowel Disease Center, AsanMedical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Zhihua Ran
- Department of Gastroenterology Zhou Pu Hospital, Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Ailsa Hart
- Inflammatory Bowel Disease Unit, St Mark's Hospital, London, UK
| | - Vipul Jairath
- Departments of Gastroenterology and Medicine, Western University Schulich School of Medicine & Dentistry, London, Ontario, Canada
| | - Gionata Fiorino
- IBD Unit, Department of Gastroenterology and Digestive Endoscopy, San Camillo-Forlanini Hospital, Rome, Italy
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology, Nancy University Hospital, Vandœuvre-lès-Nancy, France
- Department of Gastroenterology, Inserm, NGERE, University of Lorraine, Nancy, France
- Department of Gastroenterology, INFINY Institute, Nancy University Hospital, Vandœuvre-lès-Nancy, France
- Department of Gastroenterology, FHU-CURE, Nancy University Hospital, Vandœuvre-lès-Nancy, France
- Department of Gastroenterology, Groupe Hospitalier privé Ambroise Paré - Hartmann, Paris IBD center, Neuilly sur Seine, France
- Department of Gastroenterology, Division of Gastroenterology and Hepatology, McGill University Health Centre, Montreal, QC, Canada
| | - Silvio Danese
- Gastroenterology and Endoscopy, IRCCS San Raffaele Hospital, Milan, Italy
- Gastroenterology and Endoscopy, Vita-Salute San Raffaele University, Milan, Italy
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Costa MHDM, Sassaki LY, Chebli JMF. Fecal calprotectin and endoscopic scores: The cornerstones in clinical practice for evaluating mucosal healing in inflammatory bowel disease. World J Gastroenterol 2024; 30:3022-3035. [PMID: 38983953 PMCID: PMC11230062 DOI: 10.3748/wjg.v30.i24.3022] [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: 03/03/2024] [Revised: 05/01/2024] [Accepted: 05/27/2024] [Indexed: 06/25/2024] Open
Abstract
Managing inflammatory bowel disease (IBD) is becoming increasingly complex and personalized, considering the advent of new advanced therapies with distinct mechanisms of action. Achieving mucosal healing (MH) is a pivotal therapeutic goal in IBD management and can prevent IBD progression and reduce flares, hospitalization, surgery, intestinal damage, and colorectal cancer. Employing proactive disease and therapy assessment is essential to achieve better control of intestinal inflammation, even if subclinical, to alter the natural course of IBD. Periodic monitoring of fecal calprotectin (FC) levels and interval endoscopic evaluations are cornerstones for evaluating response/remission to advanced therapies targeting IBD, assessing MH, and detecting subclinical recurrence. Here, we comment on the article by Ishida et al Moreover, this editorial aimed to review the role of FC and endoscopic scores in predicting MH in patients with IBD. Furthermore, we intend to present some evidence on the role of these markers in future targets, such as histological and transmural healing. Additional prospective multicenter studies with a stricter MH criterion, standardized endoscopic and histopathological analyses, and virtual chromoscopy, potentially including artificial intelligence and other biomarkers, are desired.
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Affiliation(s)
| | - Ligia Yukie Sassaki
- Department of Internal Medicine, Medical School, São Paulo State University (Unesp), Botucatu 18618-686, São Paulo, Brazil
| | - Júlio Maria Fonseca Chebli
- Division of Gastroenterology, Department of Medicine, University Hospital of The Federal University of Juiz de Fora, University of Juiz de Fora School of Medicine, Juiz de Fora 36036-247, Minas Gerais, Brazil
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Wiley JW, Higgins GA. Epigenomics and the Brain-gut Axis: Impact of Adverse Childhood Experiences and Therapeutic Challenges. JOURNAL OF TRANSLATIONAL GASTROENTEROLOGY 2024; 2:125-130. [PMID: 40012740 PMCID: PMC11864786 DOI: 10.14218/jtg.2024.00017] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 02/28/2025]
Abstract
The brain-gut axis represents a bidirectional communication network that integrates neural, hormonal, and immunological signaling between the central nervous system and the gastrointestinal tract. Adverse childhood experiences (ACEs) have increasingly been recognized for their profound impact on this axis, with implications for both mental and physical health outcomes. This mini-review explores the emerging field of epigenomics-specifically, how epigenetic modifications incurred by ACEs can influence the brain-gut axis and contribute to the pathophysiology of various disorders. We examine the evidence linking epigenetic mechanisms such as DNA methylation, histone modifications, and non-coding RNAs to the modulation of gene expression involved in stress responses, neurodevelopment, and immune function-all of which intersect at the brain-gut axis. Additionally, we discuss the emerging potential of the gut microbiome as both a target and mediator of epigenetic changes, further influencing brain-gut communication in the context of ACEs. The methodological and therapeutic challenges posed by these insights are significant. The reversibility of epigenetic marks and the long-term consequences of early life stress require innovative and comprehensive approaches to intervention. This underscores the need for comprehensive strategies encompassing psychosocial, pharmacological, neuromodulation, and lifestyle interventions tailored to address ACEs' individualized and persistent effects. Future directions call for a multi-disciplinary approach and longitudinal studies to uncover the full extent of ACEs' impact on epigenetic regulation and the brain-gut axis, with the goal of developing targeted therapies to mitigate the long-lasting effects on health.
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Affiliation(s)
- John W. Wiley
- Department of Internal Medicine, University of Michigan Medicine, Ann Arbor, MI, USA
| | - Gerald A. Higgins
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA
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Lee YM, Kim ES, Choi S, Jang HJ, Kim YB, Choi SY, Choe BH, Kang B. Fecal Calprotectin at Postinduction Is Capable of Predicting Persistent Remission and Endoscopic Healing after 1 Year of Treatment with Infliximab in Pediatric Patients with Crohn's Disease. Gut Liver 2024; 18:498-508. [PMID: 38013474 PMCID: PMC11096907 DOI: 10.5009/gnl230022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 07/02/2023] [Accepted: 08/25/2023] [Indexed: 11/29/2023] Open
Abstract
BACKGROUND/AIMS : The recent update on Selecting Therapeutic Targets in Inflammatory Bowel Disease initiative has added a decrease in fecal calprotectin (FC) to an acceptable range as an intermediate target for Crohn's disease (CD). We aimed to investigate whether postinduction FC could predict future persistent remission (PR) and endoscopic healing (EH) after 1 year of treatment with infliximab (IFX) in pediatric patients with CD. METHODS : This multicenter retrospective observational study included pediatric patients with CD who were followed up for at least 1 year after starting IFX. The association of postinduction FC with PR and EH was investigated. RESULTS : A total of 132 patients were included in this study. PR and EH were observed in 71.2% (94/132) and 73.9% (82/111) of the patients, respectively. In multivariate logistic regression analysis, only the postinduction FC level was associated with PR (odds ratio [OR], 0.26; 95% confidence interval [CI], 0.08 to 0.66; p=0.009). The FC levels at initiation of IFX and postinduction were significantly associated with EH (OR, 0.73; 95% CI, 0.53 to 0.99; p=0.044 and OR, 0.20; 95% CI, 0.06 to 0.49; p=0.002, respectively). According to the receiver operating characteristic curve analysis, the optimal cutoff level for postinduction FC associated with PR was 122 mg/kg, and that associated with EH was 377 mg/kg. CONCLUSIONS : Postinduction FC was associated with PR and EH after 1 year of treatment with IFX in pediatric patients with CD. Our findings emphasize the importance of FC as an intermediate target in the treat-to-target era.
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Affiliation(s)
- Yoo Min Lee
- Department of Pediatrics, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Eun Sil Kim
- Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Sujin Choi
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Korea
- Crohn’s and Colitis Association in Daegu-Gyeongbuk (CCAiD), Daegu, Korea
| | - Hyo-Jeong Jang
- Crohn’s and Colitis Association in Daegu-Gyeongbuk (CCAiD), Daegu, Korea
- Department of Pediatrics, Keimyung University Dongsan Medical Center, Keimyung University School of Medicine, Daegu, Korea
| | - Yu Bin Kim
- Department of Pediatrics, Ajou University Medical Center, Suwon, Korea
| | - So Yoon Choi
- Department of Pediatrics, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Korea
| | - Byung-Ho Choe
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Korea
- Crohn’s and Colitis Association in Daegu-Gyeongbuk (CCAiD), Daegu, Korea
| | - Ben Kang
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Korea
- Crohn’s and Colitis Association in Daegu-Gyeongbuk (CCAiD), Daegu, Korea
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Chen R, Tie Y, Huang Y, Zhang X, Zeng Z, Chen M, Li L, Zhang S. Rapidly achieving clinical remission in ulcerative colitis indicates better endoscopic and histological outcomes. United European Gastroenterol J 2024; 12:459-468. [PMID: 38159047 PMCID: PMC11091780 DOI: 10.1002/ueg2.12515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 10/27/2023] [Indexed: 01/03/2024] Open
Abstract
BACKGROUND Clinical remission (CR) is the principal short-term treatment target in patients with ulcerative colitis (UC). However, whether rapidly achieving CR indicates better outcomes remains unclear. OBJECTIVES We aimed to explore the associations between the timing of CR and therapeutic outcomes in UC. METHODS This study included UC patients from the UNIFI trial. Week-2 CR and time to CR were the major variables of interest. Endoscopic remission (ER) at week 52 was the primary outcome. Multivariate logistic regression was performed to evaluate the association between variables and outcomes. RESULTS Week-2 CR was associated with ER (aOR: 2.37 [95% CI: 1.28, 4.37], p = 0.006) and Histological remission (HR) (aOR: 2.87 [95% CI: 1.42, 5.72], p = 0.003) at week 52. Moreover, C-reactive protein (CRP) remission could further stratify patients without CR and predict week-52 outcomes. Patients with clinical activity + CRP remission (aOR: 0.49 [95% CI: 0.26, 0.93], p = 0.039) and clinical activity + CRP activity (aOR: 0.24 [95% CI: 0.11, 0.52], p < 0.001) had gradually decreased likelihood of achieving ER, when compared to those with CR. For time to CR, we found that the earlier to CR, the better endoscopic and histological outcomes patients would attain. Patients achieving CR at weeks 2, 4/8, 12/16 and >16 had gradually reduced proportions of ER (51.9% vs. 40.8% vs. 31.6% vs. 8.8%, p < 0.001) and HR (37.0% vs. 19.8% vs. 17.1% vs. 6.1%, p < 0.001) at week 52. Compared with week 2, achieving CR at weeks 4/8, 12/16 and >16 had 39%, 55% and 92% lower likelihoods of week-52 ER, respectively. CONCLUSIONS Week-2 CR indicates better outcomes in UC patients receiving ustekinumab. Moreover, achieving CR more rapidly is associated with higher probability of ER and HR.
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Affiliation(s)
- Rirong Chen
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Yizhe Tie
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Yongle Huang
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Xi Zhang
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Zhongshan School of MedicineSun Yat‐sen UniversityGuangzhouChina
| | - Zhirong Zeng
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Minhu Chen
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Li Li
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Shenghong Zhang
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
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10
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Plaza J, Mínguez A, Bastida G, Marqués R, Nos P, Poveda JL, Moret-Tatay I. Genetic Variants Associated with Biological Treatment Response in Inflammatory Bowel Disease: A Systematic Review. Int J Mol Sci 2024; 25:3717. [PMID: 38612528 PMCID: PMC11012229 DOI: 10.3390/ijms25073717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 03/05/2024] [Accepted: 03/21/2024] [Indexed: 04/14/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the digestive tract usually characterized by diarrhea, rectal bleeding, and abdominal pain. IBD includes Crohn's disease and ulcerative colitis as the main entities. IBD is a debilitating condition that can lead to life-threatening complications, involving possible malignancy and surgery. The available therapies aim to achieve long-term remission and prevent disease progression. Biologics are bioengineered therapeutic drugs that mainly target proteins. Although they have revolutionized the treatment of IBD, their potential therapeutic benefits are limited due to large interindividual variability in clinical response in terms of efficacy and toxicity, resulting in high rates of long-term therapeutic failure. It is therefore important to find biomarkers that provide tailor-made treatment strategies that allow for patient stratification to maximize treatment benefits and minimize adverse events. Pharmacogenetics has the potential to optimize biologics selection in IBD by identifying genetic variants, specifically single nucleotide polymorphisms (SNPs), which are the underlying factors associated with an individual's drug response. This review analyzes the current knowledge of genetic variants associated with biological agent response (infliximab, adalimumab, ustekinumab, and vedolizumab) in IBD. An online literature search in various databases was conducted. After applying the inclusion and exclusion criteria, 28 reports from the 1685 results were employed for the review. The most significant SNPs potentially useful as predictive biomarkers of treatment response are linked to immunity, cytokine production, and immunorecognition.
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Affiliation(s)
- Javier Plaza
- Inflammatory Bowel Disease Research Group, Health Research Institute La Fe (IIS La Fe), 46026 Valencia, Spain; (J.P.); (A.M.)
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, 46100 Valencia, Spain
| | - Alejandro Mínguez
- Inflammatory Bowel Disease Research Group, Health Research Institute La Fe (IIS La Fe), 46026 Valencia, Spain; (J.P.); (A.M.)
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain; (G.B.); (P.N.)
| | - Guillermo Bastida
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain; (G.B.); (P.N.)
| | - Remedios Marqués
- Pharmacy Department, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain; (R.M.); (J.L.P.)
| | - Pilar Nos
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain; (G.B.); (P.N.)
| | - Jose Luis Poveda
- Pharmacy Department, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain; (R.M.); (J.L.P.)
| | - Inés Moret-Tatay
- Inflammatory Bowel Disease Research Group, Health Research Institute La Fe (IIS La Fe), 46026 Valencia, Spain; (J.P.); (A.M.)
- General Directorate of Public Health, Council of Healthcare, 46021 Valencia, Spain
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11
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Cuccia G, Privitera G, Di Vincenzo F, Monastero L, Parisio L, Carbone L, Scaldaferri F, Pugliese D. Predictors of Efficacy of Janus Kinase Inhibitors in Patients Affected by Ulcerative Colitis. J Clin Med 2024; 13:766. [PMID: 38337460 PMCID: PMC10856140 DOI: 10.3390/jcm13030766] [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: 12/31/2023] [Revised: 01/20/2024] [Accepted: 01/25/2024] [Indexed: 02/12/2024] Open
Abstract
Personalised medicine and the identification of predictors of the efficacy of specific drugs represent the ultimate goal for the treatment of ulcerative colitis (UC) in order to break the current therapeutic ceiling. JAK inhibitors are a new class of advanced therapies, orally administered, showing a good profile of efficacy and safety in both randomised controlled trials (RCTs) and real-world studies. Unfortunately, to date, it is not possible to draw the ideal profile of a patient maximally benefiting from this class of drugs to guide clinicians' therapeutic choices. Baseline clinical activities and inflammatory biomarkers, as well as their early variation after treatment initiation, emerged as the main predictors of efficacy from post hoc analyses of RCTs with tofacitinib. Similar findings were also observed in the real-life studies including mainly patients with a history of pluri-refractoriness to biological therapies. At last, a few new biomarkers have been explored, even though they have not been validated in large cohorts. This paper provides a review of the current knowledge on clinical variables and biomarkers predicting response to JAK inhibitors in UC.
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Affiliation(s)
- Giuseppe Cuccia
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, L. Go A. Gemelli 8, 00168 Rome, Italy; (G.C.); (F.D.V.); (L.M.); (F.S.)
| | - Giuseppe Privitera
- Dipartimento di Scienze della Salute, Università degli Studi di Milano, 20122 Milan, Italy;
| | - Federica Di Vincenzo
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, L. Go A. Gemelli 8, 00168 Rome, Italy; (G.C.); (F.D.V.); (L.M.); (F.S.)
| | - Lucia Monastero
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, L. Go A. Gemelli 8, 00168 Rome, Italy; (G.C.); (F.D.V.); (L.M.); (F.S.)
| | - Laura Parisio
- IBD UNIT-CEMAD (Centro Malattie Apparato Digerente), Medicina Interna e Gastroenterologia, Fondazione Policlinico A. Gemelli IRCCS, 00168 Rome, Italy;
| | - Luigi Carbone
- UOC Pronto Soccorso, Medicina d’Urgenza e Medicina Interna, Ospedale Isola Tiberina Gemelli Isola, 00186 Rome, Italy;
| | - Franco Scaldaferri
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, L. Go A. Gemelli 8, 00168 Rome, Italy; (G.C.); (F.D.V.); (L.M.); (F.S.)
- IBD UNIT-CEMAD (Centro Malattie Apparato Digerente), Medicina Interna e Gastroenterologia, Fondazione Policlinico A. Gemelli IRCCS, 00168 Rome, Italy;
| | - Daniela Pugliese
- Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, L. Go A. Gemelli 8, 00168 Rome, Italy; (G.C.); (F.D.V.); (L.M.); (F.S.)
- IBD UNIT-CEMAD (Centro Malattie Apparato Digerente), Medicina Interna e Gastroenterologia, Fondazione Policlinico A. Gemelli IRCCS, 00168 Rome, Italy;
- UOS Gastroenterologia, Ospedale Isola Tiberina Gemelli Isola, 00186 Rome, Italy
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12
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Blesl A, Borenich A, Gröchenig HP, Novacek G, Primas C, Reinisch W, Kutschera M, Illiasch C, Hennlich B, Steiner P, Koch R, Tillinger W, Haas T, Reicht G, Mayer A, Ludwiczek O, Miehsler W, Steidl K, Binder L, Baumann-Durchschein F, Fürst S, Reider S, Watschinger C, Wenzl H, Moschen A, Berghold A, Högenauer C. Factors Associated with Response to Systemic Corticosteroids in Active Ulcerative Colitis: Results from a Prospective, Multicenter Trial. J Clin Med 2023; 12:4853. [PMID: 37510968 PMCID: PMC10382050 DOI: 10.3390/jcm12144853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Revised: 07/19/2023] [Accepted: 07/20/2023] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND Among patients with ulcerative colitis, 30-50% receive corticosteroids within the first five years after diagnosis. We aimed to reconsider their effectiveness in the context of the biologic era. METHODS In this prospective, multicenter study, patients with active ulcerative colitis (Lichtiger score ≥ 4) were eligible if initiating systemic corticosteroids. The primary endpoint was clinical response (decrease in the Lichtiger score of ≥50%) at week 4. Secondary endpoints included combined response defined as clinical response and any reduction in elevated biomarkers (CRP and/or calprotectin). Steroid dependence was assessed after three months. RESULTS A total of 103 patients were included. Clinical response was achieved by 73% of patients, and combined response by 68%. A total of 15% of patients were steroid-dependent. Activity of colitis did not influence short-term response to treatment but increased the risk for steroid dependence. Biologic-naïve patients responded better than biologic-experienced patients. Past smoking history (OR 5.38 [1.71, 20.1], p = 0.003), hemoglobin levels (OR 0.76 [0.57, 0.99] for higher levels, p = 0.045), and biologic experience (OR 3.30 [1.08, 10.6], p = 0.036) were independently associated with nonresponse. CONCLUSION Disease activity was not associated with short-term response to systemic corticosteroids but was associated with steroid dependence in patients with active ulcerative colitis. Exposure to biologics negatively affects response rates.
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Affiliation(s)
- Andreas Blesl
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, 8036 Graz, Austria
| | - Andrea Borenich
- Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, 8036 Graz, Austria
| | | | - Gottfried Novacek
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, 1090 Vienna, Austria
| | - Christian Primas
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, 1090 Vienna, Austria
| | - Walter Reinisch
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, 1090 Vienna, Austria
| | - Maximilian Kutschera
- Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, 1090 Vienna, Austria
| | | | | | | | - Robert Koch
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, 6020 Innsbruck, Austria
| | | | | | - Gerhard Reicht
- Brothers of Saint John of God Hospital, 8020 Graz, Austria
| | - Andreas Mayer
- University Hospital St. Pölten, 3100 St. Pölten, Austria
| | | | | | - Karin Steidl
- Brothers of Saint John of God Hospital, 9300 St. Veit an der Glan, Austria
| | - Lukas Binder
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, 8036 Graz, Austria
| | - Franziska Baumann-Durchschein
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, 8036 Graz, Austria
| | - Stefan Fürst
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, 8036 Graz, Austria
| | - Simon Reider
- Department of Internal Medicine II (Gastroenterology and Hepatology), Faculty of Medicine, Kepler University Hospital, Johannes Kepler University, 4021 Linz, Austria
- Christian Doppler Laboratory for Mucosal Immunology, Johannes Kepler University, 4021 Linz, Austria
| | - Christina Watschinger
- Department of Internal Medicine II (Gastroenterology and Hepatology), Faculty of Medicine, Kepler University Hospital, Johannes Kepler University, 4021 Linz, Austria
- Christian Doppler Laboratory for Mucosal Immunology, Johannes Kepler University, 4021 Linz, Austria
| | - Heimo Wenzl
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, 8036 Graz, Austria
| | - Alexander Moschen
- Department of Internal Medicine II (Gastroenterology and Hepatology), Faculty of Medicine, Kepler University Hospital, Johannes Kepler University, 4021 Linz, Austria
- Christian Doppler Laboratory for Mucosal Immunology, Johannes Kepler University, 4021 Linz, Austria
| | - Andrea Berghold
- Institute for Medical Informatics, Statistics and Documentation, Medical University of Graz, 8036 Graz, Austria
| | - Christoph Högenauer
- Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, 8036 Graz, Austria
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13
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Smith SL, Alexander S, Nair N, Viatte S, Eyre S, Hyrich KL, Morgan AW, Wilson AG, Isaacs JD, Plant D, Barton A. Pre-treatment calprotectin (MRP8/14) provides no added value to testing CRP alone in terms of predicting response to TNF inhibitors in rheumatoid arthritis in a post hoc analysis. Ann Rheum Dis 2023; 82:611-620. [PMID: 36810200 PMCID: PMC10176427 DOI: 10.1136/ard-2022-222519] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 01/12/2023] [Indexed: 02/23/2023]
Abstract
OBJECTIVES The inflammatory protein calprotectin (MRP8/14) has been identified as a promising biomarker of treatment response in rheumatoid arthritis (RA). Our aim was to test MRP8/14 as a biomarker of response to tumour necrosis factor (TNF)-inhibitors in the largest RA cohort to date and to compare with C-reactive protein (CRP). METHODS Serum MRP8/14 was measured in 470 patients with RA about to commence treatment with adalimumab (n=196) or etanercept (n=274). Additionally, MRP8/14 was measured in the 3-month sera of 179 adalimumab-treated patients. Response was determined using European League against Rheumatism (EULAR) response criteria calculated using the traditional 4-component (4C) DAS28-CRP and alternate validated versions using 3-component (3C) and 2-component (2C), clinical disease activity index (CDAI) improvement criteria and change in individual outcome measures. Logistic/linear regression models were fitted for response outcome. RESULTS In the 3C and 2C models, patients with RA were 1.92 (CI: 1.04 to 3.54) and 2.03 (CI: 1.09 to 3.78) times more likely to be classified as EULAR responders if they had high (75th quartile) pre-treatment levels of MRP8/14 compared with low (25th quartile). No significant associations were observed for the 4C model. When only using CRP as a predictor, in the 3C and 2C analyses, patients above the 75th quartile were 3.79 (CI: 1.81 to 7.93) and 3.58 (CI: 1.74 to 7.35) times more likely to be EULAR responders and addition of MRP8/14 did not significantly improve model fit (p values=0.62 and 0.80, respectively). No significant associations were observed in the 4C analysis. Exclusion of CRP from the outcome measure (CDAI) did not result in any significant associations with MRP8/14 (OR 1.00 (CI: 0.99 to 1.01), suggesting that the associations were due to the correlation with CRP and that there is no additional utility of MRP8/14 beyond use of CRP in patients with RA starting TNFi therapy. CONCLUSION Beyond correlation with CRP, we found no evidence to suggest that MRP8/14 explains additional variability in response to TNFi in patients with RA over and above CRP alone.
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Affiliation(s)
- Samantha Louise Smith
- Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
| | - Sheree Alexander
- Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
| | - Nisha Nair
- Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
- NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - Sebastien Viatte
- Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
- Lydia Becker Institute of Immunology and Inflammation, Division of Musculoskeletal and Dermatological Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Stephen Eyre
- Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
| | - Kimme L Hyrich
- NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
- Centre for Epidemiology Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester, UK
| | - Ann W Morgan
- School of Medicine, University of Leeds and NIHR Leeds Musculoskeletal Biomedical Research Centre, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Anthony G Wilson
- UCD School of Medicine and Medical Science, Conway Institute, University College Dublin, Dublin, Ireland
| | - John D Isaacs
- Musculoskeletal Research Group, Translational and Clinical Research Institute, Newcastle University and NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Darren Plant
- Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
- NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
| | - Anne Barton
- Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Manchester Academic Health Science Centre, The University of Manchester, Manchester, UK
- NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK
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14
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Shi JT, Chen N, Xu J, Goyal H, Wu ZQ, Zhang JX, Xu HG. Diagnostic Accuracy of Fecal Calprotectin for Predicting Relapse in Inflammatory Bowel Disease: A Meta-Analysis. J Clin Med 2023; 12:1206. [PMID: 36769850 PMCID: PMC9917450 DOI: 10.3390/jcm12031206] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 01/28/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Fecal calprotectin (FC) levels correlate with the disease activity of inflammatory bowel diseases (IBD); however, the utility of FC in predicting IBD relapse remains to be determined. We aim to evaluate the efficacy of fecal calprotectin in predicting the relapse of inflammatory bowel disease. We searched Pubmed (MEDLINE), Embase, Web of Science, and the Cochrane library databases up to 7 July 2021. Our study estimated the pooled sensitivity and specificity, summary receiver operating characteristic (SROC) curve, and the optimal cut-off value for predicting IBD relapse using a multiple threshold model. A total of 24 prospective studies were included in the meta-analysis. The optimal FC cut-off value was 152 μg/g. The pooled sensitivity and specificity of FC was 0.720 (0.528 to 0.856) and 0.740 (0.618 to 0.834), respectively. FC is a useful, non-invasive, and inexpensive biomarker for the early prediction of IBD relapse. An FC value of 152 μg/g is an ideal threshold to identify patients with a high relapse probability.
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Affiliation(s)
- Jin-Tong Shi
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Nuo Chen
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Jia Xu
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Hemant Goyal
- Division of Gastroenterology, Hepatology & Nutrition, University of Texas Health Sciences Center, Houston, TX 77030, USA
| | - Zhi-Qi Wu
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Jie-Xin Zhang
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Hua-Guo Xu
- Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
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15
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Liu L, Ouyang H, Su J, Lin Y, Hu Y, Shi H, Xie C. Increased modified DUBLIN scores are associated with serious ulcerative colitis and treatment failure. Therap Adv Gastroenterol 2022; 15:17562848221142671. [PMID: 36545387 PMCID: PMC9761801 DOI: 10.1177/17562848221142671] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Accepted: 11/15/2022] [Indexed: 12/23/2022] Open
Abstract
BACKGROUND Grading of endoscopic lesions is important for determining the severity of ulcerative colitis and developing treatment strategies, but the commonly used methods are not sufficient. OBJECTIVES This study aimed to investigate whether new endoscopic scoring systems incorporating lesions and disease extent are associated with clinical disease severity and maintainable remission. DESIGN This was a retrospective study. In all, 110 patients with ulcerative colitis were included and 87 completed 12-month follow-up. METHODS Colonoscopy was performed within 1 week before blood samples were taken. Degree of ulcerative colitis burden of luminal inflammation (DUBLIN) scores were calculated as the product of Mayo endoscopic score (MES) by disease extent and ulcerative colitis endoscopic index of severity was used to replace MES when calculating modified DUBLIN scores. RESULTS DUBLIN and modified DUBLIN scores were increased in the moderate and severe groups significantly (p < 0.05). Both of increased scores contributed to the detection of serious diseases, and the clinical cutoff values of DUBLIN and modified DUBLIN were 3[area under the curve (AUC) = 0.809, p = 0.001) and 7(AUC = 0.815, p = 0.001), respectively. They were with high sensitivity, but the specificity of DUBLIN was lower. Both scores were correlated to partial Mayo scores, C-reactive protein and erythrocyte sedimentation rate positively, and they were correlated to the albumin negatively (p < 0.05). Higher modified DUBLIN scores (>7) were associated with an increased risk of treatment failure (hazard ratio = 4.96, 95% confidence interval: 1.17-21.00, p = 0.03), but there were no association between DUBLIN scores and long-term remission (p > 0.05). CONCLUSION Increased DUBLIN and modified DUBLIN scores were conducive to screening serious disease, but only modified DUBLIN scores had the potential to assist in making an upgraded therapeutic schedule.
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Affiliation(s)
| | | | - Jingling Su
- Department of Gastroenterology, Zhongshan
Hospital Xiamen University, Xiamen, Fujian, China
| | - Yumei Lin
- Department of Gastroenterology, Zhongshan
Hospital Xiamen University, Xiamen, Fujian, China
| | - Yiqun Hu
- Department of Gastroenterology, Zhongshan
Hospital Xiamen University, Xiamen, Fujian, China
| | - Huaxiu Shi
- Department of Gastroenterology, Zhongshan
Hospital Xiamen University, Xiamen, Fujian, China
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16
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Mosli MH, Almudaiheem HY, AlAmeel T, Bakkari SA, Alharbi OR, Alenzi KA, Khardaly AM, AlMolaiki MA, Al-Omari BA, Albarakati RG, Al-Jedai AH, Saadah OI, Almadi MA, Al-Bawardy B. Saudi Arabia consensus guidance for the diagnosis and management of adults with inflammatory bowel disease. Saudi J Gastroenterol 2022; 29:361671. [PMID: 36412460 PMCID: PMC10540981 DOI: 10.4103/sjg.sjg_277_22] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 08/23/2022] [Accepted: 09/05/2022] [Indexed: 02/10/2023] Open
Abstract
Optimal management of inflammatory bowel disease (IBD) relies on a clear understanding and tailoring evidence-based interventions by clinicians in partnership with patients. This article provides concise guidelines for the management of IBD in adults, based on the most up-to-date information at the time of writing and will be regularly updated. These guidelines were developed by the Saudi Ministry of Health in collaboration with the Saudi Gastroenterology Association and the Saudi Society of Clinical Pharmacy. After an extensive literature review, 78 evidence-and expert opinion-based recommendations for diagnosing and treating ulcerative colitis and Crohn's disease in adults were proposed and further refined by a voting process. The consensus guidelines include the finally agreed on statements with their level of evidence covering different aspects of IBD diagnosis and treatment.
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Affiliation(s)
- Mahmoud H. Mosli
- Department of Internal Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- Inflammatory Bowel Disease Unit, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
| | | | - Turki AlAmeel
- Department of Medicine, King Fahad Specialist Hospital, Dammam, Saudi Arabia
| | - Shakir A. Bakkari
- Division of Gastroenterology, King Saud Medical City, Riyadh, Saudi Arabia
| | - Othman R. Alharbi
- Department of Medicine, College of Medicine, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
| | - Khalidah A. Alenzi
- Regional Drug Information and Pharmacovigilance Center, Ministry of Health, Tabuk, Saudi Arabia
| | | | - Maha A. AlMolaiki
- Department of Pharmaceutical Care, National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Bedor A. Al-Omari
- Pharmaceutical Care Services, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
| | - Rayan G. Albarakati
- Department of Obstetrics and Gynecology, Majmaah University, Riyadh, Saudi Arabia
| | - Ahmed H. Al-Jedai
- Deputyship of Therapeutic Affairs, Ministry of Health, Riyadh, Saudi Arabia
| | - Omar I. Saadah
- Inflammatory Bowel Disease Unit, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
- Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Majid A. Almadi
- Department of Medicine, College of Medicine, King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia
| | - Badr Al-Bawardy
- Section of Digestive Diseases, Yale School of Medicine, New Haven, CT, USA
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17
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Facciorusso A, Ramai D, Ricciardelli C, Paolillo R, Maida M, Chandan S, Mohan BP, Domislovic V, Sacco R. Prognostic Role of Post-Induction Fecal Calprotectin Levels in Patients with Inflammatory Bowel Disease Treated with Biological Therapies. Biomedicines 2022; 10:2305. [PMID: 36140408 PMCID: PMC9496232 DOI: 10.3390/biomedicines10092305] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Revised: 09/09/2022] [Accepted: 09/14/2022] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND There is currently scarce knowledge about markers of early therapeutic response in patients with inflammatory bowel disease (IBD) treated with biologics. The aim of this study was to evaluate the role of fecal calprotectin (FC) as an early predictor of mucosal healing and clinical remission. METHODS Data from a multicenter series of 172 IBD patients treated with biologics between 2017 and 2020 were analyzed. Treatment outcomes were mucosal healing and clinical remission assessed at 2 years. FC levels were assessed at 14 weeks (post-induction), at 6 months, and yearly. The receiver operating characteristic (ROC) curve analysis was performed to calculate the best cut-off in % change of FC levels between post-induction and baseline predicting treatment outcomes. Sensitivity, specificity, and accuracy for several post-induction FC cut-off points were also calculated. RESULTS At 2 years, mucosal healing was noted in 77 patients (44.7%), of whom were 41 Crohn's disease (CD) and 36 ulcerative colitis (UC) patients, whereas 106 patients experienced clinical remission (61.6%), of whom were 59 CD and 47 UC patients. Both baseline and post-induction FC levels were significantly higher in non-responders as compared to responders. On the other hand, FC decrease was less pronounced in non-responders. Similar results were observed in all subgroups, namely according to disease (CD vs. UC), or treatment used (TNF-inhibitors vs. vedolizumab). The best cut-off points were -86% in % change in FC levels to predict mucosal healing and -83% for clinical remission. CONCLUSIONS The current study suggests a predictive role of post-induction FC assessment to predict treatment response in IBD patients treated with biologics.
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Affiliation(s)
- Antonio Facciorusso
- Gastroenterology Unit, Department of Surgical and Medical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Daryl Ramai
- Division of Gastroenterology, Hepatology and Nutrition, School of Medicine, University of Utah, Salt Lake City, UT 84112, USA
| | - Cristina Ricciardelli
- Gastroenterology Unit, Department of Surgical and Medical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Rosa Paolillo
- Gastroenterology Unit, Department of Surgical and Medical Sciences, University of Foggia, 71122 Foggia, Italy
| | - Marcello Maida
- Gastroenterology and Endoscopy Unit, S. Elia-Raimondi Hospital, 93100 Caltanissetta, Italy
| | - Saurabh Chandan
- Gastroenterology Unit, CHI Health Creighton University Medical Center, Omaha, NE 68131, USA
| | - Babu P. Mohan
- Division of Gastroenterology, Hepatology and Nutrition, School of Medicine, University of Utah, Salt Lake City, UT 84112, USA
| | - Viktor Domislovic
- Department of Gastroenterology and Hepatology, University Hospital Centre Zagreb, 10000 Zagreb, Croatia
| | - Rodolfo Sacco
- Gastroenterology Unit, Department of Surgical and Medical Sciences, University of Foggia, 71122 Foggia, Italy
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18
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Bertani L. Treatment and Management of Chronic Inflammatory Bowel Diseases: Optimizing Present and Future Therapeutic Choices. J Clin Med 2022; 11:jcm11185267. [PMID: 36142914 PMCID: PMC9501929 DOI: 10.3390/jcm11185267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 08/31/2022] [Accepted: 09/03/2022] [Indexed: 11/16/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are chronic relapsing diseases of the gastrointestinal tract of unknown origin, resulting from an aberrant immune response to microbial and gut-specific antigens in genetically susceptible patients [...]
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Affiliation(s)
- Lorenzo Bertani
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy;
- Department of Surgery, Tuscany North-West ASL, Pontedera Hospital, 56025 Pontedera, Italy
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Lee YJ, Park JH. Fecal Calprotectin Assay at an Early Stage of Treatment Can Be Used as a Surrogate Marker to Predict Clinical Remission and Mucosal Healing in Pediatric Crohn's Disease. Pediatr Gastroenterol Hepatol Nutr 2022; 25:396-405. [PMID: 36148291 PMCID: PMC9482829 DOI: 10.5223/pghn.2022.25.5.396] [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: 09/18/2021] [Revised: 01/05/2022] [Accepted: 07/28/2022] [Indexed: 11/14/2022] Open
Abstract
PURPOSE This study evaluated the predictive role of fecal calprotectin (FC) measured at an early stage of treatment for monitoring clinical remission (CR) after six months and endoscopic remission (ER) after one year of treatment in pediatric Crohn's disease (CD). METHODS This retrospective study included 45 patients who simultaneously underwent ileocolonoscopy and FC testing during follow-up. FC levels were measured before and after six weeks of treatment. CR was assessed after six months of treatment using Pediatric Crohn' s Disease Activity Index and acute-phase reactants. ER was assessed after one year using the Simple Endoscopic Score for Crohn's Disease. RESULTS Twenty-nine (64.4%) patients used oral prednisolone for remission induction and 16 (35.6%) patients used anti-tumor necrosis factor-alpha. Thirty (66.7%) patients achieved CR, while 24 (53.3%) achieved ER. The FC level measured after six weeks of treatment could predict CR (χ2=9.15, p=0.0025) and ER (χ2=12.31, p=0.0004). The δFC could predict CR (χ2=7.91, p=0.0049), but not ER (χ2=1.85, p=0.1738). With a threshold of ≤950.4 µg/g, FC at week six could predict CR with 76.7% sensitivity and 73.3% specificity. The area under the curve (AUC) was 0.769 (standard error 0.0773, p=0.0005). The same threshold predicted ER with 87.5% sensitivity and 71.4% specificity. The AUC was 0.774 (standard error 0.074, p=0.0002). CONCLUSION FC assay at an early stage of treatment can be used as a surrogate marker to predict CR and mucosal healing in pediatric CD.
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Affiliation(s)
- Yeoun Joo Lee
- Department of Pediatrics, Pusan National University School of Medicine, Yangsan, Korea
| | - Jae Hong Park
- Department of Pediatrics, Pusan National University School of Medicine, Yangsan, Korea
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Zhu C, Hu J, Wang X, Li C, Gao Y, Li J, Ge Y, Wu X. A novel clinical radiomics nomogram at baseline to predict mucosal healing in Crohn's disease patients treated with infliximab. Eur Radiol 2022; 32:6628-6636. [PMID: 35857074 DOI: 10.1007/s00330-022-08989-9] [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: 03/23/2022] [Revised: 06/17/2022] [Accepted: 06/27/2022] [Indexed: 11/29/2022]
Abstract
OBJECTIVES Mucosal healing (MH) is currently the gold standard in Crohn's disease (CD) management. Noninvasive assessment of MH in CD patients is increasingly a concern of clinicians. METHODS This retrospective study included 106 patients with confirmed CD who were divided into a training cohort (n = 73) and a testing cohort (n = 33). Patient demographics were evaluated to establish a clinical model. Radiomics features were extracted from computed tomography enterography (CTE) images. A radiomics signature was constructed, and a radiomics score (Rad-score) was calculated by using the radiomics signature-based formula. A clinical radiomics nomogram was then built by incorporating the Rad-score and significant clinical features. The diagnostic performance of the three models was evaluated using receiver operating characteristic (ROC) curve analysis. RESULTS Of the 106 patients with CD, 37 exhibited MH after 26 weeks of infliximab (IFX) treatment. The area under the ROC curve (AUC) of the clinical radiomics nomogram for distinguishing MH from non-MH, which was based on the disease duration and Rad-score, was 0.880 (95% confidence interval [CI]: 0.809-0.943) in the training cohort and 0.877 (95% CI: 0.745-0.983) in the testing cohort. Decision curve analysis (DCA) confirmed the clinical utility of the clinical radiomics nomogram. CONCLUSIONS This is a preliminary study suggesting that this CTE-based radiomics model has potential value for predicting MH in CD patients. A nomogram constructed by combining radiomics signatures and clinical features can help clinicians select appropriate therapeutic strategies for CD patients. KEY POINTS • The disease duration (odds ratio (OR) = 0.969, 95% confidence interval (CI) = 0.943-0.995, p = 0.021) was an independent predictor of MH in the clinical model. • The AUC of the radiomics model constructed by the five radiomics features was 0.846 (95% CI: 0.759-0.921) in the training cohort and 0.817 (95% CI: 0.665-0.945) in the testing cohort for differentiating MH from non-MH. • The AUC of the clinical radiomics nomogram was 0.880 (95% CI: 0.809-0.943) in the training cohort and 0.877 (95% CI: 0.745-0.983) in the testing cohort for distinguishing MH from non-MH.
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Affiliation(s)
- Chao Zhu
- Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
| | - Jing Hu
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
| | - Xia Wang
- Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
| | - Cuiping Li
- Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
| | - Yankun Gao
- Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
| | - Jianying Li
- CT Research Center, GE Healthcare China, Shanghai, 210000, China
| | - Yaqiong Ge
- CT Research Center, GE Healthcare China, Shanghai, 210000, China
| | - Xingwang Wu
- Department of Radiology, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
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Fairbrass KM, Gracie DJ, Ford AC. Relative Contribution of Disease Activity and Psychological Health to Prognosis of Inflammatory Bowel Disease During 6.5 Years of Longitudinal Follow-Up. Gastroenterology 2022; 163:190-203.e5. [PMID: 35339461 DOI: 10.1053/j.gastro.2022.03.014] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 02/02/2022] [Accepted: 03/04/2022] [Indexed: 12/30/2022]
Abstract
BACKGROUND & AIMS Symptoms of common mental disorders, such as anxiety or depression, are common in inflammatory bowel disease (IBD) and may affect prognosis. However, unlike clinical or biochemical markers of disease activity, psychological health is not a recommended therapeutic target. We assessed relative contribution of poor psychological health and clinical or biochemical activity to prognosis. METHODS Demographic features, IBD subtype, treatments, and anxiety and depression scores were recorded at baseline for 760 adults, with clinical activity determined using validated scoring systems. Fecal calprotectin was analyzed in 379 (49.9%) patients (≥250 μg/g used to define biochemical activity). Glucocorticosteroid prescription or flare, escalation, hospitalization, intestinal resection, or death were assessed during 6.5 years of follow-up. Occurrence was compared using multivariate Cox regression across 4 patient groups according to presence of disease remission or activity, with or without symptoms of a common mental disorder, at baseline. RESULTS In total, 718 (94.5%) participants provided data. Compared with clinical remission without symptoms of a common mental disorder at baseline, need for glucocorticosteroid prescription or flare (hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.58-3.54), escalation (HR, 1.65; 95% CI, 1.14--2.40), and death (HR, 4.99; 95% CI, 1.80-13.88) were significantly higher in those with clinical activity and symptoms of a common mental disorder. Rates in those with clinical remission and symptoms of a common mental disorder at baseline or those with clinical activity without symptoms of a common mental disorder were not significantly higher. Similarly, with biochemical activity and symptoms of a common mental disorder, rates of glucocorticosteroid prescription or flare (HR, 2.48; 95% CI, 1.38-4.46), escalation (HR, 2.97; 95% CI, 1.74-5.06), hospitalization (HR, 3.10; 95% CI, 1.43-6.68), and death (HR, 6.26; 95% CI, 2.23-17.56) were significantly higher. CONCLUSIONS Psychological factors are important determinants of poor prognostic outcomes in IBD and should be considered as a therapeutic target.
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Affiliation(s)
- Keeley M Fairbrass
- Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, United Kingdom; Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, United Kingdom
| | - David J Gracie
- Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, United Kingdom; Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, United Kingdom
| | - Alexander C Ford
- Leeds Gastroenterology Institute, St. James's University Hospital, Leeds, United Kingdom; Leeds Institute of Medical Research at St. James's, University of Leeds, Leeds, United Kingdom.
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22
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Pugliese D, Privitera G, Fiorani M, Parisio L, Calvez V, Papa A, Gasbarrini A, Armuzzi A. Targeting IL12/23 in ulcerative colitis: update on the role of ustekinumab. Therap Adv Gastroenterol 2022; 15:17562848221102283. [PMID: 35721840 PMCID: PMC9201364 DOI: 10.1177/17562848221102283] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 05/04/2022] [Indexed: 02/06/2023] Open
Abstract
As our comprehension of the pathogenic mechanisms of inflammatory bowel disease (IBD) increases, the therapeutic armamentarium for its treatment can expand, and novel target therapies join the treatment pipeline. Interleukin (IL)-12 and IL23 are two key cytokines responsible for promoting and perpetuating bowel inflammation in IBD. Ustekinumab is a monoclonal antibody directed against the shared p40 subunit of both cytokines, and it was recently approved for the treatment of ulcerative colitis (UC). In the pivotal phase III UNIFI trial, ustekinumab showed a superiority over placebo in both clinical and endoscopic outcomes; furthermore, it was characterized by a favorable safety profile, with a similar rate of adverse events as compared with placebo. Recent evidence from real-life experiences have started accumulating, generally confirming the effectiveness and safety figures emerged from the registration studies. However, most of these observational studies enrolled multirefractory patients; moreover, comparative data with other target therapies are lacking, leaving physicians without clear indications about the appropriate positioning of ustekinumab in the therapeutic pipeline for UC. This review examines the basis of targeting IL12-23 in UC therapy and summarizes the data from both clinical trials and real-life studies, to highlight the main evidence already available and the research gaps that need to be filled for the optimal usage of ustekinumab in UC.
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Affiliation(s)
- Daniela Pugliese
- CEMAD, IBD CENTER, Unità Operativa Complessa di
Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e
Chirurgiche, Fondazione Policlinico Universitario ‘A. Gemelli’ IRCCS, Rome,
Italy
| | - Giuseppe Privitera
- Dipartimento Universitario di Medicina e
Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome,
Italy
| | - Marcello Fiorani
- Dipartimento Universitario di Medicina e
Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome,
Italy
| | - Laura Parisio
- CEMAD, IBD CENTER, Unità Operativa Complessa di
Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e
Chirurgiche, Fondazione Policlinico Universitario ‘A. Gemelli’ IRCCS, Rome,
Italy
| | - Valentin Calvez
- Dipartimento Universitario di Medicina e
Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome,
Italy
| | - Alfredo Papa
- CEMAD, IBD CENTER, Unità Operativa Complessa di
Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e
Chirurgiche, Fondazione Policlinico Universitario ‘A. Gemelli’ IRCCS, Rome,
Italy,Dipartimento Universitario di Medicina e
Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome,
Italy
| | - Antonio Gasbarrini
- CEMAD, IBD CENTER, Unità Operativa Complessa di
Medicina Interna e Gastroenterologia, Dipartimento di Scienze Mediche e
Chirurgiche, Fondazione Policlinico Universitario ‘A. Gemelli’ IRCCS, Rome,
Italy,Dipartimento Universitario di Medicina e
Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome,
Italy
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23
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Gergely M, Deepak P. Tools for the Diagnosis and Management of Crohn's Disease. Gastroenterol Clin North Am 2022; 51:213-239. [PMID: 35595412 DOI: 10.1016/j.gtc.2021.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/21/2023]
Abstract
Numerous tools have emerged over recent decades to aid in the increasingly complex management of patients with Crohn's disease (CD) beyond endoscopy, including video capsule endoscopy, magnetic resonance enterography, computed tomography enterography, a variety of biomarkers, and even wearable biosensors and smartphone applications. These tools have allowed for a more sophisticated and less invasive complementary approach to the evaluation of disease activity and treatment response in patients with CD. This article details the characteristics, practical application, and limitations of these various modalities and discusses how updated guidelines are now incorporating many of them into a treat-to-target strategy.
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Affiliation(s)
- Maté Gergely
- Division of Gastroenterology, Inflammatory Bowel Diseases Center, Washington University School of Medicine, 600 South Euclid Avenue, Campus Box 8124, Saint Louis, MO 63110, USA
| | - Parakkal Deepak
- Division of Gastroenterology, Inflammatory Bowel Diseases Center, Washington University School of Medicine, 600 South Euclid Avenue, Campus Box 8124, Saint Louis, MO 63110, USA.
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24
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Han F, Zhao X, Li X, Peng L, Liu W, Han J. Bovine lactoferricin ameliorates intestinal inflammation and mucosal barrier lesions in colitis through NF-κB/NLRP3 signaling pathways. J Funct Foods 2022. [DOI: 10.1016/j.jff.2022.105090] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
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25
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Plevris N, Lees CW. Disease Monitoring in Inflammatory Bowel Disease: Evolving Principles and Possibilities. Gastroenterology 2022; 162:1456-1475.e1. [PMID: 35101422 DOI: 10.1053/j.gastro.2022.01.024] [Citation(s) in RCA: 79] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 01/07/2022] [Accepted: 01/18/2022] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease is a progressive and debilitating condition. Early and effective treatment using a treat-to-target approach is key to improving patient outcomes. Therefore, proactive monitoring is essential to ensure that treatment strategies are working and targets are being met. In this review we discuss the current monitoring tools available to us and how they can be used. We also discuss the importance of monitoring during key phases of the disease and propose an optimum treat-to-target monitoring strategy for Crohn's disease and ulcerative colitis. Regarding the advent of new technology, we discuss how this may improve our monitoring capabilities and how we envisage future monitoring strategies of inflammatory bowel diseases.
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Affiliation(s)
- Nikolas Plevris
- The Edinburgh IBD Unit, Western General Hospital, Edinburgh, Scotland, United Kingdom; Centre for Genomics and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital Campus, Edinburgh, Scotland, United Kingdom
| | - Charlie W Lees
- The Edinburgh IBD Unit, Western General Hospital, Edinburgh, Scotland, United Kingdom; Centre for Genomics and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital Campus, Edinburgh, Scotland, United Kingdom.
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Ustekinumab concentrations shortly after escalation to monthly dosing may identify endoscopic remission in refractory Crohn's disease. Eur J Gastroenterol Hepatol 2021; 33:e831-e836. [PMID: 34402470 DOI: 10.1097/meg.0000000000002275] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Some patients with Crohn's disease do not achieve remission with the approved maintenance dosing of ustekinumab every 8 weeks, possibly due to insufficient drug exposure. We aimed to study the exposure-response relationship for endoscopic remission and biomarker normalization with ustekinumab dose escalation to every 4 weeks. METHODS Out of 135 consecutive patients, 44 with active Crohn's disease despite standard maintenance dosing [at least one of C-reactive protein (CRP) >5 mg/L, fecal calprotectin >100 mg/kg, simple endoscopic score (SES) for Crohn's disease >3] underwent dose escalation to every 4 weeks. Subsequent endoscopic remission (SES-CD ≤3 without ulceration) and biomarker normalization were compared against ustekinumab concentrations. RESULTS Dose escalation led to endoscopic remission in 28.6% (8/28), CRP normalization 29.2% (7/24) and fecal calprotectin normalization 51.7% (15/29) of patients. Ustekinumab concentrations after escalation were higher in patients with endoscopic remission (6.90 vs. 4.29 mg/L; P = 0.025) and fecal calprotectin normalization (6.65 vs. 3.74 mg/L; P = 0.001). A threshold of 6.00 mg/L identified endoscopic remission [area under the receiver operating curve (AUROC): 0.775; 95% confidence interval (CI), 0.551-0.999), a threshold of 4.40 mg/L (AUROC 0.755; 95% CI, 0.545-0.964) two months after escalation identified patients with fecal calprotectin normalization at the end of follow-up. Concentrations <3.5 mg/L after escalation precluded endoscopic remission or biomarker normalization. CONCLUSION Endoscopic remission was associated with higher ustekinumab concentrations after dose escalation. Patients with concentrations <3.5 mg/L after dose escalation are unlikely to achieve endoscopic remission or biomarker normalization.
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Aguiar Zdovc J, Hanžel J, Kurent T, Sever N, Koželj M, Smrekar N, Novak G, Štabuc B, Dreesen E, Thomas D, Vovk T, Ostanek B, Drobne D, Grabnar I. Ustekinumab Dosing Individualization in Crohn's Disease Guided by a Population Pharmacokinetic-Pharmacodynamic Model. Pharmaceutics 2021; 13:pharmaceutics13101587. [PMID: 34683880 PMCID: PMC8538292 DOI: 10.3390/pharmaceutics13101587] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 09/23/2021] [Accepted: 09/24/2021] [Indexed: 12/22/2022] Open
Abstract
Ustekinumab is a monoclonal antibody used in Crohn’s disease (CD). Dose optimization in case of non-response and the role of pharmacokinetic–pharmacodynamic (PK-PD) monitoring remain unresolved dilemmas in clinical practice. We aimed to develop a population PK-PD model for ustekinumab in CD and simulate efficacy of alternative dosing regimens. We included 57 patients and recorded their characteristics during 32 weeks after starting with ustekinumab therapy. Serum ustekinumab concentration was prospectively measured and fecal calprotectin (FC) concentration was used to monitor the disease activity. Ustekinumab PK-PD was described by a two-compartment target-mediated drug disposition model linked to an indirect response model. Lower fat-free mass, higher serum albumin, previous non-exposure to biologics, FCGR3A-158 V/V variant and lower C-reactive protein were associated with higher ustekinumab exposure. Model-based simulation suggested that 41.9% of patients receiving standard dosing achieve biochemical remission at week 32. In patients not achieving remission with standard dosing at week 16, transition to 4-weekly subcutaneous maintenance dosing with or without intravenous reinduction resulted in comparably higher remission rates at week 32 (51.1% vs. 49.2%, respectively). Our findings could be used to guide stratified ustekinumab treatment in CD, particularly in patients with unfavorable characteristics, who might benefit from early transition to 4-weekly maintenance dosing.
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Affiliation(s)
- Jurij Aguiar Zdovc
- Department of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia; (J.A.Z.); (T.V.)
| | - Jurij Hanžel
- Department of Gastroenterology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (J.H.); (T.K.); (N.S.); (M.K.); (N.S.); (G.N.); (B.Š.); (D.D.)
- Department of Internal Medicine, Medical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Tina Kurent
- Department of Gastroenterology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (J.H.); (T.K.); (N.S.); (M.K.); (N.S.); (G.N.); (B.Š.); (D.D.)
| | - Nejc Sever
- Department of Gastroenterology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (J.H.); (T.K.); (N.S.); (M.K.); (N.S.); (G.N.); (B.Š.); (D.D.)
| | - Matic Koželj
- Department of Gastroenterology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (J.H.); (T.K.); (N.S.); (M.K.); (N.S.); (G.N.); (B.Š.); (D.D.)
| | - Nataša Smrekar
- Department of Gastroenterology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (J.H.); (T.K.); (N.S.); (M.K.); (N.S.); (G.N.); (B.Š.); (D.D.)
| | - Gregor Novak
- Department of Gastroenterology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (J.H.); (T.K.); (N.S.); (M.K.); (N.S.); (G.N.); (B.Š.); (D.D.)
| | - Borut Štabuc
- Department of Gastroenterology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (J.H.); (T.K.); (N.S.); (M.K.); (N.S.); (G.N.); (B.Š.); (D.D.)
- Department of Internal Medicine, Medical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Erwin Dreesen
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium; (E.D.); (D.T.)
- Department of Pharmacy, Uppsala University, 751 23 Uppsala, Sweden
| | - Debby Thomas
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, 3000 Leuven, Belgium; (E.D.); (D.T.)
| | - Tomaž Vovk
- Department of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia; (J.A.Z.); (T.V.)
| | - Barbara Ostanek
- Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia;
| | - David Drobne
- Department of Gastroenterology, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia; (J.H.); (T.K.); (N.S.); (M.K.); (N.S.); (G.N.); (B.Š.); (D.D.)
- Department of Internal Medicine, Medical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia
| | - Iztok Grabnar
- Department of Biopharmaceutics and Pharmacokinetics, Faculty of Pharmacy, University of Ljubljana, 1000 Ljubljana, Slovenia; (J.A.Z.); (T.V.)
- Correspondence: ; Tel.: +386-1-4769-543
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Ueno N, Sugiyama Y, Kobayashi Y, Murakami Y, Iwama T, Sasaki T, Kunogi T, Takahashi K, Tanaka K, Ando K, Kashima S, Inaba Y, Moriichi K, Tanabe H, Taruishi M, Saitoh Y, Okumura T, Fujiya M. Fecal calprotectin is a useful biomarker for predicting the clinical outcome of granulocyte and monocyte adsorptive apheresis in ulcerative colitis patients: a prospective observation study. BMC Gastroenterol 2021; 21:316. [PMID: 34362299 PMCID: PMC8348877 DOI: 10.1186/s12876-021-01889-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 06/17/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Granulocyte and monocyte adsorptive apheresis (GMA) is widely used as a remission induction therapy for active ulcerative colitis (UC) patients. However, there are no available biomarkers for predicting the clinical outcome of GMA. We investigated the utility of Fecal calprotectin (FC) as a biomarker for predicting the clinical outcome during GMA therapy in active UC patients. METHODS In this multicenter prospective observation study, all patients received 10 sessions of GMA, twice a week, for 5 consecutive weeks. FC was measured at entry, one week, two weeks, and at the end of GMA. Colonoscopy was performed at entry and after GMA. The clinical activity was assessed based on the partial Mayo score when FC was measured. Clinical remission (CR) was defined as a partial Mayo score of ≤ 2 and endoscopic remission (ER) was defined as Mayo endoscopic subscore of either 0 or 1. We analyzed the relationships between the clinical outcome (CR and ER) and the change in FC concentration. RESULT Twenty-six patients were included in this study. The overall CR and ER rates were 50.0% and 19.2%, respectively. After GMA, the median FC concentration in patients with ER was significantly lower than that in patients without ER (469 mg/kg vs. 3107 mg/kg, p = 0.03). When the cut-off value of FC concentration was set at 1150 mg/kg for assessing ER after GMA, the sensitivity and specificity were 0.8 and 0.81, respectively. The FC concentration had significantly decreased by one week. An ROC analysis demonstrated that the reduction rate of FC (ΔFC) at 1 week was the most accurate predictor of CR at the end of GMA (AUC = 0.852, P = 0.002). When the cut-off value of ΔFC was set at ≤ 40% at 1 week for predicting CR at the end of GMA, the sensitivity and specificity were 76.9% and 84.6%, respectively. CONCLUSION We evaluated the utility of FC as a biomarker for assessing ER after GMA and predicting CR in the early phase during GMA in patients with active UC. Our findings will benefit patients with active UC by allowing them to avoid unnecessary invasive procedures and will help establish new strategies for GMA.
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Affiliation(s)
- Nobuhiro Ueno
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, Hokkaido, 078-8510, Japan.
| | - Yuya Sugiyama
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, Hokkaido, 078-8510, Japan
| | - Yu Kobayashi
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, Hokkaido, 078-8510, Japan
| | - Yuki Murakami
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, Hokkaido, 078-8510, Japan
| | - Takuya Iwama
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, Hokkaido, 078-8510, Japan
| | - Takahiro Sasaki
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, Hokkaido, 078-8510, Japan
| | - Takehito Kunogi
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, Hokkaido, 078-8510, Japan
| | - Keitaro Takahashi
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, Hokkaido, 078-8510, Japan
| | - Kazuyuki Tanaka
- Asahikawa Kosei General Hospital, Asahikawa, Hokkaido, Japan
| | - Katsuyoshi Ando
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, Hokkaido, 078-8510, Japan
| | - Shin Kashima
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, Hokkaido, 078-8510, Japan
| | - Yuhei Inaba
- Asahikawa City Hospital, Asahikawa, Hokkaido, Japan
| | - Kentaro Moriichi
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, Hokkaido, 078-8510, Japan
| | - Hiroki Tanabe
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, Hokkaido, 078-8510, Japan
| | | | | | - Toshikatsu Okumura
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, Hokkaido, 078-8510, Japan
| | - Mikihiro Fujiya
- Division of Metabolism and Biosystemic Science, Gastroenterology, and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Midorigaoka-Higashi 2-1-1-1, Asahikawa, Hokkaido, 078-8510, Japan
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Fecal Calprotectin Predicts Mucosal Healing in Patients With Ulcerative Colitis Treated With Biological Therapies: A Prospective Study. Clin Transl Gastroenterol 2021; 11:e00174. [PMID: 32677804 PMCID: PMC7263645 DOI: 10.14309/ctg.0000000000000174] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Biological therapies are widely used for the treatment of ulcerative colitis. However, only a low proportion of patients achieve clinical remission and even less mucosal healing. There is currently scarce knowledge about the early markers of therapeutic response, with particular regard to mucosal healing. The aim of this prospective study was to evaluate the role of fecal calprotectin (FC) as early predictor of mucosal healing.
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Turner D, Ricciuto A, Lewis A, D'Amico F, Dhaliwal J, Griffiths AM, Bettenworth D, Sandborn WJ, Sands BE, Reinisch W, Schölmerich J, Bemelman W, Danese S, Mary JY, Rubin D, Colombel JF, Peyrin-Biroulet L, Dotan I, Abreu MT, Dignass A. STRIDE-II: An Update on the Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) Initiative of the International Organization for the Study of IBD (IOIBD): Determining Therapeutic Goals for Treat-to-Target strategies in IBD. Gastroenterology 2021; 160:1570-1583. [PMID: 33359090 DOI: 10.1053/j.gastro.2020.12.031] [Citation(s) in RCA: 1542] [Impact Index Per Article: 385.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 10/21/2020] [Accepted: 12/15/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) initiative of the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) has proposed treatment targets in 2015 for adult patients with inflammatory bowel disease (IBD). We aimed to update the original STRIDE statements for incorporating treatment targets in both adult and pediatric IBD. METHODS Based on a systematic review of the literature and iterative surveys of 89 IOIBD members, recommendations were drafted and modified in 2 surveys and 2 voting rounds. Consensus was reached if ≥75% of participants scored the recommendation as 7 to 10 on a 10-point rating scale. RESULTS In the systematic review, 11,278 manuscripts were screened, of which 435 were included. The first IOIBD survey identified the following targets as most important: clinical response and remission, endoscopic healing, and normalization of C-reactive protein/erythrocyte sedimentation rate and calprotectin. Fifteen recommendations were identified, of which 13 were endorsed. STRIDE-II confirmed STRIDE-I long-term targets of clinical remission and endoscopic healing and added absence of disability, restoration of quality of life, and normal growth in children. Symptomatic relief and normalization of serum and fecal markers have been determined as short-term targets. Transmural healing in Crohn's disease and histological healing in ulcerative colitis are not formal targets but should be assessed as measures of the remission depth. CONCLUSIONS STRIDE-II encompasses evidence- and consensus-based recommendations for treat-to-target strategies in adults and children with IBD. This frameworkshould be adapted to individual patients and local resources to improve outcomes.
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Affiliation(s)
- Dan Turner
- Shaare Zedek Medical Center, the Hebrew University of Jerusalem, Jerusalem, Israel.
| | | | - Ayanna Lewis
- Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida
| | - Ferdinando D'Amico
- Humanitas Clinical and Research Center - IRCCS, Rozzano and Humanitas University, Department of Biomedical Sciences, Pieve Emanuele, Milan, Italy
| | - Jasbir Dhaliwal
- Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, Ohio
| | | | - Dominik Bettenworth
- Department of Medicine B for Gastroenterology and Hepatology, University Hospital Münster, Münster, Germany
| | - William J Sandborn
- Division of Gastroenterology, University of California San Diego, La Jolla, California
| | - Bruce E Sands
- Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Walter Reinisch
- Medical University of Vienna, Department of Internal Medicine III, Division Gastroenterology and Hepatology, Vienna, Austria
| | | | - Willem Bemelman
- Department of Surgery, Amsterdam UMC, University of Amsterdam, Locatie AMC, the Netherlands
| | - Silvio Danese
- Humanitas Clinical and Research Center - IRCCS, Rozzano and Humanitas University, Department of Biomedical Sciences, Pieve Emanuele, Milan, Italy
| | - Jean Yves Mary
- Inserm UMR1153 CRESS, équipe ECSTRRA, Université de Paris, Paris, France
| | - David Rubin
- Section of Gastroenterology, Hepatology and Nutrition, University of Chicago Medicine, Chicago, Illinois
| | - Jean-Frederic Colombel
- Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Laurent Peyrin-Biroulet
- Department of Gastroenterology and Inserm NGERE U1256, University Hospital of Nancy, University of Lorraine, Vandoeuvre-lès-Nancy, France
| | - Iris Dotan
- Division of Gastroenterology, Rabin Medical Center, Petah Tikva, Israel and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Maria T Abreu
- Division of Gastroenterology, Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida
| | - Axel Dignass
- Department of Medicine I, Agaplesion Markus Hospital, Goethe University, Frankfurt/Main, Germany.
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Predictors and Early Markers of Response to Biological Therapies in Inflammatory Bowel Diseases. J Clin Med 2021; 10:jcm10040853. [PMID: 33669579 PMCID: PMC7922976 DOI: 10.3390/jcm10040853] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/10/2021] [Accepted: 02/11/2021] [Indexed: 12/22/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are chronic conditions that primarily affect the gastrointestinal tract, with a complex pathogenesis; they are characterized by a significant heterogeneity of clinical presentations and of inflammatory pathways that sustain intestinal damage. After the introduction of the first biological therapies, the pipeline of therapies for IBD has been constantly expanding, and a significant number of new molecules is expected in the next few years. Evidence from clinical trials and real-life experiences has taught us that up to 40% of patients do not respond to a specific drug. Unfortunately, to date, clinicians lack a valid tool that can predict each patient’s response to therapies and that could help them in choosing what drug to administer. Several candidate biomarkers have been investigated so far, with conflicting results: clinical, genetic, immunological, pharmacokinetic and microbial markers have been tested, but no ideal marker has been identified so far. Based on recent evidence, multiparametric models seemingly hold the greatest potential for predicting response to therapy. In this narrative review, we aim to summarize the current knowledge on predictors and early markers of response to biological therapies in IBD.
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Hanžel J, Zdovc J, Kurent T, Sever N, Javornik K, Tuta K, Koželj M, Smrekar N, Novak G, Štabuc B, Dreesen E, Thomas D, Vovk T, Grabnar I, Drobne D. Peak Concentrations of Ustekinumab After Intravenous Induction Therapy Identify Patients With Crohn's Disease Likely to Achieve Endoscopic and Biochemical Remission. Clin Gastroenterol Hepatol 2021; 19:111-118.e10. [PMID: 32109630 DOI: 10.1016/j.cgh.2020.02.033] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 02/05/2020] [Accepted: 02/07/2020] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Little is known about the relationship between ustekinumab exposure during the first 2 weeks of treatment and outcomes of patients with Crohn's disease (CD). We investigated the relationship between serum concentrations of ustekinumab during the first 2 weeks of treatment and endoscopic and biochemical remission in patients with CD. METHODS In a prospective observational study, we measured concentrations of ustekinumab in serum samples from 41 consecutive patients who started treatment with ustekinumab (approximately 6 mg/kg, intravenously, then 90 mg every 8 weeks), due to endoscopic markers of active CD, at a single center from October 2017 through January 2019. We measured ustekinumab exposure parameters during the first 2 weeks (peak concentration measured immediately after intravenous infusion, week 2 concentration, and area under the curve through week 2). We investigated the correlation between these parameters and endoscopic remission (simple endoscopic score for CD scores of 3 or less without ulceration, assessed centrally) and biochemical remission (level of fecal calprotectin below 100 mg/kg) using the Mann-Whitney U test. RESULTS Endoscopic remission was achieved in 10 patients (24.4%) at week 24; biochemical remission was achieved in 17 patients (41.5%) at week 8, 17 patients (41.5%) at week 16, and 21 patients (51.2%) at week 24. Peak concentrations associated with endoscopic remission (area under the receiver operating characteristic curve, 0.717; 95% CI, 0.517-0.916); 6 of 13 patients (46%) with peak concentrations above 105 μg/mL (upper tercile) achieved endoscopic remission, compared with only 1 of 14 patients (7%) with peak concentrations below 88 μg/mL (lower tercile). All exposure parameters during the first 2 weeks were associated with biochemical remission. There was no significant difference between the associations of peak concentrations, week-2 concentrations, area under the curve through week 2, or later exposure measures (at weeks 4 and 8) with biochemical or endoscopic remission. CONCLUSIONS In a prospective study, we found that serum concentrations of ustekinumab as early as 1 hour after intravenous infusion might be used to identify patients with CD most likely to achieve endoscopic remission. This early measurement might be used to optimize treatment of CD.
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Affiliation(s)
- Jurij Hanžel
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia; Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Jurij Zdovc
- Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | - Tina Kurent
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Nejc Sever
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | | | - Katja Tuta
- Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Matic Koželj
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Nataša Smrekar
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Gregor Novak
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Borut Štabuc
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia; Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Erwin Dreesen
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | - Debby Thomas
- Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium
| | - Tomaž Vovk
- Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | - Iztok Grabnar
- Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia
| | - David Drobne
- Department of Gastroenterology, University Medical Centre Ljubljana, Ljubljana, Slovenia; Medical Faculty, University of Ljubljana, Ljubljana, Slovenia.
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A Machine Learning Model Accurately Predicts Ulcerative Colitis Activity at One Year in Patients Treated with Anti-Tumour Necrosis Factor α Agents. ACTA ACUST UNITED AC 2020; 56:medicina56110628. [PMID: 33233514 PMCID: PMC7699478 DOI: 10.3390/medicina56110628] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 11/17/2020] [Accepted: 11/18/2020] [Indexed: 02/06/2023]
Abstract
Background and objectives: The biological treatment is a promising therapeutic option for ulcerative colitis (UC) patients, being able to induce subclinical and long-term remission. However, the relatively high costs and the potential toxicity have led to intense debates over the most appropriate criteria for starting, stopping, and managing biologics in UC. Our aim was to build a machine learning (ML) model for predicting disease activity at one year in UC patients treated with anti-Tumour necrosis factor α agents as a useful tool to assist the clinician in the therapeutic decisions. Materials and Methods: Clinical and biological parameters and the endoscopic Mayo score were collected from 55 UC patients at the baseline and one year follow-up. A neural network model was built using the baseline endoscopic activity and four selected variables as inputs to predict whether a UC patient will have an active or inactive endoscopic disease at one year, under the same therapeutic regimen. Results: The classifier achieved an excellent performance predicting the disease activity at one year with an accuracy of 90% and area under curve (AUC) of 0.92 on the test set and an accuracy of 100% and an AUC of 1 on the validation set. Conclusions: Our proposed ML solution may prove to be a useful tool in assisting the clinicians’ decisions to increase the dose or switch to other biologic agents after the model’s validation on independent, external cohorts of patients.
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Papa A, Papa V, Lopetuso LR, Gasbarrini A, Tursi A. Covid-19 and the management of patients with inflammatory bowel disease: a practical decalogue for the post-pandemic phase. Therap Adv Gastroenterol 2020; 13:1756284820968747. [PMID: 33149764 PMCID: PMC7586260 DOI: 10.1177/1756284820968747] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 10/01/2020] [Indexed: 02/04/2023] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has raised several concerns for patients with chronic immune-mediated diseases, including inflammatory bowel disease (IBD). As the outbreak appears to be in the descending phase, at least in some part of the world, as in most European countries, guidance is urgently needed to provide optimal care for our IBD patients in order to gradually and safely reduce the gap in care that has been accumulated in the months of lockdown and to face all the backlogs. Therefore, we have provided a decalogue of practical recommendations for gastroenterologists to manage patients with IBD in the post-peak phase of the COVID-19 pandemic. They include all the aspects of IBD care, not only pharmacological ones but also endoscopy, surgery, psychological treatment, telemedicine, diagnostics and educational tasks provided by doctors and patient associations.
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Affiliation(s)
| | - Valerio Papa
- Catholic University, Rome, Italy,Department of Digestive Surgery, Policlinico Universitario “A. Gemelli” IRCCS Foundation, Rome, Italy
| | - Loris Riccardo Lopetuso
- Department of Medical and Surgical Sciences, Division of Internal Medicine and Gastroenterology, Policlinico Universitario “A. Gemelli” IRCCS Foundation, Rome, Italy,Department of Medicine and Ageing Sciences, “G. d’Annunzio” University of Chieti-Pescara, Chieti, Italy,Center for Advanced Studies and Technology (CAST), “G. d’Annunzio” University of Chieti-Pescara, Chieti, Italy
| | - Antonio Gasbarrini
- Department of Medical and Surgical Sciences, Division of Internal Medicine and Gastroenterology, Policlinico Universitario “A. Gemelli” IRCCS Foundation, Rome, Italy Catholic University, Rome, Italy
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Matar M, Shamir R, Turner D, Broide E, Weiss B, Ledder O, Guz-Mark A, Rinawi F, Cohen S, Topf-Olivestone C, Shaoul R, Yerushalmi B, Ben-Horin S, Assa A. Combination Therapy of Adalimumab With an Immunomodulator Is Not More Effective Than Adalimumab Monotherapy in Children With Crohn's Disease: A Post Hoc Analysis of the PAILOT Randomized Controlled Trial. Inflamm Bowel Dis 2020; 26:1627-1635. [PMID: 31793630 DOI: 10.1093/ibd/izz294] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Indexed: 12/16/2022]
Abstract
BACKGROUND The PAILOT trial was a randomized controlled trial aimed to evaluate proactive vs reactive therapeutic drug monitoring in children with Crohn's disease (CD) treated with adalimumab. Our aim in this post hoc analysis of the PAILOT trial was to assess the efficacy and safety of adalimumab combination treatment in comparison with monotherapy at week 72 after adalimumab induction. METHODS Participants were children 6-17 years old, biologic naïve, with moderate to severe CD, who responded to adalimumab induction at week 4. Patients receiving immunomodulators at baseline maintained a stable dose until week 24; patients could then discontinue immunomodulators. At each visit, patients were assessed for disease index, serum biomarkers, fecal calprotectin, adalimumab trough concentration, and anti-adalimumab antibodies. RESULTS Out of the 78 patients (29% female; mean age, 14.3 ± 2.6 years), 34 patients (44%) received combination therapy. During the study period, there was no significant difference in the rates of sustained corticosteroid-free clinical remission (25/34, 73%, vs 28/44, 63%; P = 0.35) or sustained composite outcome of clinical remission, C-reactive protein ≤0.5 mg/dL, and calprotectin ≤150 µg/g (10/34, 29%, vs 14/44, 32%; P = 0.77) between the combination group and the monotherapy group, respectively. Clinical and biological outcomes did not differ between the proactive and reactive subgroups within the combination and monotherapy groups. Adalimumab trough concentrations and immunogenicity were not significantly different between groups. The rate of serious adverse events was not significantly different between groups but was numerically higher in the monotherapy group. CONCLUSIONS Combination therapy of adalimumab and an immunomodulator was not more effective than adalimumab monotherapy in children with CD (ClinicalTrials.gov No. NCT02256462).
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Affiliation(s)
- Manar Matar
- The Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Hospital, Petach-Tikva, Israel
| | - Raanan Shamir
- The Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Hospital, Petach-Tikva, Israel.,The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Dan Turner
- The Juliet Keidan Institute of Pediatric Gastroenterology, Nutrition, Shaare Zedek Medical Center, The Hebrew University, Jerusalem, Israel
| | - Efrat Broide
- The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Pediatric Gastroenterology Unit, Shamir (Assaf Harofeh) Medical Center, Zerifin, Israel
| | - Batia Weiss
- The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Pediatric Gastroenterology Unit, Sheba Medical Center, Edmond and Lily Safra Childen's Hospital, Ramat-Gan, Tel-Hashomer, Israel
| | - Oren Ledder
- The Juliet Keidan Institute of Pediatric Gastroenterology, Nutrition, Shaare Zedek Medical Center, The Hebrew University, Jerusalem, Israel
| | - Anat Guz-Mark
- The Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Hospital, Petach-Tikva, Israel.,The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Firas Rinawi
- The Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Hospital, Petach-Tikva, Israel.,The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Shlomi Cohen
- The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Pediatric Gastroenterology Unit, "Dana-Dwek" Children's Hospital, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel
| | | | - Ron Shaoul
- Pediatric Gastroenterology Unit, Rambam Medical Center, Haifa, Israel
| | - Baruch Yerushalmi
- Pediatric Gastroenterology Unit, Saban Pediatric Medical Center, Soroka University Hospital and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Shomron Ben-Horin
- The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Department of Gastroenterology, Sheba Medical Center, Ramat-Gan, Tel-Hashomer, Israel
| | - Amit Assa
- The Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Hospital, Petach-Tikva, Israel.,The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Fecal calprotectin: current and future perspectives for inflammatory bowel disease treatment. Eur J Gastroenterol Hepatol 2020; 32:1091-1098. [PMID: 32282400 DOI: 10.1097/meg.0000000000001731] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Fecal calprotectin has been widely studied in inflammatory bowel disease (IBD) under clinical and therapeutic settings. It showed a good correlation with clinical, endoscopic, and histologic findings. For these reasons, fecal calprotectin is currently one of the most useful tools in IBD care, both in diagnosis and in clinical management. The development of biologic drugs allowed a deeper control of disease, which sometimes reaches histological healing; this is associated with a reduced risk of relapses and complications. The management of IBD treatment is currently carried out with a treat-to-target approach, and mucosal healing is considered at present to be the optimal therapeutic target, but the future is going through histologic remission. Fecal calprotectin is probably the best marker of mucosal healing, but it is correlated also with histologic remission: moreover, it has been recently studied as a possible therapeutic target in the CALM study. We carried out a comprehensive literature review in order to evaluate the role of fecal calprotectin at present and in the future in the management of IBD therapies.
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37
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Lie MRKL, Paulides E, van der Woude CJ. Patient sex does not affect endoscopic outcomes of biologicals in inflammatory bowel disease but is associated with adverse events. Int J Colorectal Dis 2020; 35:1489-1500. [PMID: 32592091 PMCID: PMC7340671 DOI: 10.1007/s00384-020-03663-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/10/2020] [Indexed: 02/04/2023]
Abstract
PURPOSE Biological therapies are currently the mainstay in the treatment of patients with inflammatory bowel diseases (IBD). Several factors are known to influence the efficacy and tolerability of biologicals, such as CRP levels or previous biological use. Whether patient sex affects the efficacy or tolerability is unclear but would help with better risk and benefit stratification. This systematic review assesses patient sex on the efficacy and tolerability of biological therapies in IBD patients. METHODS A systematic literature review was performed using Embase (including MEDLINE), MEDLINE OvidSP, Cochrane Central Register of Controlled Trials, Web of Science and PubMed. The primary outcome was the influence of patient sex on endoscopic outcomes in IBD patients treated with biologicals. The secondary outcome was the influence of patient sex on adverse events. Studies were included in the assessment regardless of study type or setting. RESULTS The search yielded 19,461 citations; after review, 55 studies were included in the study, involving 28,465 patients treated with adalimumab, certolizumab pegol, infliximab, or vedolizumab. There was no significant association between patient sex and endoscopic efficacy in 41 relevant studies. Increased adverse events were associated with female sex in 7 out of 14 relevant studies. CONCLUSIONS There is no evidence for a sex difference in endoscopically measured response to biological therapies in IBD patients. However, there is an influence of sex on the occurrence of adverse events.
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Affiliation(s)
- Mitchell R. K. L. Lie
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands
| | - Emma Paulides
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands
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Li Y, Khamou M, Schaarschmidt BM, Umutlu L, Forsting M, Demircioglu A, Haubold J, Koch AK, Bruckmann NM, Sawicki LM, Herrmann K, Boone JH, Langhorst J. Comparison of 18F-FDG PET-MR and fecal biomarkers in the assessment of disease activity in patients with ulcerative colitis. Br J Radiol 2020; 93:20200167. [PMID: 32579403 DOI: 10.1259/bjr.20200167] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
OBJECTIVE To compare the diagnostic performance of fecal biomarkers and 18F-fludeoxyglucose (18F-FDG) positron emmision tomography-MR (PET-MR) in the assessment of disease activity in patients with ulcerative colitis. METHODS This study was conducted under the framework of a single-center clinical trial (clinicaltrials.gov [NCT03781284]). N = 50 participants were enrolled. Fecal samples were collected before bowel preparation. All patients underwent whole-body 18F-FDG PET-MR followed by ileocolonoscopy within 24 h. Diagnostic performance of five fecal biomarkers (calprotectin, lactoferrin, polymorphonuclear leukocyte elastase, S100A12 and eosinophil-derived neurotoxin), MR morphological parameters (MRmorph), diffusion-weighted imaging and PET in detecting active disease determined by Rachmilewitz endoscopic activity index (EAI) were evaluated and compared with each other. Correlations between fecal biomarkers, PET and endoscopy were calculated. RESULTS According to EAI, n = 38 patients presented with endoscopically active disease (16 mild, 19 moderate and 3 severe). All five biomarkers, PET and MRmorph could differentiate endoscopically active disease from endoscopic remission without significant difference regarding their operating characteristics (accuracies between 0.673 for calprotectin and 0.898 for lactoferrin). In predicting endoscopically moderate to severe disease, PET showed the highest diagnostic performance (accuracy = 0.857) compared to calprotectin and lactoferrin (accuracy = 0.633 and 0.735). PET had also the strongest correlation with endoscopy (ρ = 0.685, p < 0.001), while within fecal biomarkers the levels of lactoferrin and eosinophil-derived neurotoxin correlated significantly with EAI (ρ = 0.423 and 0.528, both p < 0.05). CONCLUSION Both fecal biomarkers and PET-MR were excellent non-invasive diagnostic tools in the assessment of disease activity in ulcerative colitis. ADVANCES IN KNOWLEDGE Both fecal biomarkers and PET-MR parameters are able to predict endoscopically active disease with comparable diagnostic performance. PET had the highest correlation with endoscopy and outperformed fecal biomarkers in differentiating moderate to severe from mild disease.
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Affiliation(s)
- Yan Li
- Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany
| | - Michael Khamou
- Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany
| | - Benedikt Michael Schaarschmidt
- Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany
| | - Lale Umutlu
- Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany
| | - Michael Forsting
- Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany
| | - Aydin Demircioglu
- Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany
| | - Johannes Haubold
- Department of Diagnostic and Interventional Radiology and Neuroradiology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany
| | - Anna Katharina Koch
- Department of Internal and Integrative Medicine, Kliniken Essen-Mitte, University of Duisburg-Essen, Am Deimelsberg 34a, 45276 Essen, Germany
| | - Nils-Martin Bruckmann
- Department of Diagnostic and Interventional Radiology, University Hospital Dusseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
| | - Lino Morris Sawicki
- Department of Diagnostic and Interventional Radiology, University Hospital Dusseldorf, Moorenstraße 5, 40225, Düsseldorf, Germany
| | - Ken Herrmann
- Department of Nuclear Medicine, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany
| | - James Hunter Boone
- Research and Development, TechLab, INC., 2001 Kraft Drive, Blacksburg, USA
| | - Jost Langhorst
- Department of Internal and Integrative Medicine, Kliniken Essen-Mitte, University of Duisburg-Essen, Am Deimelsberg 34a, 45276 Essen, Germany.,Department for Internal and Integrative Medicine, Social Foundation Bamberg, Clinic Bamberg, Buger Straße 80, 96049 Bamberg, Germany.,Chair for Integrative Medicine, University of Duisburg-Essen, Am Deimelsberg 34a, 45276 Essen, Germany
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Barberio B, Zingone F, Frazzoni L, D'Incà R, Maccarone MC, Ghisa M, Massimi D, Lorenzon G, Savarino EV. Real-Life Comparison of Different Anti-TNF Biologic Therapies for Ulcerative Colitis Treatment: A Retrospective Cohort Study. Dig Dis 2020; 39:16-24. [PMID: 32450562 DOI: 10.1159/000508865] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 05/21/2020] [Indexed: 02/02/2023]
Abstract
BACKGROUND Head-to-head comparison studies evaluating the effectiveness and tolerability of anti-tumor necrosis factor (anti-TNF) drugs in inflammatory bowel disease patients are lacking. AIM To compare the effectiveness and tolerability of anti-TNF-α drugs used in clinical practice in a cohort of patients with moderate-to-severe ulcerative colitis (UC). METHODS Retrospectively, 122 UC patients treated with infliximab (IFX) originator and biosimilar, adalimumab (ADA), and golimumab (GOL) were included. We performed an ITT analysis to evaluate clinical response and remission, steroid-free clinical remission, and endoscopy response according to the different time points of the follow-up. Baseline and post induction predictor factors of these outcomes were evaluated using multivariate logistic regression models. Moreover, a propensity score-based weighting analysis was performed. Data were analyzed using R and STATA11 software. RESULTS The overall clinical response was 77% after induction, 81.4% at 30 weeks, and 76.9% at 52 weeks, while the steroid-free clinical remission was 39.7, 46, and 54.6%, respectively. After induction, a higher rate of treatment failure was observed in the GOL group. At the end of follow-up, lower rates of steroid-free clinical remission and clinical response were obtained by GOL. At week 52, endoscopic response was achieved by 46.5% of the population. CONCLUSIONS Among the different anti-TNF treatments, moderate-to-severe UC seems to respond better to IFX and ADA, whereas GOL seems to be less effective, despite a similar good safety profile.
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Affiliation(s)
- Brigida Barberio
- Division of Gastroenterology, Department of Surgery, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, Padua, Italy
| | - Fabiana Zingone
- Division of Gastroenterology, Department of Surgery, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, Padua, Italy,
| | - Leonardo Frazzoni
- Department of Medical and Surgical Sciences DIMEC, University of Bologna, Bologna, Italy
| | - Renata D'Incà
- Division of Gastroenterology, Department of Surgery, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, Padua, Italy
| | - Maria Chiara Maccarone
- Division of Gastroenterology, Department of Surgery, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, Padua, Italy
| | - Matteo Ghisa
- Division of Gastroenterology, Department of Surgery, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, Padua, Italy
| | - Davide Massimi
- Division of Gastroenterology, Department of Surgery, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, Padua, Italy
| | - Greta Lorenzon
- Division of Gastroenterology, Department of Surgery, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, Padua, Italy
| | - Edoardo Vincenzo Savarino
- Division of Gastroenterology, Department of Surgery, Oncological and Gastroenterological Sciences (DISCOG), University of Padua, Padua, Italy
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40
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Mateos B, Sáez-González E, Moret I, Hervás D, Iborra M, Cerrillo E, Tortosa L, Nos P, Beltrán B. Plasma Oncostatin M, TNF-α, IL-7, and IL-13 Network Predicts Crohn's Disease Response to Infliximab, as Assessed by Calprotectin Log Drop. Dig Dis 2020; 39:1-9. [PMID: 32325460 DOI: 10.1159/000508069] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 04/22/2020] [Indexed: 02/02/2023]
Abstract
BACKGROUND Cytokines emerge as possible biomarkers of response in Crohn's disease (CD). We aimed to determine the plasmatic cytokine profiles of active CD patients who started infliximab (IFX) treatment and their capacity to predict the response to IFX. METHODS A total of 30 active CD patients receiving an induction therapy of IFX were enrolled in the study. Peripheral blood samples pretreatment were collected. Concentrations of 15 cytokines were measured by Luminex technology. Responses to IFX were evaluated by the drop in fecal calprotectin based on its logarithm-transformed values. A random forest (RF) predictive model was used for data analyses. RESULTS Samples of 22 patients were analyzed. The RF model ranked the following cytokines as the top predictors of the response: tumor necrosis factor alpha (TNFα), interleukin (IL)-13, oncostatin M (OSM), and IL-7 (p < 0.005). Partial dependency plots showed that high levels of IL-13 pretreatment, low TNFα levels, and low IL-7 levels were associated with a favorable IFX response. Increased levels of OSM and TNFα predicted unfavorable responses to IFX. CONCLUSIONS We here show that a log drop in calprotectin strongly correlates with clinical parameters and it can be proposed as a useful objective clinical response predictor. Plasma TNFα, IL-13, Il-7, and OSM network could predict CD response to IFX before induction therapy, as assessed by calprotectin log drop.
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Affiliation(s)
- Beatriz Mateos
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Esteban Sáez-González
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain.,Inflammatory Bowel Disease Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain
| | - Inés Moret
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain.,Inflammatory Bowel Disease Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - David Hervás
- Biostatictics Unit, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain
| | - Marisa Iborra
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain.,Inflammatory Bowel Disease Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Elena Cerrillo
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain.,Inflammatory Bowel Disease Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain
| | - Luis Tortosa
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain.,Inflammatory Bowel Disease Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Pilar Nos
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain.,Inflammatory Bowel Disease Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Belén Beltrán
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain, .,Inflammatory Bowel Disease Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain, .,Centro de Investigación Biomédica en Red de Enfermedades hepáticas y Digestivas (CIBEREHD), Madrid, Spain,
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41
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Bertani L, Baglietto L, Antonioli L, Fornai M, Tapete G, Albano E, Ceccarelli L, Mumolo MG, Pellegrini C, Lucenteforte E, de Bortoli N, Bellini M, Marchi S, Blandizzi C, Costa F. Assessment of serum cytokines predicts clinical and endoscopic outcomes to vedolizumab in ulcerative colitis patients. Br J Clin Pharmacol 2020; 86:1296-1305. [PMID: 32027388 DOI: 10.1111/bcp.14235] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Revised: 11/26/2019] [Accepted: 12/01/2019] [Indexed: 12/13/2022] Open
Abstract
AIMS Vedolizumab (VDZ) prevents migration of activated leucocytes into inflamed mucosa. This study aimed to assess the patterns of serum cytokines in ulcerative colitis (UC) patients at baseline and during VDZ treatment, and to investigate their association with mucosal healing and clinical remission. METHODS We enrolled consecutive UC patients eligible for treatment with VDZ. A panel of serum cytokines were measured by fluorescence assay at weeks 0, 6 and 22. Colonoscopy was performed at baseline and week 54, to evaluate mucosal healing. The time trends of serum cytokines were analysed by log-linear mixed effect models, and their prognostic accuracy was evaluated by logistic regression. RESULTS Out of 27 patients included in the analysis, at week 54 mucosal healing was achieved in 12 (44%) and clinical remission in 17 (63%). Mucosal healing was associated with higher interleukin (IL)-8 values at baseline and with significant decrease in IL-6 and IL-8 levels over the first 6 weeks. A significant reduction of IL-6 and IL-8 levels over the first 6 weeks of treatment was associated also with clinical remission. Logistic models including, among the predictors, IL-6 and IL-8 at baseline and their changes over the first 6 weeks of treatment had 83% sensitivity and 87% specificity to predict mucosal healing, and 82% sensitivity and 90% specificity to predict clinical remission. CONCLUSION In UC patients, the serum patterns of IL-6 and IL-8 at baseline and over the first 6 weeks of treatment with VDZ could be useful to predict therapeutic outcome.
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Affiliation(s)
- Lorenzo Bertani
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.,Department of General Surgery and Gastroenterology, IBD Unit, Pisa University Hospital, Pisa, Italy
| | - Laura Baglietto
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Luca Antonioli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Matteo Fornai
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Gherardo Tapete
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Eleonora Albano
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Linda Ceccarelli
- Department of General Surgery and Gastroenterology, IBD Unit, Pisa University Hospital, Pisa, Italy
| | - Maria Gloria Mumolo
- Department of General Surgery and Gastroenterology, IBD Unit, Pisa University Hospital, Pisa, Italy
| | | | - Ersilia Lucenteforte
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Nicola de Bortoli
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Massimo Bellini
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Santino Marchi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Corrado Blandizzi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Francesco Costa
- Department of General Surgery and Gastroenterology, IBD Unit, Pisa University Hospital, Pisa, Italy
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Cornish JS, Wirthgen E, Däbritz J. Biomarkers Predictive of Response to Thiopurine Therapy in Inflammatory Bowel Disease. Front Med (Lausanne) 2020; 7:8. [PMID: 32064265 PMCID: PMC7000528 DOI: 10.3389/fmed.2020.00008] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Accepted: 01/10/2020] [Indexed: 12/15/2022] Open
Abstract
The complex nature of inflammatory bowel disease (IBD) often results in treatment failure for many patients. With some patients cycling through multiple therapies before achieving a sustained period of remission, the ability to predict a patient's response to therapeutics could decrease the time from active disease to clinical remission and mucosal healing. The prospect of such individualized treatment of IBD would be aided by accurate biomarkers, both fecal and serological, which have to date shown value as indicators of IBD activity. Here we review the utility of generic biomarkers for inflammation or mucosal healing, such as calprotectin, C-reactive protein (CRP), and fecal hemoglobin (fHb) as predictors of response to treatment of IBD. We further provide a deeper insight into the utility of monitoring the thiopurine treatment by thiopurine metabolites or alternative hematologic parameters. In light of multiple recent publications of biomarkers and biological therapy, our focus in this review is predicting response to thiopurine treatment only, that is, Azathioprine and 6-Mercaptopurine.
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Affiliation(s)
- Jack S Cornish
- University Hospital Geelong, Barwon Health, Geelong, VIC, Australia
| | - Elisa Wirthgen
- Department of Pediatrics, Rostock University Medical Center, Rostock, Germany
| | - Jan Däbritz
- Department of Pediatrics, Rostock University Medical Center, Rostock, Germany.,Center for Immunobiology, The Barts and the London School of Medicine and Dentistry, Blizard Institute, Barts Cancer Institute, Queen Mary University, London, United Kingdom
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Assa A, Matar M, Turner D, Broide E, Weiss B, Ledder O, Guz-Mark A, Rinawi F, Cohen S, Topf-Olivestone C, Shaoul R, Yerushalmi B, Shamir R. Proactive Monitoring of Adalimumab Trough Concentration Associated With Increased Clinical Remission in Children With Crohn's Disease Compared With Reactive Monitoring. Gastroenterology 2019; 157:985-996.e2. [PMID: 31194979 DOI: 10.1053/j.gastro.2019.06.003] [Citation(s) in RCA: 195] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 06/02/2019] [Accepted: 06/05/2019] [Indexed: 01/07/2023]
Abstract
BACKGROUND & AIMS Proactive monitoring of drug trough concentrations and antibodies against drugs might help determine whether patients are likely to respond to treatment and increase efficacy. We investigated whether proactive drug monitoring is associated with higher rates of clinical remission in pediatric patients with Crohn's disease (CD). METHODS We performed a nonblinded, randomized controlled trial of 78 children with CD (6-18 years old; 29% female; mean age, 14.3 ± 2.6 years) who had not received prior treatment with a biologic agent but had responded to adalimumab induction therapy, under scheduled monitoring of clinical and biologic measures (based on clinical factors and levels of C-reactive protein and fecal calprotectin), at pediatric gastroenterology units in Israel from July 2015 through December 2018. The patients were randomly assigned to groups that received proactive monitoring (trough concentrations measured at weeks 4 and 8 and then every 8 weeks until week 72, n = 38) or reactive monitoring (physicians were informed of trough concentrations after loss of response, n = 40). In both groups, doses and intervals of adalimumab were adjusted to achieve trough concentrations of 5 μg/mL. The primary endpoint was sustained corticosteroid-free clinical remission at all visits (week 8 through week 72). RESULTS The primary endpoint was achieved by 31 children (82%) in the proactive group and 19 children (48%) in the reactive group (P = .002). Sixteen patients in the proactive monitoring group (42%) achieved a composite outcome of sustained corticosteroid-free remission, C-reactive protein ≤0.5 mg/dL, and level of fecal calprotectin ≤150 μg/g compared with 5 patients in the reactive monitoring group (12%) (P = .003). By week 72 of treatment, 33 patients in the proactive monitoring group had received adalimumab intensification (87%) compared with 24 patients in the reactive monitoring group (60%) (P = .001). CONCLUSIONS In a randomized controlled trial of pediatric patients with CD, we found that proactive monitoring of adalimumab trough concentrations and adjustment of doses and intervals resulted in significantly higher rates corticosteroid-free clinical remission than reactive monitoring (measuring trough concentration after loss of response). Clinicaltrials.gov no.: NCT02256462.
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Affiliation(s)
- Amit Assa
- The Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Hospital, Petach-Tikva, Israel; The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - Manar Matar
- The Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Hospital, Petach-Tikva, Israel
| | - Dan Turner
- The Juliet Keidan Institute of Pediatric Gastroenterology, Nutrition, Shaare Zedek Medical Center, The Hebrew University, Jerusalem, Israel
| | - Efrat Broide
- The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Pediatric Gastroenterology Unit, Assaf Harofeh Medical Center, Zerifin, Israel
| | - Batia Weiss
- The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Pediatric Gastroenterology Unit, Sheba Medical Center, Edmond and Lily Safra Childen's Hospital, Ramat-Gan, Tel-Hashomer, Israel
| | - Oren Ledder
- The Juliet Keidan Institute of Pediatric Gastroenterology, Nutrition, Shaare Zedek Medical Center, The Hebrew University, Jerusalem, Israel
| | - Anat Guz-Mark
- The Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Hospital, Petach-Tikva, Israel; The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Firas Rinawi
- The Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Hospital, Petach-Tikva, Israel; The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Shlomi Cohen
- The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; Pediatric Gastroenterology Unit, "Dana-Dwek" Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel
| | | | - Ron Shaoul
- Pediatric Gastroenterology Unit, Rambam Medical Center, Haifa, Israel
| | - Baruch Yerushalmi
- Pediatric Gastroenterology Unit, Soroka University Medical Center and Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | - Raanan Shamir
- The Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Hospital, Petach-Tikva, Israel; The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Engström J, Lönnkvist M, Befrits R, Ljung T, Diaz-Tartera H, Holst M, Hellström PM. Comparison of fecal calprotectin and serum C-reactive protein in early prediction of outcome to infliximab induction therapy. Scand J Gastroenterol 2019; 54:1081-1088. [PMID: 31499013 DOI: 10.1080/00365521.2019.1660402] [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] [Indexed: 02/04/2023]
Abstract
Background: Fecal calprotectin (FC) and serum C-reactive protein (CRP) are biomarkers of disease activity in Crohn's disease (CD) and ulcerative colitis (UC). We assessed FC, CRP, Harvey-Bradshaw index (HBi), partial Mayo Clinic Scoring (pMCS) and a cytokine panel during infliximab induction to predict therapy outcome. Methods: FC, CRP and clinical indices were evaluated in 123 (76 CD, 47 UC) patients before infliximab induction and after 12 weeks. Responders were monitored 48 weeks for an 'incident' (dosage increase, shortened dosage interval, surgery). Cutoff values for FC and CRP were obtained using receiver-operating characteristics (ROC). Disease progression was analyzed with Kaplan-Meier survivals, log-rank test and logistic regression for combined biomarkers. Cytokines were analyzed with Luminex multiplexing system. Results: Following infliximab, FC and CRP declined (p < .0001) along with HBi for CD and pMCS for UC. Simultaneously, IL-6 and TNF-α decreased, while IL-10 increased. Optimal FC ROC cutoff was 221 µg/g (sensitivity 66%, specificity 67%, AUC 0.71) and CRP ROC cutoff 2.1 mg/L (sensitivity 54%, specificity 60%, AUC 0.58). In CD, FC > 221 µg/g (p < .0001), but not CRP > 2.1 mg/L predicted an 'incident'. However, combined FC and CRP also predicted an 'incident' (p < .042). In UC, both FC > 221 µg/g (p < .0005) and CRP > 2.1 mg/L (p = .0334) predicted 'incident', as did combined biomarkers (p < .005). Conclusions: Clinical disease activity is reduced by treatment with infliximab. In CD, persistently high FC, but not CRP, predict a treatment 'incident', whereas in UC both high FC and high CRP predict 'incident'. Combined FC and CRP values also predict an 'incident'.
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Affiliation(s)
- Johanna Engström
- Department of Medical Sciences, Gastroenterology and Hepatology, Uppsala University , Uppsala , Sweden
| | - Maria Lönnkvist
- Department of Medical Sciences, Gastroenterology and Hepatology, Uppsala University , Uppsala , Sweden
| | - Ragnar Befrits
- Department of Medicine, Gastroenterology and Hepatology, Karolinska University Hospital Solna, Karolinska Institutet , Stockholm , Sweden
| | - Tryggve Ljung
- Department of Medical Sciences, Gastroenterology and Hepatology, Uppsala University , Uppsala , Sweden
| | - Hetzel Diaz-Tartera
- Department of Medical Sciences, Gastroenterology and Hepatology, Uppsala University , Uppsala , Sweden
| | - Mikael Holst
- Department of Women's and Children's Health, Karolinska University Hospital Solna, Karolinska Institutet , Stockholm , Sweden
| | - Per M Hellström
- Department of Medical Sciences, Gastroenterology and Hepatology, Uppsala University , Uppsala , Sweden
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45
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Ollech JE, Weisshof R, Rubin DT. PREVENTION OF INFLAMMATORY BOWEL DISEASE COMPLICATIONS AND RECURRENCE. REVISTA MÉDICA CLÍNICA LAS CONDES 2019. [DOI: 10.1016/j.rmclc.2019.08.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022] Open
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46
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Ooi CJ, Hilmi I, Banerjee R, Chuah SW, Ng SC, Wei SC, Makharia GK, Pisespongsa P, Chen MH, Ran ZH, Ye BD, Park DI, Ling KL, Ong D, Ahuja V, Goh KL, Sollano J, Lim WC, Leung WK, Ali RAR, Wu DC, Ong E, Mustaffa N, Limsrivilai J, Hisamatsu T, Yang SK, Ouyang Q, Geary R, De Silva JH, Rerknimitr R, Simadibrata M, Abdullah M, Leong RWL. Best practices on immunomodulators and biologic agents for ulcerative colitis and Crohn's disease in Asia. J Gastroenterol Hepatol 2019; 34:1296-1315. [PMID: 30848854 DOI: 10.1111/jgh.14648] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 02/05/2019] [Accepted: 03/02/2019] [Indexed: 02/05/2023]
Abstract
The Asia-Pacific Working Group on Inflammatory Bowel Disease was established in Cebu, Philippines, under the auspices of the Asia-Pacific Association of Gastroenterology with the goal of improving inflammatory bowel disease care in Asia. This consensus is carried out in collaboration with Asian Organization for Crohn's and Colitis. With biologic agents and biosimilars becoming more established, it is necessary to conduct a review on existing literature and establish a consensus on when and how to introduce biologic agents and biosimilars in conjunction with conventional treatments for ulcerative colitis and Crohn's disease in Asia. These statements also address how pharmacogenetics influences the treatments of ulcerative colitis and Crohn's disease and provides guidance on response monitoring and strategies to restore loss of response. Finally, the review includes statements on how to manage treatment alongside possible hepatitis B and tuberculosis infections, both common in Asia. These statements have been prepared and voted upon by members of inflammatory bowel disease workgroup employing the modified Delphi process. These statements do not intend to be all-encompassing, and future revisions are likely as new data continue to emerge.
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Affiliation(s)
- Choon Jin Ooi
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
- Duke-NUS Medical School, Singapore
| | - Ida Hilmi
- Faculty of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia
| | - Rupa Banerjee
- Asian Institute of Gastroenterology, New Delhi, India
| | | | - Siew Chien Ng
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
| | - Shu Chen Wei
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Govind K Makharia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | | | - Min Hu Chen
- Division of Gastroenterology, The First University Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhi Hua Ran
- Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Byong Duk Ye
- Department of Gastroenterology and IBD Center, University of Ulsan College of Medicine, Ulsan, Korea
| | - Dong Il Park
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | | | - David Ong
- Division of Gastroenterology & Hepatology, University Medicine Cluster, National University Hospital of Singapore, Singapore
| | - Vineet Ahuja
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Khean Lee Goh
- University of Malaya Specialist Centre, Kuala Lumpur, Malaysia
| | - Jose Sollano
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - Wee Chian Lim
- Department of Gastroenterology & Hepatology, Tan Tock Seng Hospital, Singapore
| | - Wai Keung Leung
- Division of Gastroenterology & Hepatology, Department of Medicine, University of Hong Kong, Hong Kong
| | | | - Deng Chyang Wu
- Department of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Evan Ong
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - Nazri Mustaffa
- Department of Internal Medicine, School of Medical Sciences, Health Campus, Universiti Sains, George Town, Malaysia
| | - Julajak Limsrivilai
- Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Tadakazu Hisamatsu
- The Third Department of Internal Medicine, Kyorin University School of Medicine, Mitaka, Japan
| | - Suk Kyun Yang
- Department of Gastroenterology, University of Ulsan College of Medicine, Ulsan, Korea
| | - Qin Ouyang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Richard Geary
- Department of Medicine, University of Otago, Christchurch, Christchurch, New Zealand
| | | | | | - Marcellus Simadibrata
- Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Depok, Indonesia
| | - Murdani Abdullah
- Division of Gastroenterology, Department of Internal Medicine, Dr Cipto Mangankusumo National Hospital, Central Jakarta, Indonesia
| | - Rupert W L Leong
- Gastroenterology and Liver Services, Concord Hospital, Sydney, New South Wales, Australia
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Ooi CJ, Hilmi I, Banerjee R, Chuah SW, Ng SC, Wei SC, Makharia GK, Pisespongsa P, Chen MH, Ran ZH, Ye BD, Park DI, Ling KL, Ong D, Ahuja V, Goh KL, Sollano J, Lim WC, Leung WK, Ali RAR, Wu DC, Ong E, Mustaffa N, Limsrivilai J, Hisamatsu T, Yang SK, Ouyang Q, Geary R, De Silva JH, Rerknimitr R, Simadibrata M, Abdullah M, Leong RWL. Best practices on immunomodulators and biologic agents for ulcerative colitis and Crohn's disease in Asia. Intest Res 2019; 17:285-310. [PMID: 31146509 PMCID: PMC6667368 DOI: 10.5217/ir.2019.00026] [Citation(s) in RCA: 65] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 04/10/2019] [Accepted: 04/15/2019] [Indexed: 02/07/2023] Open
Abstract
The Asia-Pacific Working Group on inflammatory bowel disease (IBD) was established in Cebu, Philippines, under the auspices of the Asian Pacific Association of Gastroenterology with the goal of improving IBD care in Asia. This consensus is carried out in collaboration with Asian Organization for Crohn's and Colitis. With biologic agents and biosimilars becoming more established, it is necessary to conduct a review on existing literature and establish a consensus on when and how to introduce biologic agents and biosimilars in the conjunction with conventional treatments for ulcerative colitis (UC) and Crohn's disease (CD) in Asia. These statements also address how pharmacogenetics influence the treatments of UC and CD and provide guidance on response monitoring and strategies to restore loss of response. Finally, the review includes statements on how to manage treatment alongside possible hepatitis B and tuberculosis infections, both common in Asia. These statements have been prepared and voted upon by members of IBD workgroup employing the modified Delphi process. These statements do not intend to be all-encompassing and future revisions are likely as new data continue to emerge.
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Affiliation(s)
- Choon Jin Ooi
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore
- Duke-NUS Medical School, Singapore
| | - Ida Hilmi
- Department of Medicine, Faculty of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia
| | - Rupa Banerjee
- Asian Institute of Gastroenterology, New Delhi, India
| | | | - Siew Chien Ng
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong
| | - Shu Chen Wei
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Govind K Makharia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Pises Pisespongsa
- Gastroenterology and Hepatology, Bumrungrad International University, Bangkok, Thailand
| | - Min Hu Chen
- Division of Gastroenterology, The First University Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhi Hua Ran
- Department of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Byong Duk Ye
- Department of Gastroenterology and IBD Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Dong Il Park
- Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
| | | | - David Ong
- Division of Gastroenterology and Hepatology, National University Hospital of Singapore, University Medicine Cluster, Singapore
| | - Vineet Ahuja
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Khean Lee Goh
- University of Malaya Specialist Centre, Kuala Lumpur, Malaysia
| | - Jose Sollano
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - Wee Chian Lim
- Department of Gastroenterology and Hepatology, Tan Tock Seng Hospital, Singapore
| | - Wai Keung Leung
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Hong Kong, Hong Kong
| | - Raja Affendi Raja Ali
- Faculty of Medicine, UKM Medical and Specialist Centres, The National University of Malaysia, Kuala Lumpur, Malaysia
| | - Deng Chyang Wu
- Department of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Evan Ong
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - Nazri Mustaffa
- Department of Internal Medicine, School of Medical Sciences, Health Campus, Sains University, Kubang Kerian, Malaysia
| | - Julajak Limsrivilai
- Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
| | - Tadakazu Hisamatsu
- The Third Department of Internal Medicine, Kyorin University School of Medicine, Mitaka, Japan
| | - Suk Kyun Yang
- Department of Gastroenterology, University of Ulsan College of Medicine, Seoul, Korea
| | - Qin Ouyang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Richard Geary
- Department of Medicine, University of Otago, Christchurch, New Zealand
| | | | | | - Marcellus Simadibrata
- Department of Internal Medicine, Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
| | - Murdani Abdullah
- Division of Gastroenterology, Department of Internal Medicine, Cipto Mangunkusumo National Hospital, Jakarta, Indonesia
| | - Rupert WL Leong
- Gastroenterology and Liver Services, Concord Hospital, Sydney, Australia
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Kato J, Yoshida T, Hiraoka S. Prediction of treatment outcome and relapse in inflammatory bowel disease. Expert Rev Clin Immunol 2019; 15:667-677. [PMID: 30873890 DOI: 10.1080/1744666x.2019.1593140] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Prediction of treatment outcome and clinical relapse in patients with inflammatory bowel disease (IBD), either ulcerative colitis (UC) or Crohn's disease (CD), is particularly important because therapeutics for IBD are not always effective and patients in remission could frequently relapse. Because undergoing endoscopy for the purpose is sometimes invasive and burdensome to patients, the performance of surrogate biomarkers has been investigated. Areas covered: We particularly featured the performance of patient symptoms, blood markers including C-reactive protein (CRP), fecal markers including fecal calprotectin (Fcal) and fecal immunochemical test (FIT) for prediction of endoscopic mucosal healing (MH) and prediction of relapse. Studies of other modalities and therapeutic drug monitoring (TDM) have also been explored. Expert opinion: Meticulous evaluation of patient symptoms could be predictive for MH in UC. CRP and Fcal may be accurate in prediction of MH of CD when MH is evaluated throughout the entire intestine including the small bowel. Repeated measurements of fecal markers including Fcal and FIT in patients with clinical remission would raise predictability of relapse. Prediction of treatment outcome by monitoring with blood markers including CRP, fecal markers including Fcal, and TDM has frequently been performed in recent clinical trials and shown to be effective.
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Affiliation(s)
- Jun Kato
- a Department of Gastroenterology , Mitsui Memorial Hospital , Tokyo , Japan
| | - Takeichi Yoshida
- b Second Department of Internal Medicine , Wakayama Medical University , Wakayama , Japan
| | - Sakiko Hiraoka
- c Department of Gastroenterology and Hepatology , Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences , Okayama , Japan
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49
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Sollelis E, Quinard RM, Bouguen G, Goutte M, Goutorbe F, Bouvier D, Pereira B, Bommelaer G, Buisson A. Combined evaluation of biomarkers as predictor of maintained remission in Crohn’s disease. World J Gastroenterol 2019; 25:2354-2364. [PMID: 31148906 PMCID: PMC6529885 DOI: 10.3748/wjg.v25.i19.2354] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Revised: 04/16/2019] [Accepted: 04/20/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The individual performances and the complementarity of Crohn’s disease (CD) activity index (CDAI), C-reactive protein (CRP) and faecal calprotectin (Fcal) to monitor patients with CD remain poorly investigated in the era of “tight control” and “treat to target” strategies.
AIM To assess CDAI, CRP and Fcal variation, alone or combined, after 12 wk (W12) of anti-tumor necrosis factor (TNF) therapy to predict corticosteroids-free remission (CFREM = CDAI < 150, CRP < 2.9 mg/L and Fcal < 250 μg/g with no therapeutic intensification and no surgery) at W52.
METHODS CD adult patients needing anti-TNF therapy with CDAI > 150 and either CRP > 2.9 mg/L or Fcal > 250 μg/g were prospectively enrolled.
RESULTS Among the 40 included patients, 13 patients (32.5%) achieved CFREM at W52. In univariable analysis, CDAI < 150 at W12 (P = 0.012), CRP level < 2.9 mg/L at W12 (P = 0.001) and Fcal improvement at W12 (Fcal < 300 μg/g; or, for patients with initial Fcal < 300 μg/g, at least 50% decrease of Fcal or normalization of Fcal (< 100 μg/g) (P = 0.001) were predictive of CFREM at W52. Combined endpoint (CDAI < 150 and CRP ≤ 2.9 mg/L and FCal improvement) at W12 was the best predictor of CFREM at W52 with positive predictive value = 100.0% (100.0-100.0) and negative predictive value = 87.1% (75.3-98.9). In multivariable analysis, Fcal improvement at W12 [odd ratio (OR) = 45.1 (2.96-687.9); P = 0.03] was a better predictor of CFREM at W52 than CDAI < 150 [OR = 9.3 (0.36-237.1); P = 0.145] and CRP < 2.9 mg/L (0.77-278.0; P = 0.073).
CONCLUSION The combined monitoring of CDAI, CRP and Fcal after anti-TNF induction therapy is able to predict favorable outcome within one year in patients with CD.
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Affiliation(s)
- Elisa Sollelis
- Inserm 3iHP, CHU Clermont-Ferrand, Service d’Hépato-Gastro Entérologie, Université Clermont Auvergne, Clermont-Ferrand F-63000, France
- Inserm U1071, M2iSH, USC-INRA 2018, Université Clermont Auvergne, Clermont-Ferrand F-63000, France
| | - Régine Minet Quinard
- Biochemistry laboratory, University Hospital G. Montpied, Clermont-Ferrand F-63000, France
| | - Guillaume Bouguen
- CHU Rennes, Univ Rennes, INSERM, CIC1414, Institut NUMECAN (Nutrition Metabolisms and Cancer), Rennes F-35000, France
| | - Marion Goutte
- Inserm 3iHP, CHU Clermont-Ferrand, Service d’Hépato-Gastro Entérologie, Université Clermont Auvergne, Clermont-Ferrand F-63000, France
- Inserm U1071, M2iSH, USC-INRA 2018, Université Clermont Auvergne, Clermont-Ferrand F-63000, France
| | - Félix Goutorbe
- Gastroenterology Department, Hospital of Bayonne, Bayonne F-64100, France
| | - Damien Bouvier
- Biochemistry laboratory, University Hospital G. Montpied, Clermont-Ferrand F-63000, France
| | - Bruno Pereira
- Biostatistics Unit, DRCI, University Hospital, Clermont-Ferrand F-63000, France
| | - Gilles Bommelaer
- Inserm 3iHP, CHU Clermont-Ferrand, Service d’Hépato-Gastro Entérologie, Université Clermont Auvergne, Clermont-Ferrand F-63000, France
- Inserm U1071, M2iSH, USC-INRA 2018, Université Clermont Auvergne, Clermont-Ferrand F-63000, France
| | - Anthony Buisson
- Inserm 3iHP, CHU Clermont-Ferrand, Service d’Hépato-Gastro Entérologie, Université Clermont Auvergne, Clermont-Ferrand F-63000, France
- Inserm U1071, M2iSH, USC-INRA 2018, Université Clermont Auvergne, Clermont-Ferrand F-63000, France
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50
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Simon EG, Wardle R, Thi AA, Eldridge J, Samuel S, Moran GW. Does fecal calprotectin equally and accurately measure disease activity in small bowel and large bowel Crohn's disease?: a systematic review. Intest Res 2019; 17:160-170. [PMID: 30704158 PMCID: PMC6505091 DOI: 10.5217/ir.2018.00114] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 01/01/2019] [Accepted: 01/02/2019] [Indexed: 12/13/2022] Open
Abstract
Fecal calprotectin (FC) is a highly sensitive disease activity biomarker in inflammatory bowel disease. However, there are conflicting reports on whether the diagnostic accuracy in Crohn's disease is influenced by disease location. The aim of this study was to undertake a systematic review of the published literature. Relevant databases were searched from inception to November 8, 2016 for cohort and case control studies which had data on FC in patients with isolated small bowel (SB) and large bowel (LB) Crohn's disease. Reference standards for disease activity were endoscopy, magnetic resonance imaging, computed tomography or a combination of these. The QUADAS-2 research tool was used to assess the risk of bias. There were 5,619 records identified at initial search. The 2,098 duplicates were removed and 3,521 records screened. Sixty-one full text articles were assessed for eligibility and 16 studies were included in the final review with sensitivities and specificities per disease location available from 8 studies. Sensitivities of FC at SB and LB locations ranged from 42.9% to 100% and 66.7% to 100% respectively while corresponding specificities were 50% to 100% and 28.6% to 100% respectively. The sensitivities and specificities of FC to accurately measure disease activity in Crohn's disease at different disease locations are diverse and no firm conclusion can be made. Better studies need to be undertaken to categorically answer the effect of disease location on the diagnostic accuracy of FC.
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Affiliation(s)
- Ebby George Simon
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK
- National Institute of Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals and the University of Nottingham, Nottingham, UK
- Department of Gastroenterology, Christian Medical College, Vellore, India
| | - Richard Wardle
- National Institute of Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals and the University of Nottingham, Nottingham, UK
| | - Aye Aye Thi
- National Institute of Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals and the University of Nottingham, Nottingham, UK
| | - Jeanette Eldridge
- Libraries, Research & Learning Resources, University of Nottingham, Nottingham, UK
| | - Sunil Samuel
- National Institute of Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals and the University of Nottingham, Nottingham, UK
| | - Gordon William Moran
- Nottingham Digestive Diseases Centre, University of Nottingham, Nottingham, UK
- National Institute of Health Research, Nottingham Biomedical Research Centre, Nottingham University Hospitals and the University of Nottingham, Nottingham, UK
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