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Watson KL. Calling in Your Markers: Can Biomarkers Predict the Response to Anti-TNF Therapy in Pediatric Patients with Crohn's Disease? Dig Dis Sci 2025; 70:888-889. [PMID: 39856482 DOI: 10.1007/s10620-025-08856-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 01/07/2025] [Indexed: 01/27/2025]
Affiliation(s)
- Kevin L Watson
- Division of Pediatric Gastroenterology, Hepatology and Nutrition, Akron Children's Hospital, 215 W Bowery Street, 6th floor, Akron, OH, 44308, USA.
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Lisai-Goldstein Y, Focht G, Orlanski-Meyer E, Yogev D, Lev-Tzion R, Ledder O, Assa A, Navas-López VM, Baldassano RN, Otley A, Shouval DS, Griffiths AM, Turner D, Atia O. Serological Markers as Predictors of Anti-TNF Response in Children with Crohn's Disease. Dig Dis Sci 2025; 70:333-339. [PMID: 39604667 DOI: 10.1007/s10620-024-08732-y] [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: 09/30/2024] [Accepted: 11/04/2024] [Indexed: 11/29/2024]
Abstract
BACKGROUND To advance personalized medicine in pediatric Crohn's disease (CD), we aimed to explore the utility of serological biomarkers in predicting response to anti-tumor necrosis factor (TNF). METHODS Children with CD were enrolled at initiation of anti-TNF and followed prospectively at 4 and 12 months thereafter, as well as at last follow-up. At baseline, 10 serological markers of the "PROMETHEUS® IBD sgi Diagnostic test" were measured, including pANCA, ASCA IgG and IgA, anti-CBir1, anti-OmpC, anti-A4-Fla2, anti-Fla-X, SAA, ICAM-1 and VCAM-1. The primary outcome was sustained steroid-free remission (SSFR, i.e. clinical remission without steroids at both 4 and 12 months) and the secondary outcome was primary non-response (PNR). RESULTS Of the 72 included children (mean age, 12.8 ± 3.1 years; median disease duration, 6.4 months [IQR 2.5-17.3]), 42 (58%) were treated with adalimumab and 30 (42%) with infliximab. PNR was noted in 20 (28%) children and failure to achieve SSFR in 36 (50%). The most common positive serological markers were SAA (86%) and ICAM-1 (82%). In univariate analyses, none of the serological markers achieved statistical significance in association with SSFR or with PNR. In multivariable analysis, positivity of ASCA IgG (OR 3.3 [95%CI 0.8-14.4]) and pANCA (OR 5.3 [95%CI 0.9-48]) were the closest to achieving significance in predicting SSFR, with fair predictive performance for the model (AUC 0.67 [95%CI 0.55-0.80]). CONCLUSION The serological markers tested here have limited utility in predicting response to anti-TNF treatment. Further studies with larger sample sizes are needed to confirm the utility of ASCA IgG and pANCA.
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Affiliation(s)
- Yaara Lisai-Goldstein
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Eisenberg R&D Authority, P.O. Box 3235, 9103102, Jerusalem, Israel
| | - Gili Focht
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Eisenberg R&D Authority, P.O. Box 3235, 9103102, Jerusalem, Israel
| | - Esther Orlanski-Meyer
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Eisenberg R&D Authority, P.O. Box 3235, 9103102, Jerusalem, Israel
| | - Dotan Yogev
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Eisenberg R&D Authority, P.O. Box 3235, 9103102, Jerusalem, Israel
| | - Raffi Lev-Tzion
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Eisenberg R&D Authority, P.O. Box 3235, 9103102, Jerusalem, Israel
| | - Oren Ledder
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Eisenberg R&D Authority, P.O. Box 3235, 9103102, Jerusalem, Israel
| | - Amit Assa
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Eisenberg R&D Authority, P.O. Box 3235, 9103102, Jerusalem, Israel
| | - Victor Manuel Navas-López
- Pediatric Gastroenterology and Nutrition Unit, Regional University Hospital of Málaga, Málaga, Spain
| | - Robert N Baldassano
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Anthony Otley
- Department of Pediatrics, IWK Health, Dalhousie University, Halifax, NS, Canada
| | - Dror S Shouval
- Institute of Gastroenterology, Nutrition and Liver Diseases, Schneider Children's Medical Center of Israel, Petah Tikvah, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | | | - Dan Turner
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Eisenberg R&D Authority, P.O. Box 3235, 9103102, Jerusalem, Israel
| | - Ohad Atia
- Juliet Keidan Institute of Pediatric Gastroenterology Hepatology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Eisenberg R&D Authority, P.O. Box 3235, 9103102, Jerusalem, Israel.
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Khrom M, Long M, Dube S, Robbins L, Botwin GJ, Yang S, Mengesha E, Li D, Naito T, Bonthala NN, Ha C, Melmed G, Rabizadeh S, Syal G, Vasiliauskas E, Ziring D, Brant SR, Cho J, Duerr RH, Rioux J, Schumm P, Silverberg M, Ananthakrishnan AN, Faubion WA, Jabri B, Lira SA, Newberry RD, Sandler RS, Xavier RJ, Kugathasan S, Hercules D, Targan SR, Sartor RB, Haritunians T, McGovern DPB. Comprehensive Association Analyses of Extraintestinal Manifestations in Inflammatory Bowel Disease. Gastroenterology 2024; 167:315-332. [PMID: 38490347 PMCID: PMC11193636 DOI: 10.1053/j.gastro.2024.02.026] [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: 07/16/2022] [Revised: 02/11/2024] [Accepted: 02/13/2024] [Indexed: 03/17/2024]
Abstract
BACKGROUND & AIMS Patients with inflammatory bowel disease (IBD) frequently develop extraintestinal manifestations (EIMs) that contribute substantially to morbidity. We assembled the largest multicohort data set to date to investigate the clinical, serologic, and genetic factors associated with EIM complications in IBD. METHODS Data were available in 12,083 unrelated European ancestry IBD cases with presence or absence of EIMs (eg, ankylosing spondylitis [ankylosing spondylitis and sacroiliitis], primary sclerosing cholangitis [PSC], peripheral arthritis, and skin and ocular manifestations) across 4 cohorts (Cedars-Sinai Medical Center, National Institute for Diabetes and Digestive and Kidney Diseases IBD Genetics Consortium, Sinai Helmsley Alliance for Research Excellence Consortium, and Risk Stratification and Identification of Immunogenetic and Microbial Markers of Rapid Disease Progression in Children with Crohn's Disease cohort). Clinical and serologic parameters were analyzed by means of univariable and multivariable regression analyses using a mixed-effects model. Within-case logistic regression was performed to assess genetic associations. RESULTS Most EIMs occurred more commonly in female subjects (overall EIM: P = 9.0E-05, odds ratio [OR], 1.2; 95% CI, 1.1-1.4), with CD (especially colonic disease location; P = 9.8E-09, OR, 1.7; 95% CI, 1.4-2.0), and in subjects who required surgery (both CD and UC; P = 3.6E-19, OR, 1.7; 95% CI, 1.5-1.9). Smoking increased risk of EIMs except for PSC, where there was a "protective" effect. Multiple serologic associations were observed, including with PSC (anti-nuclear cytoplasmic antibody; IgG and IgA, anti-Saccharomyces cerevisiae antibodies; and anti-flagellin) and any EIM (anti-nuclear cytoplasmic antibody; IgG and IgA, anti-Saccharomyces cerevisiae antibodies; and anti-Pseudomonas fluorescens-associated sequence). We identified genome-wide significant associations within major histocompatibility complex (ankylosing spondylitis and sacroiliitis, P = 1.4E-15; OR, 2.5; 95% CI, 2.0-3.1; PSC, P = 2.7E-10; OR, 2.8; 95% CI, 2.0-3.8; ocular, P = 2E-08, OR, 3.6; 95% CI, 2.3-5.6; and overall EIM, P = 8.4E-09; OR, 2.2; 95% CI, 1.7-2.9) and CPEB4 (skin, P = 2.7E-08; OR, 1.5; 95% CI, 1.3-1.8). Genetic associations implicated tumor necrosis factor, JAK-STAT, and IL6 as potential targets for EIMs. Contrary to previous reports, only 2% of our subjects had multiple EIMs and most co-occurrences were negatively correlated. CONCLUSIONS We have identified demographic, clinical, and genetic associations with EIMs that revealed underlying mechanisms and implicated novel and existing drug targets-important steps toward a more personalized approach to IBD management.
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MESH Headings
- Humans
- Female
- Male
- Adult
- Cholangitis, Sclerosing/immunology
- Cholangitis, Sclerosing/genetics
- Cholangitis, Sclerosing/diagnosis
- Cholangitis, Sclerosing/complications
- Middle Aged
- Colitis, Ulcerative/immunology
- Colitis, Ulcerative/genetics
- Colitis, Ulcerative/diagnosis
- Crohn Disease/immunology
- Crohn Disease/genetics
- Crohn Disease/diagnosis
- Adolescent
- Risk Factors
- Child
- Spondylitis, Ankylosing/genetics
- Spondylitis, Ankylosing/immunology
- Spondylitis, Ankylosing/diagnosis
- Spondylitis, Ankylosing/complications
- Genetic Predisposition to Disease
- Young Adult
- Sex Factors
- Skin Diseases/etiology
- Skin Diseases/immunology
- Skin Diseases/genetics
- Eye Diseases/etiology
- Eye Diseases/immunology
- Eye Diseases/diagnosis
- Eye Diseases/genetics
- Eye Diseases/epidemiology
- Phenotype
- Inflammatory Bowel Diseases/genetics
- Inflammatory Bowel Diseases/immunology
- Inflammatory Bowel Diseases/diagnosis
- Logistic Models
- Aged
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Affiliation(s)
- Michelle Khrom
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Millie Long
- Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina
| | - Shishir Dube
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Lori Robbins
- Palmetto Digestive Health Specialists, Charleston, South Carolina
| | - Gregory J Botwin
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Shaohong Yang
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Emebet Mengesha
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Dalin Li
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Takeo Naito
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Nirupama N Bonthala
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Christina Ha
- Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California
| | - Gil Melmed
- Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California
| | - Shervin Rabizadeh
- Department of Pediatrics, Pediatric Inflammatory Bowel Disease Program, Cedars-Sinai Medical Center, Los Angeles, California
| | - Gaurav Syal
- Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California
| | - Eric Vasiliauskas
- Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California
| | - David Ziring
- Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California
| | - Steven R Brant
- Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
| | - Judy Cho
- Icahn School of Medicine at Mount Sinai, Dr Henry D. Janowitz Division of Gastroenterology, New York, New York
| | - Richard H Duerr
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - John Rioux
- Department of Medicine, Université de Montréal and Research Center, Montreal Heart Institute, Montréal, Québec, Canada
| | - Phil Schumm
- Department of Public Health Sciences, University of Chicago, Chicago, Illinois
| | - Mark Silverberg
- University of Toronto, Samuel Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada
| | | | | | - Bana Jabri
- University of Chicago, Pritzker School of Medicine, Chicago, Illinois
| | - Sergio A Lira
- Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Rodney D Newberry
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri
| | - Robert S Sandler
- Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina
| | - Ramnik J Xavier
- Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Subra Kugathasan
- Children's Healthcare of Atlanta Combined Center for Pediatric Inflammatory Bowel Disease, Atlanta, Georgia; Emory School of Medicine, Atlanta, Georgia
| | | | - Stephan R Targan
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - R Balfour Sartor
- Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina
| | - Talin Haritunians
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Dermot P B McGovern
- F. Widjaja Inflammatory Bowel Disease Institute, Cedars-Sinai Medical Center, Los Angeles, California.
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Hong SM, Baek DH. Diagnostic Procedures for Inflammatory Bowel Disease: Laboratory, Endoscopy, Pathology, Imaging, and Beyond. Diagnostics (Basel) 2024; 14:1384. [PMID: 39001273 PMCID: PMC11241288 DOI: 10.3390/diagnostics14131384] [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: 05/17/2024] [Revised: 06/26/2024] [Accepted: 06/27/2024] [Indexed: 07/16/2024] Open
Abstract
Diagnosing inflammatory bowel disease (IBD) can often be challenging, and differentiating between Crohn's disease and ulcerative colitis can be particularly difficult. Diagnostic procedures for IBD include laboratory tests, endoscopy, pathological tests, and imaging tests. Serological and stool tests can be easily performed in an outpatient setting and provide critical diagnostic clues. Although endoscopy is an invasive procedure, it offers essential diagnostic information and allows for tissue biopsy and therapeutic procedures. Video capsule endoscopy and device-assisted enteroscopy are endoscopic procedures used to evaluate the small bowel. In addition to endoscopy, magnetic resonance imaging, computed tomography, and ultrasound (US) are valuable tools for small bowel assessment. Among these, US is noninvasive and easily utilized, making its use highly practical in daily clinical practice. Endoscopic biopsy aids in the diagnosis of IBD and is crucial for assessing the histological activity of the disease, facilitating a thorough evaluation of disease remission, and aiding in the development of treatment strategies. Recent advances in artificial intelligence hold promise for enhancing various aspects of IBD management, including diagnosis, monitoring, and precision medicine. This review compiles current procedures and promising future tools for the diagnosis of IBD, providing comprehensive insights.
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Affiliation(s)
- Seung Min Hong
- Department of Internal Medicine, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea
| | - Dong Hoon Baek
- Department of Internal Medicine, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, Busan 49241, Republic of Korea
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5
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Pu D, Zhang Z, Feng B. Alterations and Potential Applications of Gut Microbiota in Biological Therapy for Inflammatory Bowel Diseases. Front Pharmacol 2022; 13:906419. [PMID: 35734396 PMCID: PMC9207480 DOI: 10.3389/fphar.2022.906419] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 04/26/2022] [Indexed: 12/12/2022] Open
Abstract
Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is a chronic immune-mediated inflammatory disorder of the gastrointestinal tract that is closely associated with dysbiosis of the intestinal microbiota. Currently, biologic agents are the mainstream therapies for IBD. With the increasing incidence of IBD, limitations of biologic agents have gradually emerged during treatment. Recent studies have indicated that gut microbiota is highly correlated with the efficacy of biologic agents. This review focuses on alterations in both the components and metabolites of gut microbiota during biological therapy for IBD, systematically summarises the specific gut microbiota closely related to the clinical efficacy, and compares current predictive models for the efficacy of biologics, further highlighting the predictive value of intestinal microbiota. Based on the mechanistic analysis of faecal microbiota transplantation (FMT) and biologic agents, a new therapeutic strategy, comprising a combination of FMT and biologics, has been proposed as a promising treatment for IBD with improved efficacy.
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Affiliation(s)
| | - Zhe Zhang
- *Correspondence: Zhe Zhang, ; Baisui Feng,
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6
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Bourgonje AR, Vogl T, Segal E, Weersma RK. Antibody signatures in inflammatory bowel disease: current developments and future applications. Trends Mol Med 2022; 28:693-705. [DOI: 10.1016/j.molmed.2022.05.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 05/01/2022] [Accepted: 05/03/2022] [Indexed: 11/25/2022]
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Guijarro LG, Cano-Martínez D, Toledo-Lobo MV, Ruiz-Llorente L, Chaparro M, Guerra I, Iborra M, Cabriada JL, Bujanda L, Taxonera C, García-Sánchez V, Marín-Jiménez I, Barreiro-de Acosta M, Vera I, Martín-Arranz MD, Mesonero F, Sempere L, Gomollón F, Hinojosa J, Zoullas S, Monserrat J, Menor-Salvan C, Alvarez-Mon M, Gisbert JP, Ortega MA, Hernández-Breijo B. Evaluation of AIF-1 (Allograft Inflammatory Factor-1) as a Biomarker of Crohn's Disease Severity. Biomedicines 2022; 10:727. [PMID: 35327530 PMCID: PMC8945466 DOI: 10.3390/biomedicines10030727] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 03/16/2022] [Accepted: 03/18/2022] [Indexed: 11/17/2022] Open
Abstract
Background: Recently, increased tissue levels of AIF-1 have been shown in experimental colitis, supporting its role in intestinal inflammation. Therefore, we studied the levels of AIF-1 in Crohn’s disease (CD). Methods: This study included 33 patients with CD (14 men and 19 women) who participated in the PREDICROHN project, a prospective multicenter study of the Spanish Group of Inflammatory bowel disease (GETECCU). Results: This article demonstrates declines with respect to baseline levels of serum AIF-1 in Crohn’s disease (CD) patients after 14 weeks of treatment with anti-TNFs. Furthermore, in patients with active CD (HB ≥ 5), serum AIF-1 levels were significantly higher than those in patients without activity (HB ≤ 4). The study of serum AIF-1 in the same cohort, revealed an area under the ROC curve (AUC) value of AUC = 0.66 (p = 0.014), while for the CRP (C-reactive protein), (AUC) value of 0.69 (p = 0.0066), indicating a similar ability to classify CD patients by their severity. However, the combination of data on serum levels of AIF-1 and CRP improves the predictive ability of these analyses for classifying CD patients as active (HB ≥ 5) or inactive (HB ≤ 4). When we used the odds ratio (OR) formula, we observed that patients with CRP > 5 mg/L or AIF-1 > 200 pg/mL or both conditions were 13 times more likely to show HB ≥ 5 (active CD) than were those with both markers below these thresholds. Conclusion: The development of an algorithm that includes serum levels of AIF-1 and CRP could be useful for assessing Crohn’s disease severity.
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Affiliation(s)
- Luis G. Guijarro
- Department of System Biology, University of Alcalá, 28805 Alcalá de Henares, Madrid, Spain; (L.G.G.); (D.C.-M.); (L.R.-L.); (S.Z.); (C.M.-S.)
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Madrid, Spain; (J.M.); (M.A.-M.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Madrid, Spain
| | - David Cano-Martínez
- Department of System Biology, University of Alcalá, 28805 Alcalá de Henares, Madrid, Spain; (L.G.G.); (D.C.-M.); (L.R.-L.); (S.Z.); (C.M.-S.)
| | - M. Val Toledo-Lobo
- Department of Biomedicine and Biotechnology, University of Alcalá, 28805 Alcalá de Henares, Madrid, Spain;
| | - Lidia Ruiz-Llorente
- Department of System Biology, University of Alcalá, 28805 Alcalá de Henares, Madrid, Spain; (L.G.G.); (D.C.-M.); (L.R.-L.); (S.Z.); (C.M.-S.)
| | - María Chaparro
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, 28049 Madrid, Madrid, Spain;
| | - Iván Guerra
- Gastroenterology Unit, Hospital Universitario de Fuenlabrada, Instituto de Investigación Hospital Universitario La Paz (IdiPaz), 28029 Fuenlabrada, Madrid, Spain;
| | - Marisa Iborra
- Gastroenterology Unit, Hospital Universitario de La Fe (CIBEREHD), 46026 Valencia, Valencia, Spain;
| | - José Luis Cabriada
- Gastroenterology Unit, Hospital Universitario de Galdakano, 48960 Galdakao, Vizcaya, Spain;
| | - Luis Bujanda
- Gastroenterology Unit, Hospital Universitario de Donostia, 20014 San Sebastián, Guipúzcoa, Spain;
| | - Carlos Taxonera
- Gastroenterology Unit, Hospital Universitario Clínico San Carlos, IdISSC, 28040 Madrid, Madrid, Spain;
| | - Valle García-Sánchez
- Gastroenterology Unit, Hospital Universitario Reina Sofía, 14004 Córdoba, Córdoba, Spain;
| | - Ignacio Marín-Jiménez
- Gastroenterology Unit, Hospital Universitario Gregorio Marañón, IiSGM, 28007 Madrid, Madrid, Spain;
| | - Manuel Barreiro-de Acosta
- Gastroenterology Unit, Hospital Universitario Clínico de Santiago, 15706 Santiago de Compostela, La Coruña, Spain;
| | - Isabel Vera
- Gastroenterology Unit, Hospital Universitario Puerta de Hierro Majadahonda, 28222 Majadahonda, Madrid, Spain;
| | | | - Francisco Mesonero
- Gastroenterology Unit, Hospital Universitario Ramón y Cajal, 28034 Madrid, Madrid, Spain;
| | - Laura Sempere
- Gastroenterology Unit, Hospital Universitario Alicante, 03010 Alicante, Alicante, Spain;
| | - Fernando Gomollón
- Gastroenterology Unit, Hospital Clínico Universitario Lozano Blesa, IIS Aragón, 50009 Zaragoza, Zaragoza, Spain;
| | - Joaquín Hinojosa
- Gastroenterology Unit, Hospital Universitario Manises, 46940 Valencia, Valencia, Spain;
| | - Sofía Zoullas
- Department of System Biology, University of Alcalá, 28805 Alcalá de Henares, Madrid, Spain; (L.G.G.); (D.C.-M.); (L.R.-L.); (S.Z.); (C.M.-S.)
| | - Jorge Monserrat
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Madrid, Spain; (J.M.); (M.A.-M.)
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Madrid, Spain
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Madrid, Spain
| | - Cesar Menor-Salvan
- Department of System Biology, University of Alcalá, 28805 Alcalá de Henares, Madrid, Spain; (L.G.G.); (D.C.-M.); (L.R.-L.); (S.Z.); (C.M.-S.)
| | - Melchor Alvarez-Mon
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Madrid, Spain; (J.M.); (M.A.-M.)
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Madrid, Spain
- Immune System Diseases-Rheumatology, Oncology Service and Internal Medicine, University Hospital Príncipe de Asturias, 28805 Alcalá de Henares, Madrid, Spain
| | - Javier P. Gisbert
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 28029 Madrid, Madrid, Spain; (J.M.); (M.A.-M.)
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP), Universidad Autónoma de Madrid, 28049 Madrid, Madrid, Spain;
| | - Miguel A. Ortega
- Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Madrid, Spain
- Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcalá, 28801 Alcalá de Henares, Madrid, Spain
| | - Borja Hernández-Breijo
- Immuno-Rheumatology Research Group, Instituto de Investigación Hospital Universitario La Paz (IdiPaz), 28046 Madrid, Madrid, Spain;
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Underhill DM, Braun J. Fungal microbiome in inflammatory bowel disease: a critical assessment. J Clin Invest 2022; 132:155786. [PMID: 35229726 PMCID: PMC8884899 DOI: 10.1172/jci155786] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The gut microbiome is at the center of inflammatory bowel disease (IBD) pathogenesis and disease activity. While this has mainly been studied in the context of the bacterial microbiome, recent advances have provided tools for the study of host genetics and metagenomics of host-fungal interaction. Through these tools, strong evidence has emerged linking certain fungal taxa, such as Candida and Malassezia, with cellular and molecular pathways of IBD disease biology. Mouse models and human fecal microbial transplant also suggest that some disease-participatory bacteria and fungi may act not via the host directly, but via their fungal-bacterial ecologic interactions. We hope that these insights, and the study design and multi-omics strategies used to develop them, will facilitate the inclusion of the fungal community in basic and translational IBD research.
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Affiliation(s)
- David M Underhill
- F. Widjaja Inflammatory Bowel and Immunobiology Research Institute.,Division of Gastroenterology, Department of Medicine, and.,Research Division of Immunology, Department of Biomedical Sciences; Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Jonathan Braun
- F. Widjaja Inflammatory Bowel and Immunobiology Research Institute.,Division of Gastroenterology, Department of Medicine, and.,Research Division of Immunology, Department of Biomedical Sciences; Cedars-Sinai Medical Center, Los Angeles, California, USA
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Kim MJ, Kim E, Kang B, Lee Y, Kang ES, Choe YH. Anti- Saccharomyces cerevisiae Antibody in Pediatric Crohn's Disease Patients without Mucosal Healing Is a Useful Marker of Mucosal Damage. Gut Liver 2021; 15:763-770. [PMID: 33376230 PMCID: PMC8444098 DOI: 10.5009/gnl20212] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 09/24/2020] [Accepted: 09/25/2020] [Indexed: 12/12/2022] Open
Abstract
Background/Aims We evaluated whether anti-Saccharomyces cerevisiae antibody (ASCA) titers are associated with diagnostic findings, disease activity, Paris classification phenotypes, and persistence after infliximab (IFX) treatment in children with Crohn’s disease (CD). We also investigated the role of ASCA as a predictor of mucosal healing (MH) and clinical remission (CR). Methods This study included 61 CD patients aged 19 years or younger who were diagnosed and treated between September 2010 and January 2019 and followed for at least 1 year. ASCA was regularly measured at the diagnosis of CD and at least 1 year after IFX therapy. Results The average follow-up period was 3.8±3.4 years (range, 1.0 to 7.2 years). Regression analysis showed that the ASCA titer was the only factor associated with Simple Endoscopic Score for Crohn's Disease (SES-CD) or CR among all the parameters. In patients who had achieved MH (SES-CD=0), ASCA immunoglobulin G (IgG) was not associated with MH, but in patients without MH, ASCA IgG was associated with SES-CD (p=0.005) and CR (p<0.001). The cutoff value of ASCA IgG in patients with CR was 21.8 units. However, there was no difference in the relapse rate between the ASCA IgG-positive and -negative groups during the follow-up period. Conclusions In patients who have not achieved MH, ASCA IgG is closely related to mucosal damage and CR. Unlike Western studies, ASCA IgG may be more helpful in predicting prognosis than immunoglobulin A in Korean patients, but it is not an appropriate indicator to predict the relapse of CD. (Gut Liver 2021;15-770)
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Affiliation(s)
- Mi Jin Kim
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Eunsil Kim
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ben Kang
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Yoon Lee
- Department of Pediatrics, Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea
| | - Eun-Suk Kang
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yon Ho Choe
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Aleksandrova EN, Novikov AA, Lukina GV, Parfenov AI. [Clinical value of antibodies in inflammatory bowel diseases]. TERAPEVT ARKH 2021; 93:228-235. [PMID: 36286642 DOI: 10.26442/00403660.2021.02.200610] [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: 04/05/2021] [Accepted: 04/05/2021] [Indexed: 11/22/2022]
Abstract
Inflammatory bowel disease IBD (Crohns disease CD, ulcerative colitis UC) immune-mediated diseases of the digestive tract of unknown etiology. The basis of the pathogenesis of IBD is a violation of the protective mechanisms of the intestinal barrier as a result of a complex interaction of environmental factors, a genetic predisposition and defects in the activation of the immune response in the lymphoid tissue of the intestinal mucosa. Three groups of antibodies are detected in the sera of IBD patients: autoantibodies, antimicrobial antibodies and antibodies to peptide antigens. In CD, the most useful diagnostic markers are ASCA; in UC patients pANCA. Antibodies are not among the diagnostic criteria for CD and UC, the diagnosis of which is traditionally made on the basis of a complex of clinical, radiological, endoscopic and histological signs, but can be used as useful additional non-invasive markers for early diagnosis, assessment of clinical phenotypes, prognosis and effectiveness of treatment of these diseases.
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Affiliation(s)
| | - A A Novikov
- Loginov Moscow Clinical Research and Practical Center
| | - G V Lukina
- Loginov Moscow Clinical Research and Practical Center
| | - A I Parfenov
- Loginov Moscow Clinical Research and Practical Center
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11
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Castro-Dopico T, Colombel JF, Mehandru S. Targeting B cells for inflammatory bowel disease treatment: back to the future. Curr Opin Pharmacol 2020; 55:90-98. [PMID: 33166872 PMCID: PMC7894973 DOI: 10.1016/j.coph.2020.10.002] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 09/30/2020] [Accepted: 10/05/2020] [Indexed: 02/08/2023]
Abstract
B cells are critical to immune homeostasis at mucosal surfaces including those of the gastrointestinal tract. B cell-related abnormalities, comprising of a lympho-plasmacytic infiltrate, as well as anti-microbial antibodies, are well reported in patients with inflammatory bowel disease (IBD). However, B cell-targeting is not part of the therapeutic armamentarium in IBD. Recently, driven by the identification of genetic associations between IgG Fc receptors and IBD susceptibility, there has been renewed interest in defining the immunobiology of B cells during mucosal inflammation. Functional studies have demonstrated mechanisms of IgG-mediated disease pathogenesis and deep mucosal immunophenotyping using single cell RNA sequencing has elaborated a significant remodelling of the B cell compartment in IBD. In light of these novel data, here we discuss potential strategies to target B cell immunity in IBD. Finally, we discuss potential risks and pitfalls of these approaches and emphasize on distinguishing between homeostatic and pathological B cell signatures, allowing for a data-based, prudent therapeutic approach.
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Affiliation(s)
- Tomas Castro-Dopico
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Molecular Immunity Unit, Department of Medicine, University of Cambridge, Cambridge, UK
| | - Jean-Frederic Colombel
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Saurabh Mehandru
- Division of Gastroenterology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
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12
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Caenepeel C, Sadat Seyed Tabib N, Vieira-Silva S, Vermeire S. Review article: how the intestinal microbiota may reflect disease activity and influence therapeutic outcome in inflammatory bowel disease. Aliment Pharmacol Ther 2020; 52:1453-1468. [PMID: 32969507 DOI: 10.1111/apt.16096] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 02/08/2020] [Accepted: 09/03/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Intestinal bacteria produce metabolites and by-products necessary for homeostasis. Imbalance in this equilibrium is linked to multiple pathologies including inflammatory bowel disease (IBD). The role of the gut microbiota in determining treatment response is becoming apparent, and may act as biomarker for efficacy. AIM To describe knowledge about the intestinal microbiota on disease severity and treatment outcomes in IBD METHODS: Descriptive review using PubMed to identify literature on the intestinal microbiota in IBD RESULTS: Severe IBD has a less diverse microbiota with fewer commensal microbiota communities and more opportunistic pathogenic bacteria originating from the oral cavity or respiratory tract. IBD treatments can alter gut microbiota composition, but in vitro/in vivo studies are needed to prove causation. A diversification of the microbiota is observed during remission. Patients with a more diverse baseline microbiome and higher microbial diversity show better response to anti-tumour necrosis factor-α, vedolizumab and ustekinumab therapy. Higher abundance of short chain fatty acid-producing bacteria, fewer mucus-colonising bacteria and lower abundance of pro-inflammatory bacteria have also been associated with a favourable outcome. Predictive models, based on a combination of microbiota, clinical data and serological markers, have good accuracy for treatment outcome and disease severity. CONCLUSION The intestinal microbiota in IBD carries a set of promising biomarkers of disease activity and prediction of therapeutic outcome. Current insights may also help in designing microbiota modulation strategies to improve outcomes in IBD.
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Affiliation(s)
| | | | - Sara Vieira-Silva
- Department of Microbiology and Immunology, Laboratory of Molecular Bacteriology, Rega Institute for Medical Research, VIB, KU Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Department of Chronic Diseases & Metabolism, Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium.,Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium
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13
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Moiseev S, Cohen Tervaert JW, Arimura Y, Bogdanos DP, Csernok E, Damoiseaux J, Ferrante M, Flores-Suárez LF, Fritzler MJ, Invernizzi P, Jayne D, Jennette JC, Little MA, McAdoo SP, Novikov P, Pusey CD, Radice A, Salama AD, Savige JA, Segelmark M, Shoenfeld Y, Sinico RA, Sousa MJ, Specks U, Terrier B, Tzioufas AG, Vermeire S, Zhao MH, Bossuyt X. 2020 international consensus on ANCA testing beyond systemic vasculitis. Autoimmun Rev 2020; 19:102618. [PMID: 32663621 DOI: 10.1016/j.autrev.2020.102618] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 03/08/2020] [Indexed: 02/07/2023]
Abstract
This document follows up on a 2017 revised international consensus on anti-neutrophil cytoplasm antibodies (ANCA) testing in granulomatosis with polyangiitis and microscopic polyangiitis and focuses on the clinical and diagnostic value of ANCA detection in patients with connective tissue diseases, idiopathic interstitial pneumonia, autoimmune liver diseases, inflammatory bowel diseases, anti-glomerular basement membrane (GBM) disease, infections, malignancy, and during drug treatment. Current evidence suggests that in certain settings beyond systemic vasculitis, ANCA may have clinical, pathogenic and/or diagnostic relevance. Antigen-specific ANCA targeting proteinase-3 and myeloperoxidase should be tested by solid phase immunoassays in any patient with clinical features suggesting ANCA-associated vasculitis and in all patients with anti-GBM disease, idiopathic interstitial pneumonia, and infective endocarditis associated with nephritis, whereas in patients with other aforementioned disorders routine ANCA testing is not recommended. Among patients with autoimmune liver diseases or inflammatory bowel diseases, ANCA testing may be justified in patients with suspected autoimmune hepatitis type 1 who do not have conventional autoantibodies or in case of diagnostic uncertainty to discriminate ulcerative colitis from Crohn's disease. In these cases, ANCA should be tested by indirect immunofluorescence as the target antigens are not yet well characterized. Many questions concerning the optimal use of ANCA testing in patients without ANCA-associated vasculitis remain to be answered.
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Affiliation(s)
- Sergey Moiseev
- Tareev Clinic of Internal Diseases, Sechenov First Moscow State Medical University, Moscow, Russia.
| | - Jan Willem Cohen Tervaert
- Department of Medicine, Division of Rheumatology, University of Alberta, Edmonton, Canada and Maastricht University, Maastricht, The Netherlands
| | - Yoshihiro Arimura
- Department of Nephrology and Rheumatology, Kyorin University School of Medicine, Tokyo, Japan
| | - Dimitrios P Bogdanos
- Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, Larissa, Greece
| | - Elena Csernok
- Department of Internal Medicine, Rheumatology and Immunology, Vasculitis-Center Tübingen-Kirchheim, Medius Klinik Kirchheim, University of Tübingen, Kirchheim-Teck, Germany
| | - Jan Damoiseaux
- Central Diagnostic Laboratory, Maastricht University Medical Centre, Maastricht, The Netherlands
| | - Marc Ferrante
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium
| | - Luis Felipe Flores-Suárez
- Primary Systemic Vasculitides Clinic, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico
| | - Marvin J Fritzler
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Pietro Invernizzi
- Division Gastroenterology and Center for Autoimmune Liver Diseases, University of Milano-Bicocca School of Medicine, Monza, Italy
| | - David Jayne
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - J Charles Jennette
- Division of Nephropathology, School of Medicine, University of North Carolina, Chapel Hill, NC, USA
| | - Mark A Little
- Trinity Health Kidney Centre, Trinity Translational Medicine Institute, Dublin, Ireland
| | - Stephen P McAdoo
- Centre for Inflammatory Disease, Department of Medicine, Imperial College London, London, UK
| | - Pavel Novikov
- Tareev Clinic of Internal Diseases, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Charles D Pusey
- Centre for Inflammatory Disease, Department of Medicine, Imperial College London, London, UK
| | - Antonella Radice
- Microbiology and Virology Institute, ASST Santi Paolo e Carlo, San Carlo Borromeo Hospital, Milan, Italy
| | - Alan D Salama
- UCL Department of Renal Medicine, Royal Free Hospital, London, UK
| | - Judith A Savige
- Department of Medicine, Melbourne Health, University of Melbourne, Melbourne, Australia
| | - Mårten Segelmark
- Department of Clinical Sciences, Lund University, Department of Nephrology and Rheumatology, Skane University Hospital, Lund, Sweden
| | - Yehuda Shoenfeld
- Zabludowicz Center for Autoimmune Diseases, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel, Sechenov First Moscow State Medical University, Moscow, Russia
| | - Renato A Sinico
- Department of Medicine and Surgery, Università degli Studi di Milano-Bicocca, Monza, Italy
| | - Maria-José Sousa
- Immunopathology and Autoimmunity Department, Centro de Medicina Laboratorial Germano de Sousa, Lisbon, Portugal
| | - Ulrich Specks
- Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA
| | - Benjamin Terrier
- Department of Internal Medicine, National Referral Center for Rare Systemic and Autoimmune Diseases, Hôpital Cochin, Paris, France
| | - Athanasios G Tzioufas
- Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Severine Vermeire
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, KU Leuven, Leuven, Belgium
| | - Ming-Hui Zhao
- Renal Division, Peking University First Hospital, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Peking-Tsinghua Centre for Life Sciences, Beijing, China
| | - Xavier Bossuyt
- Laboratory Medicine, University Hospitals Leuven, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
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14
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Gisbert JP, Chaparro M. Predictors of Primary Response to Biologic Treatment [Anti-TNF, Vedolizumab, and Ustekinumab] in Patients With Inflammatory Bowel Disease: From Basic Science to Clinical Practice. J Crohns Colitis 2020; 14:694-709. [PMID: 31777929 DOI: 10.1093/ecco-jcc/jjz195] [Citation(s) in RCA: 178] [Impact Index Per Article: 35.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Inflammatory bowel diseases [IBD]-ulcerative colitis and Crohn's disease-are commonly treated with biologic drugs. However, only approximately two-thirds of patients have an initial response to these therapies. Personalised medicine has the potential to optimise efficacy, decrease the risk of adverse drug events, and reduce costs by establishing the most suitable therapy for a selected patient. AIM The present study reviews the potential predictors of short-term primary response to biologic treatment, including not only anti-tumour necrosis factor [TNF] agents [such as infliximab, adalimumab, certolizumab, and golimumab] but also vedolizumab and ustekinumab. METHODS We performed a systematic bibliographical search to identify studies investigating predictive factors of response to biologic therapy. RESULTS For anti-TNF agents, most of the evaluated factors have not demonstrated usefulness, and many others are still controversial. Thus, only a few factors may have a potential role in the prediction of the response, including disease behaviour/phenotype, disease severity, C-reactive protein, albumin, cytokine expression in serum, previous anti-TNF therapy, some proteomic markers, and some colorectal mucosa markers. For vedolizumab, the availability of useful predictive markers seems to be even lower, with only some factors showing a limited value, such as the expression of α4β7 integrin in blood, the faecal microbiota, some proteomic markers, and some colorectal mucosa markers. Finally, in the case of ustekinumab, no predictive factor has been reported yet to be helpful in clinical practice. CONCLUSION In summary, currently no single marker fulfils all criteria for being an appropriate prognostic indicator of response to any biologic treatment in IBD.
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Affiliation(s)
- Javier P Gisbert
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa [IIS-IP], Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Madrid, Spain
| | - María Chaparro
- Gastroenterology Unit, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa [IIS-IP], Universidad Autónoma de Madrid, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas [CIBEREHD], Madrid, Spain
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15
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Anti-Saccharomyces cerevisiae Antibodies as a Prognostic Biomarker in Children With Crohn Disease. J Pediatr Gastroenterol Nutr 2019; 69:82-87. [PMID: 30789863 DOI: 10.1097/mpg.0000000000002311] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
OBJECTIVE Although anti-Saccharomyces cerevisiae antibodies (ASCAs) could be a useful biomarker in differentiating Crohn disease (CD) from ulcerative colitis (UC), their role as prognostic markers in children with CD has been underinvestigated. This longitudinal prospective observational study aimed to assess the prognostic value of ASCA status among children with CD managed using biologics. METHODS The study population comprised children with inflammatory bowel disease diagnosed with CD from 2012 to 2018. Cox regression model with adjustment for a priori covariates was used to examine the response to anti-tumor necrosis factor (TNF) biological therapy among ASCA-positive patients in comparison to ASCA-negative patients. RESULTS There were 273 measurements available from the study cohort comprising children with CD, who were followed up for a median duration of 14 months (interquartile range 5-42). ASCA-positive patients had a higher risk for moderate to severe clinical disease (odds ratio 2.88; 95% confidence interval [CI] 1.2-7.55) and extensive endoscopic distribution (odds ratio 3.30; CI 1.12-9.74) at baseline in comparison to ASCA-negative patients, respectively. In comparison to ASCA immunoglobulin G (IgG)-negative patients, ASCA IgG-positive patients who were treated with biologics had a significantly lower relapse rate (adjusted hazard ratio 0.12; CI 0.02-0.93). Ten (14%) patients had an unstable ASCA value with either ASCA immunoglobulin A or ASCA IgG status changing from positive to negative or vice versa. CONCLUSIONS ASCA-positive children with CD present with more extensive (endoscopic) and clinically severe disease. ASCA IgG is a useful prognostic marker among children with CD who receive biologics.
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16
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Early vedolizumab trough levels at induction in inflammatory bowel disease patients with treatment failure during maintenance. Eur J Gastroenterol Hepatol 2019; 31:478-485. [PMID: 30672828 DOI: 10.1097/meg.0000000000001356] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Vedolizumab (VDZ) is effective as an induction and maintenance treatment for Crohn's disease and ulcerative colitis, but, as observed with antitumour necrosis factor-α (anti-TNFα) agents, some patients are nonetheless experiencing loss of response. OBJECTIVE The aim of this study was to investigate the impact of the pharmacokinetics of VDZ during induction on long-term treatment response. PATIENTS AND METHODS This study focused on a single cohort of 103 inflammatory bowel disease patients treated with VDZ. VDZ trough levels (TLs) were measured by enzyme-linked immunosorbent assay (n=536 samples), and thereafter correlated to clinical, biological, endoscopic and serological data. For patients exposed previously to infliximab, antibodies to infliximab were measured at baseline. On the basis of the outcome at the end of follow-up, patients were then categorized into long-term response, optimized and treatment failure groups. RESULTS During VDZ induction, at week 6, inflammatory bowel disease patients with long-term response had higher TLs compared with patients in the treatment failure group (33 vs. 24 µg/ml, P=0.02). A cut-off TL of 28 µg/ml predicted a sustained response in the follow-up with an area under curve of 0.723 (95% confidence interval=0.567-0.878, P=0.02). Patients with mucosal healing in maintenance had higher TLs at week 6 (41.65 µg/ml) compared with patients with mild (26 µg/ml) or severe endoscopic activity (20.8 µg/ml), P=0.009. Positive perinuclear antineutrophil cytoplasmic antibody serology was associated with lower TLs. Patients previously exposed to anti-TNFα had lower TLs than naive patients (22.5 vs. 36 µg/ml, P=0.03) without any impact of detectable antibodies to infliximab. Finally, the presence of an immunomodulator at induction did not impact on VDZ TLs at induction. CONCLUSION We confirmed that a drug exposure-efficacy association was found early on at induction. This study emphasizes that previous exposure to anti-TNFα and positive perinuclear antineutrophil cytoplasmic antibody serology are important factors influencing VDZ TLs at induction.
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17
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Limon JJ, Tang J, Li D, Wolf AJ, Michelsen KS, Funari V, Gargus M, Nguyen C, Sharma P, Maymi VI, Iliev ID, Skalski JH, Brown J, Landers C, Borneman J, Braun J, Targan SR, McGovern DPB, Underhill DM. Malassezia Is Associated with Crohn's Disease and Exacerbates Colitis in Mouse Models. Cell Host Microbe 2019; 25:377-388.e6. [PMID: 30850233 DOI: 10.1016/j.chom.2019.01.007] [Citation(s) in RCA: 301] [Impact Index Per Article: 50.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 12/19/2018] [Accepted: 01/15/2019] [Indexed: 01/09/2023]
Abstract
Inflammatory bowel disease (IBD) is characterized by alterations in the intestinal microbiota and altered immune responses to gut microbiota. Evidence is accumulating that IBD is influenced by not only commensal bacteria but also commensal fungi. We characterized fungi directly associated with the intestinal mucosa in healthy people and Crohn's disease patients and identified fungi specifically abundant in patients. One of these, the common skin resident fungus Malassezia restricta, is also linked to the presence of an IBD-associated polymorphism in the gene for CARD9, a signaling adaptor important for anti-fungal defense. M. restricta elicits innate inflammatory responses largely through CARD9 and is recognized by Crohn's disease patient anti-fungal antibodies. This yeast elicits strong inflammatory cytokine production from innate cells harboring the IBD-linked polymorphism in CARD9 and exacerbates colitis via CARD9 in mouse models of disease. Collectively, these results suggest that targeting specific commensal fungi may be a therapeutic strategy for IBD.
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Affiliation(s)
- Jose J Limon
- F. Widjaja Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Jie Tang
- Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Dalin Li
- F. Widjaja Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Andrea J Wolf
- F. Widjaja Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Kathrin S Michelsen
- F. Widjaja Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Vince Funari
- Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Matthew Gargus
- F. Widjaja Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Christopher Nguyen
- F. Widjaja Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Purnima Sharma
- F. Widjaja Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Viviana I Maymi
- F. Widjaja Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Iliyan D Iliev
- Department of Medicine, Weill Cornell Medical College, New York, NY 10065, USA
| | - Joseph H Skalski
- F. Widjaja Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Jordan Brown
- Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Carol Landers
- F. Widjaja Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - James Borneman
- Department of Plant Pathology and Microbiology, University of California, Riverside, Riverside, CA 92521, USA
| | - Jonathan Braun
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Stephan R Targan
- F. Widjaja Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Dermot P B McGovern
- F. Widjaja Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - David M Underhill
- F. Widjaja Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
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18
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Hoseyni H, Xu Y, Zhou H. Therapeutic Drug Monitoring of Biologics for Inflammatory Bowel Disease: An Answer to Optimized Treatment? J Clin Pharmacol 2018; 58:864-876. [DOI: 10.1002/jcph.1084] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Accepted: 01/03/2018] [Indexed: 12/27/2022]
Affiliation(s)
- Hannah Hoseyni
- University of Pittsburgh School of Pharmacy; Pittsburgh PA USA
| | - Yan Xu
- Janssen Research & Development, LLC; Spring House PA USA
| | - Honghui Zhou
- Janssen Research & Development, LLC; Spring House PA USA
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19
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Lopetuso LR, Gerardi V, Papa V, Scaldaferri F, Rapaccini GL, Gasbarrini A, Papa A. Can We Predict the Efficacy of Anti-TNF-α Agents? Int J Mol Sci 2017; 18:ijms18091973. [PMID: 28906475 PMCID: PMC5618622 DOI: 10.3390/ijms18091973] [Citation(s) in RCA: 62] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 09/05/2017] [Accepted: 09/11/2017] [Indexed: 12/21/2022] Open
Abstract
The use of biologic agents, particularly anti-tumor necrosis factor (TNF)-α, has revolutionized the treatment of inflammatory bowel diseases (IBD), modifying their natural history. Several data on the efficacy of these agents in inducing and maintaining clinical remission have been accumulated over the past two decades: their use avoid the need for steroids therapy, promote mucosal healing, reduce hospitalizations and surgeries and therefore dramatically improve the quality of life of IBD patients. However, primary non-response to these agents or loss of response over time mainly due to immunogenicity or treatment-related side-effects are a frequent concern in IBD patients. Thus, the identification of predicting factors of efficacy is crucial to allow clinicians to efficiently use these therapies, avoiding them when they are ineffective and eventually shifting towards alternative biological therapies with the end goal of optimizing the cost-effectiveness ratio. In this review, we aim to identify the predictive factors of short- and long-term benefits of anti-TNF-α therapy in IBD patients. In particular, multiple patient-, disease- and treatment-related factors have been evaluated.
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Affiliation(s)
- Loris Riccardo Lopetuso
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Gemelli, Catholic University of Rome, 00168 Rome, Italy; (L.R.L.); (V.G.); (F.S.); (G.L.R.); (A.G.)
| | - Viviana Gerardi
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Gemelli, Catholic University of Rome, 00168 Rome, Italy; (L.R.L.); (V.G.); (F.S.); (G.L.R.); (A.G.)
| | - Valerio Papa
- Digestive Surgery Department, Fondazione Policlinico Gemelli, Catholic University of Rome, 00168 Rome, Italy;
| | - Franco Scaldaferri
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Gemelli, Catholic University of Rome, 00168 Rome, Italy; (L.R.L.); (V.G.); (F.S.); (G.L.R.); (A.G.)
| | - Gian Lodovico Rapaccini
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Gemelli, Catholic University of Rome, 00168 Rome, Italy; (L.R.L.); (V.G.); (F.S.); (G.L.R.); (A.G.)
| | - Antonio Gasbarrini
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Gemelli, Catholic University of Rome, 00168 Rome, Italy; (L.R.L.); (V.G.); (F.S.); (G.L.R.); (A.G.)
| | - Alfredo Papa
- Internal Medicine and Gastroenterology Department, Fondazione Policlinico Gemelli, Catholic University of Rome, 00168 Rome, Italy; (L.R.L.); (V.G.); (F.S.); (G.L.R.); (A.G.)
- Correspondence: ; Tel.: +39-06-3503310
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20
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Fischer S, Neurath MF. Precision Medicine in Inflammatory Bowel Diseases. Clin Pharmacol Ther 2017; 102:623-632. [DOI: 10.1002/cpt.793] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2017] [Revised: 07/07/2017] [Accepted: 07/10/2017] [Indexed: 12/19/2022]
Affiliation(s)
- Sarah Fischer
- Department of Medicine 1; Friedrich-Alexander University of Erlangen-Nürnberg; Germany
| | - Markus F. Neurath
- Department of Medicine 1; Friedrich-Alexander University of Erlangen-Nürnberg; Germany
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21
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Olbjørn C, Cvancarova Småstuen M, Thiis-Evensen E, Nakstad B, Vatn MH, Perminow G. Serological markers in diagnosis of pediatric inflammatory bowel disease and as predictors for early tumor necrosis factor blocker therapy. Scand J Gastroenterol 2017; 52:414-419. [PMID: 27887202 DOI: 10.1080/00365521.2016.1259653] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE To describe the prevalence of serological markers in newly diagnosed treatment-naïve pediatric inflammatory bowel disease (IBD), their utility in differentiating Crohn's disease (CD), ulcerative colitis (UC) and symptomatic non-IBD patients and whether serological markers are associated with early TNF blocker treatment. MATERIAL AND METHODS Ninety-six children and adolescents <18 years, 58 with IBD and 38 symptomatic non-IBD controls were included. At diagnosis and after 1-2 years, serological antibodies (anti-Saccharomyces cerevisiae antibodies (ASCA), perinuclear anti-neutrophil cytoplasmic antibody (pANCA), flagellin expressed by Clostridial phylum (anti-CBir1), outer membrane porin of Escherichia coli (anti-OmpC), Pseudomonas fluorescens-associated sequence (anti-I2), CRP, ESR and fecal calprotectin were analyzed. The choice of treatment was made at the discretion of the treating pediatrician. RESULTS Of the IBD patients, 20 (36%) and 26 (47%) were positive for ASCA and pANCA compared to 3(8%), p < .01 and 10 (27%), p = .04 of the controls. Thirteen (72%) of UC patients were pANCA positive, versus 13 (35%) of CD patients (p < .01). None of the UC patients was ASCA positive versus 20 (54%) of CD patients (p < .0001). Compared to conventionally treated patients, the 18 (49%) TNF blocker treated CD patients had higher presence of ASCA (p < .01), lower presence of pANCA (p = .02) and higher levels of fecal calprotectin, CRP and ESR at diagnosis. In multivariate analyses ASCA and pANCA status, but not CRP, ESR or calprotectin, were independently associated with early TNF blocker treatment. CONCLUSIONS ASCA and pANCA status were associated with having IBD and with early TNF blocker treatment in CD.
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Affiliation(s)
- Christine Olbjørn
- a Department of Pediatric and Adolescent Medicine , Akershus University Hospital , Lørenskog, Norway.,b Institute for Clinical Medicine, Campus Ahus , University of Oslo , Oslo, Norway
| | | | - Espen Thiis-Evensen
- d Department of Gastroenterology, Rikshospitalet , Oslo University Hospital , Oslo , Norway
| | - Britt Nakstad
- a Department of Pediatric and Adolescent Medicine , Akershus University Hospital , Lørenskog, Norway.,b Institute for Clinical Medicine, Campus Ahus , University of Oslo , Oslo, Norway
| | - Morten Harald Vatn
- e Epigen , Institute for Clinical Medicine, Campus Ahus, University of Oslo , Oslo , Norway
| | - Gøri Perminow
- f Department of Pediatrics, Ullevål , Oslo University Hospital , Oslo , Norway
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22
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Colombel JF, Narula N, Peyrin-Biroulet L. Management Strategies to Improve Outcomes of Patients With Inflammatory Bowel Diseases. Gastroenterology 2017; 152:351-361.e5. [PMID: 27720840 DOI: 10.1053/j.gastro.2016.09.046] [Citation(s) in RCA: 201] [Impact Index Per Article: 25.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 09/07/2016] [Accepted: 09/16/2016] [Indexed: 12/12/2022]
Abstract
Strategies for management of inflammatory bowel diseases are shifting from simple control of symptoms toward full control of these diseases (clinical and endoscopic remission), with the final aim of blocking their progression and preventing bowel damage and disability. New goals have been proposed for treatment, such as treat to target and tight control based on therapeutic monitoring and early intervention. For patients who achieve clinical remission, there is often interest in discontinuation of therapy due to safety or economic concerns. We review the evidence supporting these emerging paradigms, the reasons that early effective treatment can alter progression of inflammatory bowel diseases, the importance of examining objective signs of inflammation, and the safety of reducing treatment dosage. We also discuss recent findings regarding personalization of care, including factors that predict patient outcomes and response to therapies, as well as preventative strategies.
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Affiliation(s)
| | - Neeraj Narula
- Division of Gastroenterology, Department of Medicine and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Laurent Peyrin-Biroulet
- Institut National de la Santé et de la Recherche Médicale U954 and Department of Gastroenterology, Nancy University Hospital, Lorraine University, France
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23
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Lichtenstein GR, McGovern DPB. Using Markers in IBD to Predict Disease and Treatment Outcomes: Rationale and a Review of Current Status. ACTA ACUST UNITED AC 2016. [DOI: 10.1038/ajgsup.2016.17] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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24
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Turina MC, Landewé R, Baeten D. Lessons to be learned from serum biomarkers in psoriasis and IBD – the potential role in SpA. Expert Rev Clin Immunol 2016; 13:333-344. [DOI: 10.1080/1744666x.2017.1244004] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Maureen C. Turina
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands
| | - Robert Landewé
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands
| | - Dominique Baeten
- Department of Clinical Immunology and Rheumatology, Amsterdam Rheumatology and immunology Center, Academic Medical Center/University of Amsterdam, Amsterdam, The Netherlands
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25
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Iborra M, Beltrán B, Nos P. Noninvasive Testing for Mucosal Inflammation in Inflammatory Bowel Disease. Gastrointest Endosc Clin N Am 2016; 26:641-56. [PMID: 27633593 DOI: 10.1016/j.giec.2016.06.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Biomarkers have gained increasing attention for the diagnosis and follow-up of inflammatory bowel disease (IBD). Endoscopy remains the gold standard for assessing disease activity. Biomarkers are rapid, inexpensive, and noninvasive, and can be used in different stages of the disease with high sensitivity and specificity. Calprotectin and tests for C-reactive protein are used to assess the disease activity, predict relapse, and monitor treatment response. New noninvasive tests are being studied. This review discusses current evidence for these surrogate markers, their potential clinical applications, and limitations in disease management. We highlight recent advances in IBD biomarkers and future uses.
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Affiliation(s)
- Marisa Iborra
- Gastroenterology Department, Department of Digestive Disease, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), La Fe University and Polytechnic Hospital, Av. Fernando Abril Martorell, 106, Valencia 46026, Spain
| | - Belén Beltrán
- Gastroenterology Department, Department of Digestive Disease, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), La Fe University and Polytechnic Hospital, Av. Fernando Abril Martorell, 106, Valencia 46026, Spain
| | - Pilar Nos
- Gastroenterology Department, Department of Digestive Disease, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), La Fe University and Polytechnic Hospital, Av. Fernando Abril Martorell, 106, Valencia 46026, Spain.
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26
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Eder P, Korybalska K, Lykowska-Szuber L, Krela-Kazmierczak I, Stawczyk-Eder K, Klimczak K, Szymczak A, Linke K, Witowski J. Association of serum VEGF with clinical response to anti-TNFα therapy for Crohn's disease. Cytokine 2016; 76:288-293. [PMID: 26481259 DOI: 10.1016/j.cyto.2015.09.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2015] [Revised: 09/04/2015] [Accepted: 09/30/2015] [Indexed: 12/17/2022]
Abstract
Down-regulation of immune-mediated angiogenesis seems to be an important mechanism in anti-tumor necrosis factor α (anti-TNFα) therapy for Crohn's disease (CD). However, it remains to be established whether the baseline pro-angiogenic activity as reflected by the level of vascular endothelial growth factor (VEGF) could be of predictive value for successful clinical outcome of such treatment. Here, the levels of serum VEGF and other crucial angiogenesis-regulating peptides were assessed before and after induction anti-TNFα therapy in CD patients, and in age- and sex-matched healthy controls. Clinical, endoscopic, and biochemical activity of CD was estimated in parallel. CD patients were divided into two subgroups, depending on baseline VEGF levels: a "low-VEGF" subgroup with VEGF levels similar to those detected in healthy people, and a "high-VEGF" subgroup with VEGF levels significantly increased. VEGF levels were found to significantly correlate with CD clinical activity. Compared to the "low-VEGF" subgroup, the reduction in CD clinical activity as assessed by Crohn's Disease Activity Index was significantly greater in "high-VEGF" patients both in absolute numbers, and as a percentage of pre-treatment values. Accordingly, the fraction of patients who did not respond adequately to treatment was significantly greater in the "low-VEGF" group. These data indicate that VEGF may serve as an additional marker of CD activity and that baseline VEGF levels can be helpful in predicting the efficacy of anti-TNFα therapy.
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Affiliation(s)
- Piotr Eder
- Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, 49 Przybyszewskiego St., 60-355 Poznan, Poland.
| | - Katarzyna Korybalska
- Department of Pathophysiology, Poznan University of Medical Sciences, 8 Rokietnicka St., 60-806 Poznan, Poland
| | - Liliana Lykowska-Szuber
- Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, 49 Przybyszewskiego St., 60-355 Poznan, Poland
| | - Iwona Krela-Kazmierczak
- Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, 49 Przybyszewskiego St., 60-355 Poznan, Poland
| | - Kamila Stawczyk-Eder
- Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, 49 Przybyszewskiego St., 60-355 Poznan, Poland
| | - Katarzyna Klimczak
- Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, 49 Przybyszewskiego St., 60-355 Poznan, Poland
| | - Aleksandra Szymczak
- Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, 49 Przybyszewskiego St., 60-355 Poznan, Poland
| | - Krzysztof Linke
- Department of Gastroenterology, Human Nutrition and Internal Diseases, Poznan University of Medical Sciences, Heliodor Swiecicki Hospital, 49 Przybyszewskiego St., 60-355 Poznan, Poland
| | - Janusz Witowski
- Department of Pathophysiology, Poznan University of Medical Sciences, 8 Rokietnicka St., 60-806 Poznan, Poland
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Abstract
The genetic basis of antineutrophil cytoplasmic antibody, an important biomarker of inflammatory bowel disease (IBD), has never been thoroughly examined on a genome-wide scale. In this study, we performed a 2-stage genome-wide association study (GWAS) on antineutrophil cytoplasmic antibody in IBD cases. In the 2959 IBD cases in the discovery stage, we observed an association between a variant in the gene TNFRSF1B with antineutrophil cytoplasmic antibody level (rs5745994, minor allele frequency = 0.028, beta = 18.12, 95% CI, 11.82-24.22, P = 1.89 × 10). This association was replicated in an independent cohort of 419 IBD cases (beta = 16.91, 95% CI, 6.13-27.69, P = 2.38 × 10). With a Q-value of 0.036, we performed a fixed-effect meta-analysis for the association of rs5745994 in both cohorts and observed a stronger association signal (beta = 17.81, 95% CI, 12.36-23.25, P = 8.97 × 10). TNFRSF1B gene codes for tumor necrosis factor (TNF) receptor 2 (TNFR2), thereby we examined the reported TNFRSF1B variant with serum TNFR2 level. We observed a negative association with serum TNFR2 level being 8.23 EU/mL in carriers and 9.12 EU/mL in noncarriers (P = 0.033). This finding indicates the functional role of identified TNFRSF1B variant in IBD serology and may be reflective of the underlying biological mechanisms that determine clinical expression and/or response to certain therapies.
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28
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Mitsuyama K, Niwa M, Takedatsu H, Yamasaki H, Kuwaki K, Yoshioka S, Yamauchi R, Fukunaga S, Torimura T. Antibody markers in the diagnosis of inflammatory bowel disease. World J Gastroenterol 2016; 22:1304-1310. [PMID: 26811667 PMCID: PMC4716040 DOI: 10.3748/wjg.v22.i3.1304] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2015] [Revised: 07/23/2015] [Accepted: 09/30/2015] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, is a chronic intestinal inflammation of unknown etiology. The diagnosis of IBD is based on endoscopic, radiologic and histopathologic criteria. Recently, the search for a noninvasive marker that could augment or replace part of this diagnostic process has become a focus of IBD research. In this review, antibody markers, including microbial antibodies, autoantibodies and peptide antibodies, will be described, focusing on their common features. At present, no single marker with qualities that are satisfactory for the diagnosis and treatment of IBD has been identified, although panels of some antibodies are being evaluated with keen interest. The discovery of novel IBD-specific and sensitive markers is anticipated. Such markers could minimize the use of endoscopic and radiologic examinations and could enable clinicians to implement individualized treatment plans designed to improve the long-term prognosis of patients with IBD.
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29
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Ding NS, Hart A, De Cruz P. Systematic review: predicting and optimising response to anti-TNF therapy in Crohn's disease - algorithm for practical management. Aliment Pharmacol Ther 2016; 43:30-51. [PMID: 26515897 DOI: 10.1111/apt.13445] [Citation(s) in RCA: 233] [Impact Index Per Article: 25.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2015] [Revised: 09/02/2015] [Accepted: 10/05/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Nonresponse and loss of response to anti-TNF therapies in Crohn's disease represent significant clinical problems for which clear management guidelines are lacking. AIM To review the incidence, mechanisms and predictors of primary nonresponse and secondary loss of response to formulate practical clinical algorithms to guide management. METHODS Through a systematic literature review, 503 articles were identified which fit the inclusion criteria. RESULTS Primary nonresponse to anti-TNF treatment affects 13-40% of patients. Secondary loss of response to anti-TNF occurs in 23-46% of patients when determined according to dose intensification, and 5-13% of patients when gauged by drug discontinuation rates. Recent evidence suggests that the mechanisms underlying primary nonresponse and secondary loss of response are multifactorial and include disease characteristics (phenotype, location, severity); drug (pharmacokinetic, pharmacodynamic or immunogenicity) and treatment strategy (dosing regimen) related factors. Clinical algorithms that employ therapeutic drug monitoring (using anti-TNF tough levels and anti-drug antibody levels) may be used to determine the underlying cause of primary nonresponse and secondary loss of response respectively and guide clinicians as to which patients are most likely to respond to anti-TNF therapy and help optimise drug therapy for those who are losing response to anti-TNF therapy. CONCLUSIONS Nonresponse or loss of response to anti-TNF occurs commonly in Crohn's disease. Clinical algorithms utilising therapeutic drug monitoring may establish the mechanisms for treatment failure and help guide the subsequent therapeutic approach.
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Affiliation(s)
- N S Ding
- Department of Gastroenterology, St Mark's Hospital, Harrow, UK.,Department of Medicine, Imperial College London, London, UK.,Department of Medicine, University of Melbourne, Melbourne, Vic., Australia
| | - A Hart
- Department of Gastroenterology, St Mark's Hospital, Harrow, UK.,Department of Medicine, Imperial College London, London, UK
| | - P De Cruz
- Department of Medicine, University of Melbourne, Melbourne, Vic., Australia.,Department of Gastroenterology, Austin Health, Melbourne, Vic., Australia
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30
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Magnetic resonance enterographic predictors of one-year outcome in ileal and ileocolonic Crohn's disease treated with anti-tumor necrosis factor antibodies. Sci Rep 2015; 5:10223. [PMID: 25993615 PMCID: PMC4438711 DOI: 10.1038/srep10223] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 04/07/2015] [Indexed: 02/07/2023] Open
Abstract
The aim of the study was to assess the role of magnetic resonance enterography (MRE) in predicting one-year efficacy of anti-tumor necrosis factor antibodies - infliximab (IFX), adalimumab (ADA) in Crohn’s disease (CD) patients primarily responding to therapy. We performed retrospective analysis among 61 CD patients who had undergone a successful IFX/ADA induction therapy and were treated with maintenance doses. All patients underwent MRE at week 0. We assessed which MRE features were predictive for steroid-free remission at week 52, and which were associated with a secondary loss of response. 44 patients were in steroid-free remission at week 52, 17 - were secondary non-responders. The ROC curve showed that bowel thickening with contrast enhancement analyzed together at week 0 were associated with steroid-free remission at week 52 (p = 0.01; AUC 0.67). Bowel stenosis with or without prestenotic dilatation [OR 5.8 (95% CI 1.4 – 25) and 2.4 (95% CI 1.2 – 5) respectively; p = 0.01] and the presence of intra-abdominal fistulas [OR 1.4 (95% CI 1.1 – 2); p = 0.004] were related to secondary non-response. A high baseline inflammatory activity detected by MRE predicts one-year response in CD after IFX/ADA. In case of bowel stenosis, intra-abdominal fistulas, other therapeutic options should be considered.
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Abstract
The disease spectrum and natural course of Crohn's disease and ulcerative colitis are highly variable. The majority of Crohn's disease patients will require surgery at a certain stage in their disease compared to only a fraction of the ulcerative colitis patients. Similarly, some patients are destined to experience an indolent disease course while others will require early intensive therapy. Ideally, these subtypes of patients should be identified as early as possible with the help of reliable prognostic factors in order to guide personalized therapeutic decisions. In this review, the authors focused on the most relevant reports on the use of different prognostic factors to predict disease course, postoperative recurrence and response to therapy in patients with inflammatory bowel disease. The last 15 years have seen a wealth of novel genetic and serological markers of disease severity. Nevertheless, none of these markers have proven to be superior to careful clinical phenotyping and endoscopic features early in the disease course. Future attempts should apply an integrated approach that unites clinical, serological and (epi)genetic information with environmental influences, with a clear focus on the microbiome to ultimately identify molecular-based and clinically relevant subgroups.
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32
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Kevans D, Waterman M, Milgrom R, Xu W, Van Assche G, Silverberg M. Serological markers associated with disease behavior and response to anti-tumor necrosis factor therapy in ulcerative colitis. J Gastroenterol Hepatol 2015; 30:64-70. [PMID: 25041458 DOI: 10.1111/jgh.12661] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/27/2014] [Indexed: 12/18/2022]
Abstract
BACKGROUND AND AIM Information is limited on the relationship between serological markers and disease behavior and anti-tumor necrosis factor-α (anti-TNF) therapy response in ulcerative colitis (UC). This study aimed to determine the association between serological markers and unfavorable UC behavior defined as need for colectomy or UC-related hospitalization. The association between serological markers and requirement for and outcome of anti-TNF therapy was also evaluated. METHODS Two hundred thirty patients were studied. Requirement for colectomy, UC-related hospitalization, and anti-TNF therapy were documented. Response to anti-TNF therapy at 1 year and rates of therapy discontinuation were recorded. Titers of perinuclear anti-neutrophil cytoplasmic antibodies (pANCAs), anti-Saccharomyces cerevisiae antibody (ASCA), and antibody to Escherichia Coli outer membrane porin (anti-OmpC) were determined. Antibody reference ranges were used to dichotomize subjects into seropositive and seronegative groups. Where multiple tests were performed, P-values were Bonferroni corrected (pcorr). RESULTS Extensive colitis was associated with requirement for colectomy and UC-related hospitalization, HR 7.7 (95% confidence interval [CI] 1.9-32.2) pcorr = 0.03 and HR 2.7 (95% CI 1.5-4.6), pcorr = 0.006, respectively. No serological variable was associated with unfavorable UC behavior. Anti-OmpC positivity was associated with a lack of response to anti-TNF therapy at 1 year (odds ratio 0.14 [95% CI 0.03-0.60], pcorr = 0.04) and increased likelihood of therapy discontinuation (HR 2.2 [95% CI 1.1-4.7], P = 0.03). CONCLUSION Extensive colitis is associated with unfavorable disease course in UC. Anti-OmpC holds promise as a biomarker of anti-TNF therapy response in UC; however, prospective studies are required before it can be incorporated into routine clinical practice.
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Affiliation(s)
- David Kevans
- Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Canada; Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Canada
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Steeland S, Puimège L, Vandenbroucke RE, Van Hauwermeiren F, Haustraete J, Devoogdt N, Hulpiau P, Leroux-Roels G, Laukens D, Meuleman P, De Vos M, Libert C. Generation and characterization of small single domain antibodies inhibiting human tumor necrosis factor receptor 1. J Biol Chem 2014; 290:4022-37. [PMID: 25538244 DOI: 10.1074/jbc.m114.617787] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
The cytokine TNF is a well known drug target for several inflammatory diseases such as Crohn disease. Despite the great success of TNF blockers, therapy could be improved because of high costs and side effects. Selective inhibition of TNF receptor (TNFR) 1 signaling holds the potential to greatly reduce the pro-inflammatory activity of TNF, thereby preserving the advantageous immunomodulatory signals mediated by TNFR2. We generated a selective human TNFR1 inhibitor based on Nanobody (Nb) technology. Two anti-human TNFR1 Nbs were linked with an anti-albumin Nb to generate Nb Alb-70-96 named "TNF Receptor-One Silencer" (TROS). TROS selectively binds and inhibits TNF/TNFR1 and lymphotoxin-α/TNFR1 signaling with good affinity and IC50 values, both of which are in the nanomolar range. Surface plasmon resonance analysis reveals that TROS competes with TNF for binding to human TNFR1. In HEK293T cells, TROS strongly reduces TNF-induced gene expression, like IL8 and TNF, in a dose-dependent manner; and in ex vivo cultured colon biopsies of CD patients, TROS inhibits inflammation. Finally, in liver chimeric humanized mice, TROS antagonizes inflammation in a model of acute TNF-induced liver inflammation, reflected in reduced human IL8 expression in liver and reduced IL6 levels in serum. These results demonstrate the considerable potential of TROS and justify the evaluation of TROS in relevant disease animal models of both acute and chronic inflammation and eventually in patients.
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Affiliation(s)
- Sophie Steeland
- From the Inflammation Research Center, VIB, 9052 Ghent, the Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent
| | - Leen Puimège
- From the Inflammation Research Center, VIB, 9052 Ghent, the Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent
| | - Roosmarijn E Vandenbroucke
- From the Inflammation Research Center, VIB, 9052 Ghent, the Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent
| | - Filip Van Hauwermeiren
- From the Inflammation Research Center, VIB, 9052 Ghent, the Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent
| | - Jurgen Haustraete
- the Protein Service Facility, Inflammation Research Center, VIB, Ghent University, 9052 Ghent
| | - Nick Devoogdt
- the In Vivo Cellular and Molecular Imaging Laboratory and Cellular and Molecular Immunology Laboratory, Vrije Universiteit Brussel, 1000 Brussels, the Center for Vaccinology
| | - Paco Hulpiau
- From the Inflammation Research Center, VIB, 9052 Ghent, the Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent
| | | | - Debby Laukens
- Gastroenterology, Ghent University Hospital, 9000 Ghent, Belgium
| | | | - Martine De Vos
- Gastroenterology, Ghent University Hospital, 9000 Ghent, Belgium
| | - Claude Libert
- From the Inflammation Research Center, VIB, 9052 Ghent, the Department of Biomedical Molecular Biology, Ghent University, 9000 Ghent,
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Systematic review: new serological markers (anti-glycan, anti-GP2, anti-GM-CSF Ab) in the prediction of IBD patient outcomes. Autoimmun Rev 2014; 14:231-45. [PMID: 25462578 DOI: 10.1016/j.autrev.2014.11.004] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2014] [Accepted: 11/08/2014] [Indexed: 12/20/2022]
Abstract
Traditionally, IBD diagnosis is based on clinical, radiological, endoscopic, and histological criteria. Biomarkers are needed in cases of uncertain diagnosis, or to predict disease course and therapeutic response. No guideline recommends the detection of antibodies (including ASCA and ANCA) for diagnosis or prognosis of IBD to date. However, many recent data suggest the potential role of new serological markers (anti-glycan (ACCA, ALCA, AMCA, anti-L and anti-C), anti-GP2 and anti-GM-CSF Ab). This review focuses on clinical utility of these new serological markers in diagnosis, prognosis and therapeutic monitoring of IBD. Literature review of anti-glycan, anti-GP2 and anti-GM-CSF Ab and their impact on diagnosis, prognosis and prediction of therapeutic response was performed in PubMed/MEDLINE up to June 2014. Anti-glycan, anti-GP2 and anti-GM-CSF Ab are especially associated with CD and seem to be correlated with complicated disease phenotypes even if results differ between studies. Although anti-glycan Ab and anti-GP2 Ab have low sensitivity in diagnosis of IBD, they could identify a small number of CD patients not detected by other tests such as ASCA. Anti-glycan Abs are associated with a progression to a more severe disease course and a higher risk for IBD-related surgery. Anti-GP2 Ab could particularly contribute to better stratify cases of pouchitis. Anti-GM-CSF Ab seems to be correlated with disease activity and could help predict relapses. These new promising biomarkers could particularly be useful in stratification of patients according to disease phenotype and risk of complications. They could be a valuable aid in prediction of disease course and therapeutic response but more prospective studies are needed.
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Gonsky R, Deem RL, Landers CJ, Haritunians T, Yang S, Targan SR. IFNG rs1861494 polymorphism is associated with IBD disease severity and functional changes in both IFNG methylation and protein secretion. Inflamm Bowel Dis 2014; 20:1794-801. [PMID: 25171510 PMCID: PMC4327845 DOI: 10.1097/mib.0000000000000172] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND Mucosal expression of interferon (IFN)-γ plays a pivotal role in the pathogenesis of inflammatory bowel disease (IBD) and IBD risk regions flank IFNG. The conserved IFNG rs1861494 T/C introduces a new CpG methylation site, is associated with disease severity and lack of therapeutic response in other infectious and immune-mediated disorders, and is in linkage disequilibrium with a ulcerative colitis (UC) disease severity region. It seems likely that CpG-altering single nucleotide polymorphisms modify methylation and gene expression. This study evaluated the association between rs1861494 and clinical, serologic, and methylation patterns in patients with IBD. METHODS Peripheral T cells of UC and Crohn's disease (CD) patients were genotyped for rs1861494 and analyzed for allele-specific and IFNG promoter methylation. Serum antineutrophil cytoplasmic autoantibodies and IFN-γ secretion were measured by enzyme-linked immunosorbent assay and nucleoprotein complex formation by electrophoretic mobility shift assay. RESULTS IFNG rs1861494 T allele carriage in patients with IBD was associated with enhanced secretion of IFN-γ. T allele carriage was associated in UC with high levels of antineutrophil cytoplasmic autoantibodies and faster progression to colectomy. In CD, it was associated with complicated disease involving a stricturing/penetrating phenotype. Likewise, IFNG rs1861494 displayed genotype-specific modulation of DNA methylation and transcription factor complex formation. CONCLUSIONS This study reports the first association of IFNG rs1861494 T allele with enhanced IFN-γ secretion and known IBD clinical parameters indicative of more aggressive disease and serological markers associated with treatment resistance to anti-tumor necrosis factor therapy in patients with IBD. These data may be useful prognostically as predictors of early response to anti-tumor necrosis factor therapy to identify patients with IBD for improved personalized therapeutics.
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Affiliation(s)
- Rivkah Gonsky
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048 USA
| | - Richard L Deem
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048 USA
| | - Carol J Landers
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048 USA
| | - Talin Haritunians
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048 USA
| | - Shaohong Yang
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048 USA
| | - Stephan R Targan
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048 USA
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Singh S, Pardi DS. Update on anti-tumor necrosis factor agents in Crohn disease. Gastroenterol Clin North Am 2014; 43:457-78. [PMID: 25110253 DOI: 10.1016/j.gtc.2014.05.008] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Anti-tumor necrosis factor-α (TNF) agents, including infliximab, adalimumab, and certolizumab pegol, are effective medications for the management of moderate to severe Crohn disease (CD). They are effective in inducing and maintaining clinical remission, inducing mucosal healing, improving quality of life, and reducing the risk of hospitalization and surgery in adult and pediatric patients with CD. Future research into comparative effectiveness of different agents, as well as better understanding of predictors of response, is warranted to allow optimization of therapeutic response.
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Affiliation(s)
- Siddharth Singh
- Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, 200 First Street South West, Rochester, MN 55905, USA
| | - Darrell S Pardi
- Inflammatory Bowel Disease Clinic, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, 200 First Street South West, Rochester, MN 55905, USA.
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Kovács M, Müller KE, Papp M, Lakatos PL, Csöndes M, Veres G. New serological markers in pediatric patients with inflammatory bowel disease. World J Gastroenterol 2014; 20:4873-4882. [PMID: 24803798 PMCID: PMC4009518 DOI: 10.3748/wjg.v20.i17.4873] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Revised: 01/16/2014] [Accepted: 03/06/2014] [Indexed: 02/07/2023] Open
Abstract
The spectrum of serological markers associated with inflammatory bowel disease (IBD) is rapidly growing. Due to frequently delayed or missed diagnoses, the application of non-invasive diagnostic tests for IBD, as well as differentiation between ulcerative colitis (UC) and Crohn's disease (CD), would be useful in the pediatric population. In addition, the combination of pancreatic autoantibodies and antibodies against Saccharomyces cerevisiae antibodies/perinuclear cytoplasmic antibody (pANCA) improved the sensitivity of serological markers in pediatric patients with CD and UC. Some studies suggested that age-associated differences in the patterns of antibodies may be present, particularly in the youngest children. In CD, most patients develop stricturing or perforating complications, and a significant number of patients undergo surgery during the disease course. Based on recent knowledge, serum antibodies are qualitatively and quantitatively associated with complicated CD behavior and CD-related surgery. Pediatric UC is characterized by extensive colitis and a high rate of colectomy. In patients with UC, high levels of anti-CBir1 and pANCA are associated with the development of pouchitis after ileal pouch-anal anastomosis. Thus, serologic markers for IBD can be applied to stratify IBD patients into more homogeneous subgroups with respect to disease progression. In conclusion, identification of patients at an increased risk of rapid disease progression is of great interest, as the application of early and more aggressive pharmaceutical intervention could have the potential to alter the natural history of IBD, and reduce complications and hospitalizations.
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Abstract
The expanding knowledge of the role of genetic variants involved in the susceptibility to IBD heralds an era of disease categorization beyond Crohn's disease and ulcerative colitis. A more robust molecular definition of the spectrum of IBD subtypes is likely to be based on specific molecular pathways that determine not only disease susceptibility but also disease characteristics such as location, natural history and therapeutic response. Evolving diagnostic panels for IBD will include clinical variables and genetic markers as well as other indicators of gene function and interaction with environmental factors, such as the microbiome. Multimodal algorithms that combine clinical, serologic and genetic information are likely to be useful in predicting disease course. Variation in IBD-susceptibility and drug-related pathway genes seems to influence the response to anti-TNF therapy. Furthermore, gene expression signatures and composite models have both shown promise as predictors of therapeutic response. Ultimately, models based on combinations of genotype and gene expression data with clinical, biochemical, serological, and microbiome data for clinically meaningful subgroups of patients should permit the development of tools for individualized risk stratification and treatment selection.
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Porayette P, Flockhart D, Gupta SK. One size fits one: pharmacogenetics in gastroenterology. Clin Gastroenterol Hepatol 2014; 12:565-70. [PMID: 24486737 DOI: 10.1016/j.cgh.2014.01.035] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Accepted: 01/28/2014] [Indexed: 02/07/2023]
Abstract
Individual variability in response and development of adverse effects to drugs is a major challenge in clinical practice. Pharmacogenomics refers to the aspect of personalized medicine where the patient's genetic information instructs the selection and dosage of therapy while also predicting its adverse effects profile. Sequencing of the entire human genome has given us the opportunity to study commonly used drugs as well as newer therapeutic agents in a new light, opening up opportunities for better drug efficacy and decreased adverse effects. This article highlights developments in pharmacogenomics, relates these to practice of gastroenterology, and outlines roadblocks in translation of this knowledge into clinical practice.
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Affiliation(s)
- Prashanth Porayette
- Division of Pediatric Gastroenterology/Hepatology/Nutrition, Riley Hospital for Children/Indiana University School of Medicine, Indianapolis, Indiana
| | - David Flockhart
- Division of Clinical Pharmacology, Department of Medicine, Riley Hospital for Children/Indiana University School of Medicine, Indiana Institute for Personalized Medicine, Indianapolis, Indiana
| | - Sandeep K Gupta
- Division of Pediatric Gastroenterology/Hepatology/Nutrition, Riley Hospital for Children/Indiana University School of Medicine, Indianapolis, Indiana.
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Cravo M, Ferreira P, Sousa P, Moura-Santos P, Velho S, Tavares L, Deus JR, Ministro P, da Silva JP, Correia L, Velosa J, Maio R, Brito M. Clinical and genetic factors predicting response to therapy in patients with Crohn's disease. United European Gastroenterol J 2014; 2:47-56. [PMID: 24918007 PMCID: PMC4040806 DOI: 10.1177/2050640613519626] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Accepted: 12/14/2013] [Indexed: 12/18/2022] Open
Abstract
AIM To identify clinical and/or genetic predictors of response to several therapies in Crohn's disease (CD) patients. METHODS We included 242 patients with CD (133 females) aged (mean ± standard deviation) 39 ± 12 years and a disease duration of 12 ± 8 years. The single-nucleotide polymorphisms (SNPs) studied were ABCB1 C3435T and G2677T/A, IL23R G1142A, C2370A, and G9T, CASP9 C93T, Fas G670A and LgC844T, and ATG16L1 A898G. Genotyping was performed with real-time PCR with Taqman probes. RESULTS Older patients responded better to 5-aminosalicylic acid (5-ASA) and to azathioprine (OR 1.07, p = 0.003 and OR 1.03, p = 0.01, respectively) while younger ones responded better to biologicals (OR 0.95, p = 0.06). Previous surgery negatively influenced response to 5-ASA compounds (OR 0.25, p = 0.05), but favoured response to azathioprine (OR 2.1, p = 0.04). In respect to genetic predictors, we observed that heterozygotes for ATGL16L1 SNP had a significantly higher chance of responding to corticosteroids (OR 2.51, p = 0.04), while homozygotes for Casp9 C93T SNP had a lower chance of responding both to corticosteroids and to azathioprine (OR 0.23, p = 0.03 and OR 0.08, p = 0.02,). TT carriers of ABCB1 C3435T SNP had a higher chance of responding to azathioprine (OR 2.38, p = 0.01), while carriers of ABCB1 G2677T/A SNP, as well as responding better to azathioprine (OR 1.89, p = 0.07), had a lower chance of responding to biologicals (OR 0.31, p = 0.07), which became significant after adjusting for gender (OR 0.75, p = 0.005). CONCLUSIONS In the present study, we were able to identify a number of clinical and genetic predictors of response to several therapies which may become of potential utility in clinical practice. These are preliminary results that need to be replicated in future pharmacogenomic studies.
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Affiliation(s)
- Marilia Cravo
- Hospital Beatriz Angelo, Loures, Portugal
- Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
| | - Paula Ferreira
- Escola Superior de Tecnologias da Saude, Lisbon, Portugal
| | | | - Paula Moura-Santos
- Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
- Hospital Santa Maria, Lisboa, Portugal
| | | | | | | | | | | | - Luis Correia
- Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
- Hospital Santa Maria, Lisboa, Portugal
| | - Jose Velosa
- Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
- Hospital Santa Maria, Lisboa, Portugal
| | - Rui Maio
- Hospital Beatriz Angelo, Loures, Portugal
| | - Miguel Brito
- Escola Superior de Tecnologias da Saude, Lisbon, Portugal
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Preliminary Case-control Study to Evaluate Diagnostic Values of C-Reactive Protein and Erythrocyte Sedimentation Rate in Differentiating Active Crohn’s Disease From Intestinal Lymphoma, Intestinal Tuberculosis and Behcet’s Syndrome. Am J Med Sci 2013; 346:467-72. [DOI: 10.1097/maj.0b013e3182959a18] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Abstract
Inflammatory bowel diseases (IBDs; e.g., Crohn's disease [CD] and ulcerative colitis [UC]) are chronic immunologically mediated diseases characterized by frequent relapses, often requiring hospitalization and surgery. There is substantial heterogeneity in the progressive natural history of disease with cumulative accrual of bowel damage and impairment of functioning. Recent advances in therapeutics have significantly improved our ability to achieve disease remission; yet therapies remain expensive and are associated with significant side effects precluding widespread use in all patients with IBD. Consequently, algorithms for the management of patients with IBD require a personalized approach incorporating an individual's projected likely natural history, the probability of response to a specific therapeutic agent and an informed approach to management of loss of response to current therapies.
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Affiliation(s)
- Ashwin N Ananthakrishnan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, 165 Cambridge Street, 9th Floor, Boston, MA 02114, USA.
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43
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Abstract
Inflammatory bowel disease (IBD) is a heterogeneous group of chronic inflammatory disorders of the gastrointestinal tract with two main distinguishable entities, Crohn’s disease (CD) and ulcerative colitis (UC). IBD-unclassified (IBD-U) is a diagnosis that covers the “grey” zone of diagnostic uncertainty between UC and CD. Current diagnosis of IBD relies on the clinical, endoscopic, radiological, histological and biochemical features, but this approach has shortcomings especially in cases of overlapping symptoms of CD and UC. The need for a diagnostic tool that would improve the conventional methods in IBD diagnosis directed the search towards potential immunological markers, since an aberrant immune response against microbial or endogenous antigens in a genetically susceptible host seems to be implicated in IBD pathogenesis. The spectrum of antibodies to different microbial antigens and autoantibodies associated with IBD is rapidly expanding. Most of these antibodies are associated with CD like anti-glycan antibodies: anti-Saccharomices cerevisiae (ASCA) and the recently described anti-laminaribioside (ALCA), anti-chitobioside (ACCA), anti-mannobioside (AMCA), anti-laminarin (anti-L) and anti-chitin (anti-C) antibodies; in addition to other antibodies that target microbial antigens: anti-outer membrane porin C (anti-OmpC), anti-Cbir1 flagellin and anti-I2 antibody. Also, autoantibodies targeting the exocrine pancreas (PAB) were shown to be highly specific for CD. In contrast, UC has been associated with anti-neutrophil cytoplasmic autoantibodies (pANCA) and antibodies against goblet cells (GAB). Current evidence suggests that serologic panels of multiple antibodies are useful in differential diagnosis of CD versus UC and can be a valuable aid in stratifying patients according to disease phenotype and risk of complications.
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Affiliation(s)
- Andrea Tesija Kuna
- University Department of Chemistry, Medical School University Hospital Sestre Milosrdnice, Zagreb, Croatia.
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Prideaux L, De Cruz P, Ng SC, Kamm MA. Serological antibodies in inflammatory bowel disease: a systematic review. Inflamm Bowel Dis 2012; 18:1340-55. [PMID: 22069240 DOI: 10.1002/ibd.21903] [Citation(s) in RCA: 137] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2011] [Accepted: 08/25/2011] [Indexed: 12/13/2022]
Abstract
The diagnosis of inflammatory bowel disease (IBD) is traditionally based on a combination of clinical, endoscopic, histological, and radiological criteria. However, further testing is needed in cases of diagnostic uncertainty and in predicting disease course. This systematic review focuses on the potential for 10 serological antibodies to fill these roles: pANCA, ASCA, anti-OmpC, anti-CBir1, anti-I2, ALCA, ACCA, AMCA, anti-L, and anti-C. We discuss their prevalence in IBD and health; their role in disease diagnosis and risk stratification; their stability over time; their presence in unaffected relatives; their association with genetic variants; and differences across ethnic groups. Serological antibodies have some role in primary diagnosis and in differentiating between Crohn's disease and ulcerative colitis. In indeterminate colitis, preoperative measurement of serological antibodies can help to predict the likelihood of complications among patients undergoing pouch surgery. The combined presence and magnitude of a large panel of antibodies appear to be of value in predicting disease progression. There is currently insufficient evidence to recommend the use of antibody testing to predict responses to treatment or surgery in patients with IBD.
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Affiliation(s)
- Lani Prideaux
- Department of Gastroenterology, St Vincent's Hospital Melbourne, Australia
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45
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Abstract
The search for the underlying trigger of an inappropriate inflammatory reaction characteristic of inflammatory bowel diseases (IBD) has led to the discovery of several antibodies. The panel of serologic markers for IBD is rapidly expanding. Serologic markers hold the promise of helping researchers and clinicians to better understand IBD heterogeneity and natural history. The real importance of the antibodies produced against various microbial and autoantigens is still uncertain. Whether these antibodies play a primary role in the pathogenesis of IBD, or their presence is only a consequence of the inflamed mucosa is a fundamental question that remains to be clarified. The impact of the routine evaluation of these serologic markers in the everyday clinical IBD diagnostic algorithm is questionable due to their limited sensitivity. Despite their great potential, the routine use of serologic markers for diagnosis and follow-up is currently not justified. However, their correlation with disease phenotype and behavior is more established. A combination of serum markers has been shown to be of more value compared to using single markers alone. The ongoing challenge is how to best utilize these serologic markers to provide clinically relevant information in a cost-effective manner. Further prospective clinical trials are needed to determine their exact role in pathogenesis and practical clinical importance. We review the current standpoint of the clinical impact of various established and newly suggested markers in Crohn's disease and ulcerative colitis.
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Affiliation(s)
- László Herszényi
- Second Department of Medicine, Semmelweis University, Budapest, Hungary.
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Profiles of circulating cytokines in patients with Crohn's disease under maintenance therapy with infliximab. J Crohns Colitis 2012; 6:529-35. [PMID: 22398057 DOI: 10.1016/j.crohns.2011.10.010] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2011] [Revised: 09/29/2011] [Accepted: 10/25/2011] [Indexed: 02/08/2023]
Abstract
BACKGROUND AND AIMS The effects of maintenance infliximab for Crohn's disease vary widely among patients. The aim of this study was to examine the cytokine profiles and to identify possible markers predictive of therapeutic effect of maintenance infliximab. METHODS Cytokine profiles of 35 Crohn's disease patients under maintenance infliximab therapy were analyzed prospectively. Blood samples were obtained prior to, and 2 and 6 weeks after infliximab infusion. Circulating cytokine values of interleukin (IL)-23, IL-17A, IL-12, IL-6, interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α) were compared according to the disease activity and therapeutic efficacy. Patients were classified into either the active or quiescent phase according to their disease activity at baseline. Patients were also divided into a sustained response group and non-sustained response group according to therapeutic efficacy of infliximab determined 2 and 6 weeks after infliximab infusion. RESULTS At baseline, serum levels of IL-23 (p<0.05), IL-17A (p<0.01), IFN-γ (p<0.05), and IL-6 (p<0.01) were significantly higher in active Crohn's disease than in quiescent disease. These cytokine levels remained unchanged during the follow-up period. When serum cytokine levels were compared between groups classified by therapeutic efficacy of infliximab, patients in the non-sustained response group had a significantly higher level of serum IL-17A than those in the sustained response group (p<0.05). There were also trends toward higher serum IL-23 and IL-12 in the former than in the latter. CONCLUSION Higher levels of IL-17A, IL-23, and IL-12 at baseline may be predictive markers for poor therapeutic response to maintenance infliximab therapy.
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47
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Siegel CA, Melmed GY. Predicting response to Anti-TNF Agents for the treatment of crohn's disease. Therap Adv Gastroenterol 2011; 2:245-51. [PMID: 21180547 DOI: 10.1177/1756283x09336364] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The arrival of anti-tumor necrosis factor (TNF) agents has led to a dramatic improvement in the care of patients with Crohn's disease. Since these medications do not work in everyone, and are associated with rare, but serious side effects, we want to selectively treat patients who have the highest chance of responding. A number of variables have been studied to determine their association with response to anti-TNF agents. Clinical parameters include patient characteristics, smoking status and disease phenotype, and biologic markers include C-reactive protein, serum TNF levels and immune responses to microbial antigens. More recently, research has focused on genetics to identify polymorphisms associated with treatment response. Results from individual studies of these factors have not yet allowed for solid clinical applicability. However, further work in this area along with multivariate clinical prediction modeling may soon allow us to deliver 'personalized medicine' by predicting individualized treatment response in patients with Crohn's disease.
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Affiliation(s)
- Corey A Siegel
- Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA
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Daperno M, Castiglione F, de Ridder L, Dotan I, Färkkilä M, Florholmen J, Fraser G, Fries W, Hebuterne X, Lakatos PL, Panés J, Rimola J, Louis E. Results of the 2nd part Scientific Workshop of the ECCO. II: Measures and markers of prediction to achieve, detect, and monitor intestinal healing in inflammatory bowel disease. J Crohns Colitis 2011; 5:484-498. [PMID: 21939926 DOI: 10.1016/j.crohns.2011.07.003] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2011] [Accepted: 07/08/2011] [Indexed: 12/13/2022]
Abstract
The healing of the intestine is becoming an important objective in the management of inflammatory bowel diseases. It is associated with improved disease outcome. Therefore the assessment of this healing both in clinical studies and routine practice is a key issue. Endoscopy for the colon and terminal ileum and computerized tomography or magnetic resonance imaging for the small bowel are the most direct ways to evaluate intestinal healing. However, there are many unsolved questions about the definition and the precise assessment of intestinal healing using these endoscopic and imaging techniques. Furthermore, these are relatively invasive and expensive procedures that may be inadequate for regular patients' monitoring. Therefore, biomarkers such as C-reactive protein and fecal calprotectin have been proposed as surrogate markers for intestinal healing. Nevertheless, the sensitivity and specificity of these markers for the prediction of healing may be insufficient for routine practice. New stool, blood or intestinal biomarkers are currently studied and may improve our ability to monitor intestinal healing in the future.
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Affiliation(s)
- Marco Daperno
- Gastroenterology Division, AO Ordine Mauriziano, Torino, Italy
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Allenspach K. Clinical immunology and immunopathology of the canine and feline intestine. Vet Clin North Am Small Anim Pract 2011; 41:345-60. [PMID: 21486640 DOI: 10.1016/j.cvsm.2011.01.004] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The mucosal immune system is at the forefront of defense against invading pathogens, but at the same time, it must maintain tolerance toward commensals and food antigens in the intestinal lumen. The interplay between the innate immune response and commensal microorganisms is essential to maintaining this balance. Great progress has been made in identifying some of the genetic predispositions underlying inflammatory bowel disease in certain breeds, such as the German shepherd dog. Several immunologic markers are discussed with respect to their clinical usefulness in the diagnosis and management of inflammatory bowel disease.
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Affiliation(s)
- Karin Allenspach
- Royal Veterinary College, University of London, Hawkshead Lane, North Mymms AL9 7PT, UK.
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50
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Tamboli CP, Doman DB, Patel A. Current and future role of biomarkers in Crohn's disease risk assessment and treatment. Clin Exp Gastroenterol 2011; 4:127-40. [PMID: 21753895 PMCID: PMC3132855 DOI: 10.2147/ceg.s18187] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2011] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Crohn's disease (CD), a chronic inflammatory bowel disease (IBD), occurs in genetically susceptible individuals who develop aberrant immune responses to endoluminal bacteria. Recurrent inflammation increases the risk of several complications. Despite use of a traditional "step-up" therapy with corticosteroids and immunomodulators, most CD patients eventually require surgery at some time in their disease course. Newer biologic agents have been remarkably effective in controlling severe disease. Thus, "top-down," early aggressive therapy has been proposed to yield better outcomes, especially in complicated disease. However, safety and cost issues mandate the need for careful patient selection. Identification of high-risk candidates who may benefit from aggressive therapy is becoming increasingly relevant. Serologic and genetic markers of CD have great potential in this regard. The aim of this review is to highlight the clinical relevance of these markers for diagnostics and prognostication. METHODS A current PubMed literature search identified articles regarding the role of biomarkers in IBD diagnosis, severity prediction, and stratification. Studies were also reviewed on the presence of IBD markers in non-IBD diseases. RESULTS Several IBD seromarkers and genetic markers appear to be associated with complex CD phenotypes. Qualitative and quantitative serum immune reactivity to microbial antigens may be predictive of disease progression and complications. CONCLUSION The cumulative evidence provided by serologic and genetic testing has the potential to enhance clinical decision-making when formulating individualized IBD therapeutic plans.
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Affiliation(s)
- Cyrus P Tamboli
- Department of Internal Medicine, Division of Gastroenterology, University of Iowa, Iowa City, IA, USA
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