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Chen L, Zhang C, Niu R, Xiong S, He J, Wang Y, Zhang P, Su F, Liu Z, Zhou L, Mao R, Hu S, Chen M, Qiu Y, Feng R. Multi-Omics Biomarkers for Predicting Efficacy of Biologic and Small-Molecule Therapies in Adults With Inflammatory Bowel Disease: A Systematic Review. United European Gastroenterol J 2025; 13:517-530. [PMID: 39656426 PMCID: PMC12090831 DOI: 10.1002/ueg2.12720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Revised: 10/09/2024] [Accepted: 10/14/2024] [Indexed: 05/21/2025] Open
Abstract
The heterogeneity and suboptimal efficacy of biological treatments and small molecule drugs necessitate their precise selection based on biomarkers that predict therapeutic responses in inflammatory bowel disease. Recent studies have identified numerous novel biomarkers predictive of responses to biologics and small molecule modulators, utilizing a variety of omics approaches in inflammatory bowel disease. In this review, we systematically examine baseline omics biomarkers that predict responses to biological therapies and small molecule drugs, drawing on literature from PubMed. Our analysis spans multiple omics disciplines, including genomics, transcriptomics (both bulk RNA and single-cell RNA sequencing), proteomics, microbiomics, and metabolomics, with particular emphasis on the impact of models integrating multiple omics datasets. Additionally, to further the field of precision medicine, we evaluated specific biomarkers that may exhibit distinct effects on responses to multiple therapeutic interventions.
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Affiliation(s)
- Liru Chen
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Chuhan Zhang
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Ruixuan Niu
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Shanshan Xiong
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Jinshen He
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Yu Wang
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Pingxin Zhang
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Fengyuan Su
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Institute of Precision MedicineThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Zishan Liu
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Longyuan Zhou
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Ren Mao
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Shixian Hu
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Institute of Precision MedicineThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Minhu Chen
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Yun Qiu
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
| | - Rui Feng
- Department of GastroenterologyThe First Affiliated HospitalSun Yat‐sen UniversityGuangzhouChina
- Guangxi Hospital DivisionThe First Affiliated HospitalSun Yat‐sen UniversityNanningChina
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Hirten RP, Lin KC, Whang J, Shahub S, Helmus D, Muthukumar S, Sands BE, Prasad S. Longitudinal assessment of sweat-based TNF-alpha in inflammatory bowel disease using a wearable device. Sci Rep 2024; 14:2833. [PMID: 38310197 PMCID: PMC10838338 DOI: 10.1038/s41598-024-53522-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2023] [Accepted: 02/01/2024] [Indexed: 02/05/2024] Open
Abstract
Wearable devices can non-invasively monitor patients with chronic diseases. Sweat is an easily accessible biofluid for continuous sampling of analytes, including inflammatory markers and cytokines. We evaluated a sweat sensing wearable device in subjects with and without inflammatory bowel disease (IBD), a chronic inflammatory condition of the gastrointestinal tract. Participants with an IBD related hospital admission and a C-reactive protein level above 5 mg/L wore a sweat sensing wearable device for up to 5 days. Tumor necrosis factor-alpha (TNF-α) levels were continually assessed in the sweat via the sensor, and daily in the blood. A second cohort of healthy subjects without chronic diseases wore the device for up to 48 h. Twenty-eight subjects were enrolled. In the 16 subjects with IBD, a moderate linear relationship between serum and sweat TNF-α levels was observed (R2 = 0.72). Subjects with IBD were found to have a mean sweat TNF-α level of 2.11 pg/mL, compared to a mean value of 0.19 pg/mL in 12 healthy controls (p < 0.0001). Sweat TNF-α measurements differentiated subjects with active IBD from healthy subjects with an AUC of 0.962 (95% CI 0.894-1.000). A sweat sensing wearable device can longitudinally measure key sweat-based markers of IBD. TNF-α levels in the sweat of subjects with IBD correlate with serum values, suggesting feasibility in non-invasive disease monitoring.
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Affiliation(s)
- Robert P Hirten
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Kai-Chun Lin
- Bioengineering, University of Texas at Dallas, 800 West Campbell Rd., Richardson, TX, 75080-3021, USA
| | - Jessica Whang
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Sarah Shahub
- Bioengineering, University of Texas at Dallas, 800 West Campbell Rd., Richardson, TX, 75080-3021, USA
| | - Drew Helmus
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Bruce E Sands
- The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Shalini Prasad
- Bioengineering, University of Texas at Dallas, 800 West Campbell Rd., Richardson, TX, 75080-3021, USA.
- EnLiSense LLC, Allen, TX, USA.
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Wang F, Li X, Shi Y, Zhou H, Yang G, Li R, Wu T, Liang J. Efficacy and safety of adalimumab biosimilar (HS016) in inflammatory bowel disease from the real-world study. Front Pharmacol 2023; 14:1259183. [PMID: 37908975 PMCID: PMC10613675 DOI: 10.3389/fphar.2023.1259183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Accepted: 10/03/2023] [Indexed: 11/02/2023] Open
Abstract
Objective: Adalimumab (ADA) is an effective treatment for inflammatory bowel disease (IBD), both ulcerative colitis (UC) and Crohn's disease (CD). The equal effect between the original ADA and biosimilars from Europe and the United States has been shown. However, the biosimilar of ADA is different in China. The effectiveness and safety data of ADA biosimilar (HS016) in China have yet to be discovered. Patients and methods: 91 patients (75 CD, 16 UC) received HS016 treatment and were enrolled in this study. Therapeutic response and safety profiles were analyzed. Therapeutic drug monitoring (TDM) was also carried out among nonresponse patients. After being considered as "nonresponse" (after three or 6 months of treatment), 20 patients' serum TNFα concentrations were measured and correlated to their disease severity. Results: Among active CD patients (n = 61), 75.4% (46/61) at 12 w, 73.8% (45/61) at 26 w, 50.8% (31/61) at 52 w achieved the clinical response, respectively; 55.7% (34/61) at 12 w, 65.6% (40/61) at 26 w, and 45.9% (28/61) at 52 w achieved clinical remission. The maintained remission rates of CD (n = 14) in clinical remission were 100% (14/14) at 12 w, 78.6% (11/14) at 26 w, and 63.6% (7/11) at 52 w, respectively. Among active UC patients, 37.5% (6/16) at 12 w and 50% (8/16) at 26 w achieved clinical response. Total adverse event rates were 5.5% (5/91) during 52-week visits. Due to the inadequate serum drug concentration, 30.4% (7/23) of patients had poor clinical responses. Elevations of serum anti-drug antibodies occurred in one additional patient (4.3%). Conclusion: ADA biosimilar HS016 had good efficacy and safety in Chinese IBD patients.
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Affiliation(s)
| | | | | | | | | | | | - Tong Wu
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
| | - Jie Liang
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers and National Clinical Research Center for Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi’an, China
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Shi X, Wang JH, Rao SX, Liu TT, Wu H. A novel role of the splenic volume in Crohn's disease: evaluating the efficacy of infliximab. Front Pharmacol 2023; 14:1246657. [PMID: 37663264 PMCID: PMC10470019 DOI: 10.3389/fphar.2023.1246657] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2023] [Accepted: 07/25/2023] [Indexed: 09/05/2023] Open
Abstract
Background: A number of patients with Crohn's disease (CD) suffer from loss of response to infliximab (IFX) therapy. Splenic volume is reported to be enlarged in patients with CD compared to normal individuals. The association between splenic volume and IFX efficacy in CD remains unclear. Methods: We performed a retrospective study of patients with CD who received regular IFX treatment at Zhongshan Hospital, Fudan University, between August 2015 and December 2021. We collected baseline characteristics and clinical features from medical records in the CD database of Zhongshan Hospital. We accurately measured the splenic volume using semi-auto spleen segmentation software, followed by the analysis of splenic volume and IFX efficacy. Results: We included 49 patients with CD receiving IFX treatment, of whom 41 responded to IFX and 8 failed to respond to IFX. Splenic volume, as well as volume adjusted for body mass index (SV/BMI) and body weight (SV/W), was significantly decreased after IFX treatment in responders but increased in non-responders compared to the volume before the treatment. Accordingly, the levels of leukocyte count, platelet count, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR) were decreased after IFX treatment in responders. Contrarily, the levels of hemoglobin, albumin, and tumor necrosis factor (TNF)-α were elevated in responders. Moreover, both CRP and TNF-α levels were significantly positively correlated with SV/BMI in all patients. Conclusion: Splenic volume, especially SV/BMI and SV/W, was reduced after IFX treatment in CD patients responsive to IFX. SV/BMI was positively correlated with disease activity. Splenic volume is a promising indicator to evaluate IFX efficacy in CD.
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Affiliation(s)
- Xuan Shi
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jia-Hui Wang
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Sheng-Xiang Rao
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Tao-Tao Liu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Hao Wu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, China
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Uncovering Novel Pre-Treatment Molecular Biomarkers for Anti-TNF Therapeutic Response in Patients with Crohn’s Disease. J Funct Biomater 2022; 13:jfb13020036. [PMID: 35466218 PMCID: PMC9036297 DOI: 10.3390/jfb13020036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 03/25/2022] [Accepted: 03/29/2022] [Indexed: 02/01/2023] Open
Abstract
Neutralising monoclonal antibodies for tumour necrosis factor (TNF) has been widely used to treat Crohn’s disease (CD) in clinical practice. However, differential individual response necessitates a therapeutic response assessment of anti-TNF agents in CD patients for optimizing therapeutic strategy. We aimed to predict anti-TNF therapy response in CD patients using transcriptome analyses. Transcriptome analyses were performed using data from the Gene Expression Omnibus, GeneCards, and Human Protein Atlas databases. The significantly mitigated biological functions associated with anti-TNF therapy resistance in CD patients encompassed immune pathways, including Interleukin-17 (IL-17) signaling, cytokine-cytokine receptor interaction, and rheumatoid arthritis. The scores of immune cell markers, including neutrophils, monocytes, and macrophages/monocytes were also significantly decreased in non-responders compared with that measured in anti-TNF therapy responders. The KAT2B gene, associated with IL-17 cytokine mediated neutrophil mobilization and activation, was significantly under-expressed in both tissue and peripheral blood mononuclear cells (PBMCs) in anti-TNF therapy-resistant CD patients. The reduced expression of several pro-inflammatory cytokines due to down-regulated IL-17 signaling, is suggestive of the primary non-response to anti-TNF agents in CD patients. Furthermore, the PBMC KAT2B gene signature may be a promising pre-treatment prognostic biomarker for anti-TNF drug response in CD patients.
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Linares R, Francés R, Gutiérrez A, Juanola O. Bacterial Translocation as Inflammatory Driver in Crohn's Disease. Front Cell Dev Biol 2021; 9:703310. [PMID: 34557484 PMCID: PMC8452966 DOI: 10.3389/fcell.2021.703310] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 07/30/2021] [Indexed: 12/26/2022] Open
Abstract
Crohn’s disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract responsible for intestinal lesions. The multifactorial etiology attributed to CD includes a combination of environmental and host susceptibility factors, which result in an impaired host–microbe gut interaction. Bacterial overgrowth and dysbiosis, increased intestinal barrier permeability, and altered inflammatory responses in patients with CD have been described in the past. Those events explain the pathogenesis of luminal translocation of bacteria or its products into the blood, a frequent event in CD, which, in turn, favors a sustained inflammatory response in these patients. In this review, we navigate through the interaction between bacterial antigen translocation, permeability of the intestinal barrier, immunologic response of the host, and genetic predisposition as a combined effect on the inflammatory response observed in CD. Several lines of evidence support that translocation of bacterial products leads to uncontrolled inflammation in CD patients, and as a matter of fact, the presence of gut bacterial genomic fragments at a systemic level constitutes a marker for increased risk of relapse among CD patients. Also, the significant percentage of CD patients who lose response to biologic therapies may be influenced by the translocation of bacterial products, which are well-known drivers of proinflammatory cytokine production by host immune cells. Further mechanistic studies evaluating cellular and humoral immune responses, gut microbiota alterations, and genetic predisposition will help clinicians to better control and personalize the management of CD patients in the future.
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Affiliation(s)
- Raquel Linares
- Hepatic and Intestinal Immunobiology Group, Department of Clinical Medicine, Miguel Hernández University, San Juan de Alicante, Spain
| | - Rubén Francés
- Hepatic and Intestinal Immunobiology Group, Department of Clinical Medicine, Miguel Hernández University, San Juan de Alicante, Spain.,CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.,Instituto ISABIAL, Hospital General Universitario de Alicante, Alicante, Spain
| | - Ana Gutiérrez
- CIBERehd, Instituto de Salud Carlos III, Madrid, Spain.,Instituto ISABIAL, Hospital General Universitario de Alicante, Alicante, Spain.,Servicio de Medicina Digestiva, Hospital General Universitario de Alicante, Alicante, Spain
| | - Oriol Juanola
- Translational Research Laboratory, Gastroenterology and Hepatology, Ente Ospedaliero Cantonale, Lugano, Switzerland.,Faculty of Biomedical Sciences, Universitá della Svizzera Italiana, Lugano, Switzerland
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7
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Li L, Chen R, Zhang Y, Zhou G, Chen B, Zeng Z, Chen M, Zhang S. A Novel Model Based on Serum Biomarkers to Predict Primary Non-Response to Infliximab in Crohn's Disease. Front Immunol 2021; 12:646673. [PMID: 34367126 PMCID: PMC8339550 DOI: 10.3389/fimmu.2021.646673] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2020] [Accepted: 07/07/2021] [Indexed: 12/22/2022] Open
Abstract
Background Infliximab is effective in inducing and maintaining remission in patients with Crohn's disease (CD), but primary non-response (PNR) occurs in 10-30% of cases. We investigated whether serum biomarkers are effective in predicting PNR in patients with CD. Methods From January 2016 to April 2020, a total of 260 patients were recruited to this prospective and retrospective cohort study. Serum samples were collected at baseline and week 2 of infliximab treatment. Serum levels of 35 cytokines were assessed in 18 patients from the discovery cohort and were further evaluated in the 60-patient cohort 1. Then, candidate cytokines and other serological biomarkers were used to construct a predictive model by logistic regression in a 182-patient cohort 2. PNR was defined based on the change of CD activity index or clinical symptoms. Results Among the 35 cytokines, matrix metalloproteinase 3(MMP3) and C-C motif ligand 2 (CCL2) were two effective serum biomarkers associated with PNR in both the discovery cohort and cohort 1. In cohort 2, serum level of MMP3, CCL2 and C-reactive protein (CRP) at 2 weeks after infliximab injection were independent predictors of PNR, with odds ratios (95% confidence interval) of 1.108(1.059-1.159), 0.940(0.920-0.965) and 1.102(1.031-1.117), respectively. A PNR classifier combining these three indicators had a large area under the curve [0.896(95% CI:0.895-0.897)] and negative predictive value [0.918(95%CI:0.917-0.919)] to predict PNR to infliximab. Conclusions MMP3, CCL2, and CRP are promising biomarkers in prediction of PNR to infliximab, and PNR classifier could accurately predict PNR and may be useful in clinical practice for therapy selection.
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Affiliation(s)
- Li Li
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Rirong Chen
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Yingfan Zhang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Gaoshi Zhou
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Baili Chen
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhirong Zeng
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Minhu Chen
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Shenghong Zhang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
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8
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Arya SK, Estrela P. Electrochemical ELISA Protein Biosensing in Undiluted Serum Using a Polypyrrole-Based Platform. SENSORS (BASEL, SWITZERLAND) 2020; 20:E2857. [PMID: 32443483 PMCID: PMC7287672 DOI: 10.3390/s20102857] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 05/12/2020] [Accepted: 05/15/2020] [Indexed: 01/15/2023]
Abstract
An electrochemical enzyme-linked immunosorbent assay (ELISA) biosensor platform using electrochemically prepared ~11 nm thick carboxylic functionalized popypyrrole film has been developed for bio-analyte measurement in undiluted serum. Carboxyl polypyrrole (PPy-COOH) film using 3-carboxy-pyrrol monomer onto comb-shaped gold electrode microarray (Au) was prepared via cyclic voltammetry (CV). The prepared Au/PPy-COOH was then utilized for electrochemical ELISA platform development by immobilizing analyte-specific antibodies. Tumor necrosis factor-alpha (TNF-α) was selected as a model analyte and detected in undiluted serum. For enhanced performance, the use of a polymeric alkaline phosphatase tag was investigated for the electrochemical ELISA. The developed platform was characterized at each step of fabrication using CV, electrochemical impedance spectroscopy and atomic force microscopy. The bioelectrodes exhibited linearity for TNF-α in the 100 pg/mL-100 ng/mL range when measured in spiked serum, with limit of detection of 78 pg/mL. The sensor showed insignificant signal disturbance from serum proteins and other biologically important proteins. The developed platform was found to be fast and specific and can be applicable for testing and measuring various biologically important protein markers in real samples.
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Affiliation(s)
- Sunil K. Arya
- Department of Electronic & Electrical Engineering, University of Bath, Claverton Down, Bath BA2 7AY, UK;
| | - Pedro Estrela
- Department of Electronic & Electrical Engineering, University of Bath, Claverton Down, Bath BA2 7AY, UK;
- Centre for Biosensors, Bioelectronics and Biodevices (C3Bio), University of Bath, Claverton Down, Bath BA2 7AY, UK
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9
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Mateos B, Sáez-González E, Moret I, Hervás D, Iborra M, Cerrillo E, Tortosa L, Nos P, Beltrán B. Plasma Oncostatin M, TNF-α, IL-7, and IL-13 Network Predicts Crohn's Disease Response to Infliximab, as Assessed by Calprotectin Log Drop. Dig Dis 2020; 39:1-9. [PMID: 32325460 DOI: 10.1159/000508069] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2019] [Accepted: 04/22/2020] [Indexed: 02/02/2023]
Abstract
BACKGROUND Cytokines emerge as possible biomarkers of response in Crohn's disease (CD). We aimed to determine the plasmatic cytokine profiles of active CD patients who started infliximab (IFX) treatment and their capacity to predict the response to IFX. METHODS A total of 30 active CD patients receiving an induction therapy of IFX were enrolled in the study. Peripheral blood samples pretreatment were collected. Concentrations of 15 cytokines were measured by Luminex technology. Responses to IFX were evaluated by the drop in fecal calprotectin based on its logarithm-transformed values. A random forest (RF) predictive model was used for data analyses. RESULTS Samples of 22 patients were analyzed. The RF model ranked the following cytokines as the top predictors of the response: tumor necrosis factor alpha (TNFα), interleukin (IL)-13, oncostatin M (OSM), and IL-7 (p < 0.005). Partial dependency plots showed that high levels of IL-13 pretreatment, low TNFα levels, and low IL-7 levels were associated with a favorable IFX response. Increased levels of OSM and TNFα predicted unfavorable responses to IFX. CONCLUSIONS We here show that a log drop in calprotectin strongly correlates with clinical parameters and it can be proposed as a useful objective clinical response predictor. Plasma TNFα, IL-13, Il-7, and OSM network could predict CD response to IFX before induction therapy, as assessed by calprotectin log drop.
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Affiliation(s)
- Beatriz Mateos
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Esteban Sáez-González
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain.,Inflammatory Bowel Disease Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain
| | - Inés Moret
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain.,Inflammatory Bowel Disease Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - David Hervás
- Biostatictics Unit, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain
| | - Marisa Iborra
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain.,Inflammatory Bowel Disease Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Elena Cerrillo
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain.,Inflammatory Bowel Disease Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain
| | - Luis Tortosa
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain.,Inflammatory Bowel Disease Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Pilar Nos
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain.,Inflammatory Bowel Disease Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain.,Centro de Investigación Biomédica en Red de Enfermedades hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Belén Beltrán
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, Valencia, Spain, .,Inflammatory Bowel Disease Research Group, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain, .,Centro de Investigación Biomédica en Red de Enfermedades hepáticas y Digestivas (CIBEREHD), Madrid, Spain,
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10
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Berends SE, van Steeg TJ, Ahsman MJ, Singh S, Brandse JF, D'Haens GRAM, Mathôt RAA. Tumor necrosis factor-mediated disposition of infliximab in ulcerative colitis patients. J Pharmacokinet Pharmacodyn 2019; 46:543-551. [PMID: 31489538 PMCID: PMC6868113 DOI: 10.1007/s10928-019-09652-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 08/13/2019] [Indexed: 12/19/2022]
Abstract
Ulcerative Colitis (UC) is an inflammatory bowel disease typically affecting the colon. Patients with active UC have elevated tumor necrosis factor (TNF) concentrations in serum and colonic tissue. Infliximab is a monoclonal antibody directed against TNF and binds with high affinity. Target-mediated drug disposition (TMDD) is reported for monoclonal antibodies meaning that their pharmacokinetics are affected by high target affinity. Here, a TMDD model is proposed to describe the interaction between infliximab and TNF in UC patients. Data from 20 patients with moderate to severe UC was used. Patients received standard infliximab induction therapy (5 mg kg−1) at week 0, followed by infusions at week 2 and 6. IFX, anti-drug antibodies and TNF serum concentrations were measured at day 0 (1 h after infusion), 1, 4, 7, 11, 14, 18, 21, 28 and 42. A binding model, TMDD model, and a quasi-steady state (QSS) approximation were evaluated using nonlinear mixed effects modeling (NONMEM). A two-compartment model best described the concentration–time profiles of infliximab. Typical clearance of infliximab was 0.404 L day−1 and increased with the presence of anti-drug antibodies and with lower albumin concentrations. The TMDD-QSS model best described the pharmacokinetic and pharmacodynamics data. Estimate for TNF baseline (Bmax was 19.8 pg mL−1 and the dissociation constant (Kss) was 13.6 nM. This model could eventually be used to investigate the relationship between suppression of TNF and the response to IFX therapy.
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Affiliation(s)
- Sophie E Berends
- Hospital Pharmacy, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands. .,Gastroenterology & Hepatology Department, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands.
| | - Tamara J van Steeg
- Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P) Consultants, Leiden, The Netherlands
| | - Maurice J Ahsman
- Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P) Consultants, Leiden, The Netherlands
| | | | - Johannan F Brandse
- Gastroenterology & Hepatology Department, Amsterdam UMC, Location VUmc, Amsterdam, The Netherlands
| | - Geert R A M D'Haens
- Gastroenterology & Hepatology Department, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands
| | - Ron A A Mathôt
- Hospital Pharmacy, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands
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Cruz A, Queirós R, Abreu CM, Barata C, Fernandes R, Silva R, Ambrósio AF, Soares-dos-Reis R, Guimarães J, Sá MJ, Relvas JB, Freitas PP, Mendes Pinto I. Electrochemical Immunosensor for TNFα-Mediated Inflammatory Disease Screening. ACS Chem Neurosci 2019; 10:2676-2682. [PMID: 30985099 DOI: 10.1021/acschemneuro.9b00036] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Inflammation associated with cancer, neurodegenerative, ocular, and autoimmune diseases has a considerable impact on public health. Tumor necrosis factor alpha (TNFα) is a key mediator of inflammatory responses, responsible for many of the systemic manifestations during the inflammatory process. Thus, inhibition of TNFα is a commonplace practice in the treatment of these disorders. Successful therapy requires the ability to determine the appropriate dose of anti-TNFα drugs to be administered in a timely manner, based on circulating TNFα levels. In this Letter, we report the development of an immunosensor technology able to quantify TNFα at the picogram level in relevant human body fluids, holding the potential to early detect inflammation and monitor TNFα levels during treatment, enabling TNFα-targeted treatments to be tailored according to the immune status of an individual patient. This immunosensor technology is significantly more rapid and sensitive than conventional enzyme linked immunosorbent assays, maintaining high specificity and requiring small sample volumes. These features might also be advantageous in the context of personalized medicine, as this analytical platform can deliver advanced diagnostics and reduce clinical burden.
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Affiliation(s)
- Andrea Cruz
- International Iberian Nanotechnology Laboratory, Braga 4715-330, Portugal
| | - Raquel Queirós
- International Iberian Nanotechnology Laboratory, Braga 4715-330, Portugal
| | - Catarina M. Abreu
- International Iberian Nanotechnology Laboratory, Braga 4715-330, Portugal
- Swansea University Medical School, Swansea SA2 8PP, United Kingdom
| | - Catarina Barata
- International Iberian Nanotechnology Laboratory, Braga 4715-330, Portugal
- Instituto Superior Técnico, University of Lisbon, Lisbon 1649-004, Portugal
| | - Rosa Fernandes
- Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, Coimbra 3004-531, Portugal
- CNC.IBILI, University of Coimbra, Coimbra 3000-548, Portugal
| | - Rufino Silva
- Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, Coimbra 3004-531, Portugal
- Coimbra University Hospital, Coimbra 3000-075, Portugal
| | - Antonio F. Ambrósio
- Coimbra Institute for Clinical and Biomedical Research, Faculty of Medicine, University of Coimbra, Coimbra 3004-531, Portugal
- CNC.IBILI, University of Coimbra, Coimbra 3000-548, Portugal
| | - Ricardo Soares-dos-Reis
- Neurology Department, Centro Hospitalar de São João, Porto 4200-319, Portugal
- Department of Clinical Neurosciences and Mental Health, Faculty of Medicine, University of Porto, Porto 4200-135, Portugal
- Department of Biomedicine, Faculty of Medicine, University of Porto, Porto 4200-135, Portugal
| | - Joana Guimarães
- Neurology Department, Centro Hospitalar de São João, Porto 4200-319, Portugal
- Department of Clinical Neurosciences and Mental Health, Faculty of Medicine, University of Porto, Porto 4200-135, Portugal
- Center for Drug Discovery and Innovative Medicines (MedInUP), University of Porto, Porto 4200-135, Portugal
| | - Maria José Sá
- Neurology Department, Centro Hospitalar de São João, Porto 4200-319, Portugal
- Energy, Environment and Health Research Unit (FP-ENAS), University Fernando Pessoa, Porto 4200-135, Portugal
- Faculty of Health Sciences, University Fernando Pessoa, Porto 4200-135, Portugal
| | - João B. Relvas
- Institute for Research and Innovation in Health, University of Porto, Porto 4200-135, Portugal
| | - Paulo P. Freitas
- International Iberian Nanotechnology Laboratory, Braga 4715-330, Portugal
| | - Inês Mendes Pinto
- International Iberian Nanotechnology Laboratory, Braga 4715-330, Portugal
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12
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Gole B, Potočnik U. Pre-Treatment Biomarkers of Anti-Tumour Necrosis Factor Therapy Response in Crohn's Disease-A Systematic Review and Gene Ontology Analysis. Cells 2019; 8:cells8060515. [PMID: 31141991 PMCID: PMC6628089 DOI: 10.3390/cells8060515] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 05/24/2019] [Accepted: 05/25/2019] [Indexed: 12/15/2022] Open
Abstract
The most prominent treatment for the serious cases of Crohn’s disease (CD) are biological tumour necrosis factor (TNF) inhibitors. Unfortunately, therapy nonresponse is still a serious issue in ~1/3 of CD patients. Accurate prediction of responsiveness prior to therapy start would therefore be of great value. Clinical predictors have, however, proved insufficient. Here, we integrate genomic and expression data on potential pre-treatment biomarkers of anti-TNF nonresponse. We show that there is almost no overlap between genomic (annotated with tissue-specific expression quantitative trait loci data) and transcription (RNA and protein data) biomarkers. Furthermore, using interaction networks we demonstrate there is little direct interaction between the proposed biomarkers, though a majority do have common interactors connecting them into networks. Our gene ontology analysis shows that these networks have roles in apoptotic signalling, response to oxidative stress and inflammation pathways. We conclude that a more systematic approach with genome-wide search of genomic and expression biomarkers in the same patients is needed in future studies.
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Affiliation(s)
- Boris Gole
- Centre for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska ulica 8, SI-2000 Maribor, Slovenia.
| | - Uroš Potočnik
- Centre for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska ulica 8, SI-2000 Maribor, Slovenia.
- Laboratory for Biochemistry, Molecular biology and Genomics, Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova ulica 17, SI-2000 Maribor, Slovenia.
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Transmembrane TNF-α Density, but not Soluble TNF-α Level, is Associated with Primary Response to Infliximab in Inflammatory Bowel Disease. Clin Transl Gastroenterol 2017; 8:e117. [PMID: 28914262 PMCID: PMC5628358 DOI: 10.1038/ctg.2017.44] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Accepted: 07/17/2017] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVES Anti-tumor necrosis factor (TNF)-α agents like Infliximab (IFX) are effective in the treatment of inflammatory bowel diseases (IBDs) and are widely used. However, a considerable number of patients do not respond or lose response to this therapy. Preliminary evidence suggests that transmembrane TNF-α (tmTNF-α) might be linked to response to IFX by promoting reverse signaling-induced apoptosis in inflammatory cells. The main aim of this study was the evaluation of this hypothesis in primary IFX non-responders. METHODS A total of 47 IFX naive IBD patients were included in the study. Blood samples were taken before the start of IFX therapy (at week 0) and after induction therapy (at week 14). Endoscopic disease activity and markers of inflammation at baseline and at week 14 were used to evaluate response. Baseline soluble TNF-α (sTNF-α), percentage of circulating TNF-α positive cells, mean fluorescence intensity (MFI) of tmTNF-α, and apoptosis rate at week 14 in the peripheral blood mononuclear cells (PBMCs) were evaluated in IFX responders and non-responders. RESULTS Mean sTNF-α was not significantly different in responders compared to non-responders (P=0.13). Mean percentage of tmTNF-α bearing lymphocytes and monocytes was higher in the PBMCs of responders (P=0.05 and P=0.014, respectively). Mean MFI of tmTNF-α in circulating lymphocytes and monocytes was greater in responders (P=0.002 and P<0.001, respectively). Moreover, the mean percentage of apoptosis in PBMCs was significantly greater in responders compared to non-responders (P=0.002). CONCLUSIONS The percentage of tmTNF-α bearing lymphocytes and monocytes and the intensity of tmTNF-α in the circulating leukocyte population of IBD patients was directly related to primary response to IFX. This was likely due-as assessed by the apoptosis rate-to promotion of inflammatory cell death. Thus, our data suggest that peripheral leukocytes could in principle be used for predicting primary response to IFX in IBD patients.
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14
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Quetglas EG, Mujagic Z, Wigge S, Keszthelyi D, Wachten S, Masclee A, Reinisch W. Update on pathogenesis and predictors of response of therapeutic strategies used in inflammatory bowel disease. World J Gastroenterol 2015; 21:12519-12543. [PMID: 26640330 PMCID: PMC4658608 DOI: 10.3748/wjg.v21.i44.12519] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Accepted: 09/14/2015] [Indexed: 02/06/2023] Open
Abstract
The search for biomarkers that characterize specific aspects of inflammatory bowel disease (IBD), has received substantial interest in the past years and is moving forward rapidly with the help of modern technologies. Nevertheless, there is a direct demand to identify adequate biomarkers for predicting and evaluating therapeutic response to different therapies. In this subset, pharmacogenetics deserves more attention as part of the endeavor to provide personalized medicine. The ultimate goal in this area is the adjustment of medication for a patient’s specific genetic background and thereby to improve drug efficacy and safety rates. The aim of the following review is to utilize the latest knowledge on immunopathogenesis of IBD and update the findings on the field of Immunology and Genetics, to evaluate the response to the different therapies. In the present article, more than 400 publications were reviewed but finally 287 included based on design, reproducibility (or expectancy to be reproducible and translationable into humans) or already measured in humans. A few tests have shown clinical applicability. Other, i.e., genetic associations for the different therapies in IBD have not yet shown consistent or robust results. In the close future it is anticipated that this, cellular and genetic material, as well as the determination of biomarkers will be implemented in an integrated molecular diagnostic and prognostic approach to manage IBD patients.
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Martin F, Sewer A, Talikka M, Xiang Y, Hoeng J, Peitsch MC. Quantification of biological network perturbations for mechanistic insight and diagnostics using two-layer causal models. BMC Bioinformatics 2014; 15:238. [PMID: 25015298 PMCID: PMC4227138 DOI: 10.1186/1471-2105-15-238] [Citation(s) in RCA: 92] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Accepted: 06/26/2014] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND High-throughput measurement technologies such as microarrays provide complex datasets reflecting mechanisms perturbed in an experiment, typically a treatment vs. control design. Analysis of these information rich data can be guided based on a priori knowledge, such as networks or set of related proteins or genes. Among those, cause-and-effect network models are becoming increasingly popular and more than eighty such models, describing processes involved in cell proliferation, cell fate, cell stress, and inflammation have already been published. A meaningful systems toxicology approach to study the response of a cell system, or organism, exposed to bio-active substances requires a quantitative measure of dose-response at network level, to go beyond the differential expression of single genes. RESULTS We developed a method that quantifies network response in an interpretable manner. It fully exploits the (signed graph) structure of cause-and-effect networks models to integrate and mine transcriptomics measurements. The presented approach also enables the extraction of network-based signatures for predicting a phenotype of interest. The obtained signatures are coherent with the underlying network perturbation and can lead to more robust predictions across independent studies. The value of the various components of our mathematically coherent approach is substantiated using several in vivo and in vitro transcriptomics datasets. As a proof-of-principle, our methodology was applied to unravel mechanisms related to the efficacy of a specific anti-inflammatory drug in patients suffering from ulcerative colitis. A plausible mechanistic explanation of the unequal efficacy of the drug is provided. Moreover, by utilizing the underlying mechanisms, an accurate and robust network-based diagnosis was built to predict the response to the treatment. CONCLUSION The presented framework efficiently integrates transcriptomics data and "cause and effect" network models to enable a mathematically coherent framework from quantitative impact assessment and data interpretation to patient stratification for diagnosis purposes.
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Affiliation(s)
- Florian Martin
- Philip Morris International, R&D, Biological Systems Research, Quai Jeanrenaud 5, 2000 Neuchatel, Switzerland.
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Lacruz-Guzmán D, Torres-Moreno D, Pedrero F, Romero-Cara P, García-Tercero I, Trujillo-Santos J, Conesa-Zamora P. Influence of polymorphisms and TNF and IL1β serum concentration on the infliximab response in Crohn's disease and ulcerative colitis. Eur J Clin Pharmacol 2012; 69:431-8. [PMID: 22960943 DOI: 10.1007/s00228-012-1389-0] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2012] [Accepted: 08/23/2012] [Indexed: 12/11/2022]
Abstract
AIM Inflammatory bowel diseases (IBD), such as Crohn's disease (CD) and ulcerative colitis (UC), are partially attributable to an increased secretion of proinflamatory cytokines, such as tumour necrosis factor (TNF) and interleukin-1β (IL1β), which play essential roles in the disease pathogenesis and are target molecules for specific therapy. Given the inter-individual variability in the response to the anti-TNF monoclonal antibody infliximab, the aim of our study was to explore the predictive value of TNF and/or IL1β as surrogate markers of infliximab response. METHODS Serial serum concentrations of TNF and IL1β and TNF promoter region and IL1B polymorphisms were determined in 47 patients (29 CD and 18 UC) receiving infliximab and correlated with treatment response. RESULTS Baseline serum concentrations of TNF and IL1β were higher in UC patients than in CD patients (p = 0.0097 and 0.0024, respectively). CD patients showing <0.64 pg/ml IL1β at baseline were more frequently responders than non-responders (p = 0.036), and the C allele of the IL1B polymorphism was associated with higher IL1β serum concentrations (p = 0.026) and with poorer clinical remission after 14 weeks of infliximab treatment. No significant association was found between serum TNF concentration or TNF polymorphism and patient response to infliximab. CONCLUSION This is the first study evaluating the pharmacogenetic role of the rs1143634 polymorphism of IL1B and TNF polymorphisms in infliximab-treated IBD patients. We found an association between the rs1143634 C allele and higher serum IL1β concentrations and a lower response to infliximab treatment in CD patients that warrants the interest of future studies in larger and independent series.
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Affiliation(s)
- Diana Lacruz-Guzmán
- Pharmacy Department, Santa Lucía General University Hospital, Cartagena, Spain.
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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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18
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Shin JI, Lee JS, Choi JY, Kim DS, Girish M. Refractory Kawasaki disease: infliximab or methotrexate therapy? Indian J Pediatr 2009; 76:1184; author reply 1184. [PMID: 20072867 DOI: 10.1007/s12098-009-0285-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Abstract
BACKGROUND AND PURPOSE Experimental and clinical investigations have revealed that statins can downregulate both acute and chronic inflammatory processes. Whether statins express anti-inflammatory activities in the treatment of Crohn's disease is unknown. EXPERIMENTAL APPROACH Ten patients were given 80 mg atorvastatin once daily for 13 weeks and then followed up for 8 weeks after the treatment. The anti-inflammatory effects of statin were assessed by measuring levels of plasma C-reactive protein (CRP), soluble (s) CD14, tumour necrosis factor (TNF)-alpha, sTNFRI and II, CCL2 and 8 and the mucosal inflammation by faecal calprotectin. Circulating monocytes were subgrouped and their chemokine receptor expression of CCR2 and CX(3)CR1 were analysed. KEY RESULTS In 8 of 10 patients, atorvastatin treatment reduced CRP (P=0.008) and sTNFRII (P=0.064). A slight decrease in plasma levels of sCD14, TNF-alpha and sTNFRI was observed in 7/10 patients and faecal calprotectin was reduced in 8/10 patients. We also observed that the treatment diminished expression of CCR2 and CX(3)CR1 on monocyte populations (P=0.014). At the follow-up visit, 8 weeks after the atorvastatin treatment was terminated, CRP levels had returned to those seen before the treatment. CONCLUSIONS AND IMPLICATIONS Our findings imply that atorvastatin therapy reduces inflammation in patients with Crohn's disease and, therefore, encourage further investigations of statin-mediated protective effects in inflammatory bowel diseases.
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Peterson CA, Heffernan ME. Serum tumor necrosis factor-alpha concentrations are negatively correlated with serum 25(OH)D concentrations in healthy women. JOURNAL OF INFLAMMATION-LONDON 2008; 5:10. [PMID: 18652680 PMCID: PMC2503979 DOI: 10.1186/1476-9255-5-10] [Citation(s) in RCA: 168] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/01/2007] [Accepted: 07/24/2008] [Indexed: 12/14/2022]
Abstract
Background Circulating 25 hydroxyvitamin D (25 (OH)D), an accurate measure of vitamin D status, is markedly greater in individuals with increased exposure to ultraviolet B (UVB) light via sunlight or the use of artificial UV light. Aside from the known relationship between vitamin D and bone, vitamin D has also been implicated in immune function and inflammation. Furthermore, a mass of evidence is accumulating that vitamin D deficiency could lead to immune malfunction. Our overall objective was to study the relationship between vitamin D status (as determined by serum 25(OH) D concentrations) and inflammatory markers in healthy women. Methods This observational study included 69 healthy women, age 25–82 years. Women with high UVB exposure and women with minimal UVB exposure were specifically recruited to obtain a wide-range of serum 25(OH)D concentrations. Health, sun exposure and habitual dietary intake information were obtained from all subjects. Body composition was determined by dual-energy-x-ray absorptiometry. A fasting blood sample was collected in the morning and analyzed for serum 25(OH)D, parathyroid hormone (iPTH), estradiol (E2), cortisol, and inflammatory markers [tumor necrosis factor -alpha (TNF-α), interleukin-6 and -10 (IL-6, IL-10), and C-reactive protein (CRP)]. Results Women with regular UVB exposure (Hi-D) had serum 25(OH)D concentrations that were significantly higher (p < 0.0001) and iPTH concentrations that were significantly lower (p < 0.0001) than women without regular UVB exposure (Lo-D). Although IL-6, IL-10, and CRP did not have a statistically significant relationship with 25(OH)D concentrations, linear regression models revealed a significant inverse relationship between serum 25(OH)D and TNF-α concentrations. This relationship remained significant after controlling for potential covariates such as body fat mass, menopausal status, age, or hormonal contraceptive use. Conclusion Serum 25(OH)D status is inversely related to TNF-α concentrations in healthy women, which may in part explain this vitamin's role in the prevention and treatment of inflammatory diseases. Results gleaned from this investigation also support the need to re-examine the biological basis for determining optimal vitamin D status.
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Affiliation(s)
- Catherine A Peterson
- Department of Nutritional Sciences, University of Missouri-Columbia, Columbia, MO, 65211, USA
| | - Mary E Heffernan
- Department of Nutritional Sciences, University of Missouri-Columbia, Columbia, MO, 65211, USA
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Ainsworth MA, Bendtzen K, Brynskov J. Tumor necrosis factor-alpha binding capacity and anti-infliximab antibodies measured by fluid-phase radioimmunoassays as predictors of clinical efficacy of infliximab in Crohn's disease. Am J Gastroenterol 2008; 103:944-8. [PMID: 18028512 DOI: 10.1111/j.1572-0241.2007.01638.x] [Citation(s) in RCA: 128] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES To investigate if the combined assessment of anti-infliximab antibodies (Ab) and the degree of TNF-alpha binding capacity (TNF-alpha-BC) afforded by infliximab may predict the response to infliximab treatment in patients with Crohn's disease (CD). METHODS Three groups of CD patients, in total 33 patients, treated with infliximab were retrospectively selected: (a) patients with a maintained response throughout treatment; (b) patients with good initial response, but subsequent loss of response; and (c) patients with inadequate response to the first two or three doses. Blood samples were analyzed for TNF-alpha-BC and Ab using fluid-phase radioimmunoassay (RIA). RESULTS At 8 wk after last infliximab infusion, TNF-alpha-BC was significantly higher (P = 0.002) in patients maintaining response (median [interquartile range] 2.9 [0.9-4.3] microg/mL), as compared to patients losing response (0.0 [0-0.1] microg/mL). Conversely, Ab levels were significantly lower (P < 0.0001) in patients maintaining response (1.3 [0-6]% bound tracer/total tracer), as compared to patients losing response (19 [14-27]%). Ab were not present and TNF-alpha-BC was high (30 [20-32]) in patients with no primary response. CONCLUSIONS While secondary loss of response to infliximab is associated with high levels of Ab and low levels of TNF-alpha-BC, primary response failure may be seen in the presence of high effective levels of TNF-alpha-BC afforded by infliximab. The results suggest that combined assessment of anti-infliximab Ab and serum TNF-alpha-BC may pave the way for a more rational use of infliximab in patients with CD.
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Affiliation(s)
- Mark A Ainsworth
- Department of Medical Gastroenterology, Copenhagen University Hospital, Herlev, Herlev, Denmark
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Günzel D, Florian P, Richter JF, Troeger H, Schulzke JD, Fromm M, Gitter AH. Restitution of single-cell defects in the mouse colon epithelium differs from that of cultured cells. Am J Physiol Regul Integr Comp Physiol 2006; 290:R1496-507. [PMID: 16397094 DOI: 10.1152/ajpregu.00470.2005] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Integrity of colon epithelium is of crucial importance and, as small defects occur constantly, rapid repair (restitution) is essential. To investigate the mechanism of restitution, single-cell lesions were induced in mouse colonic surface epithelia by iontophoretic injection of Ca2+. Closure of the resulting defects was monitored using confocal laser scanning microscopy (CLSM), and functional sealing by electrophysiological techniques. Restitution was evaluated as the time constant tau of the exponential decrease in conductance of an induced leak and amounted to 0.28 min under control conditions. After 4 min, the leak was completely sealed. Repair was thus considerably faster than in previously investigated HT-29/B6 cells (tau=5.73 min). As in cultured cells, cytochalasin D delayed restitution in native colon epithelia (tau=0.69 min), indicating the involvement of actin in the healing process; however, no accumulation of actin surrounding the lesion was detected. Long-term incubation of epithelia with IFN-gamma alone or in combination with TNF-alpha increased tau to 0.49 and 0.59 min, respectively. In contrast to cultured cells, TNF-alpha alone did not affect restitution. A brief (<10 min) exposure to the sterile filtered supernatant of hemolytic E. coli O4 cultures did not affect the morphology of the epithelium, but delayed restitution. In CLSM studies, defects were still clearly visible 4 min after the onset of lesion induction. The supernatant of a nonhemolytic E. coli O4 mutant did not exhibit this effect. In conclusion, single-cell defects in native colon cause functional leaks that seal faster than in cell cultures. Proinflammatory cytokines and pathogenic bacteria delay restitution. This suggests a key role of very small lesions at the onset of pathogenic processes in the intestine.
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Affiliation(s)
- D Günzel
- Department of Clinical Physiology, Charité, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, and Jena University of Applied Sciences, Germany.
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Cantor MJ, Nickerson P, Bernstein CN. The role of cytokine gene polymorphisms in determining disease susceptibility and phenotype in inflammatory bowel disease. Am J Gastroenterol 2005; 100:1134-42. [PMID: 15842590 DOI: 10.1111/j.1572-0241.2005.40979.x] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Emerging data indicate that alterations in cytokine synthesis may play a role in inflammatory bowel disease (IBD) pathogenesis. The differential production of cytokines has been linked to single nucleotide polymorphisms in gene promoter regions, signal sequences, and gene introns. The aim of this study was to assess the relationship between polymorphisms involving five cytokine genes (TNF-alpha, TGF-beta, IL-10, IL-6, and IFN-gamma), and IBD susceptibility and disease phenotype. METHODS Cytokine genotyping was performed utilizing polymerase chain reaction. The specific gene polymorphisms that were probed for included: -1082(G/A), -819(T/C), and -592(A/C) in the IL-10 promoter, -308(G/A) in the TNF-alpha promoter, codon 10 (T/C), and codon 25 (G/C) of the TGF-beta signal sequence, +874(T/A) of intron 1 of IFN-gamma, and -174(C/G) in the IL-6 promoter. RESULTS A total of 193 IBD patients (138 Crohn's disease (CD) and 55 ulcerative colitis (UC)) and 92 controls were evaluated. No association between IBD, UC, or CD susceptibility and the cytokine gene polymorphisms were found. Patients with ileocolonic CD were more likely to possess the IL-6 -174 GG genotype compared to those with nonileocolonic disease (p= 0.006). Patients with ileal CD were more likely to possess the IL-6 -174 GC genotype compared to those with nonileal disease (p= 0.0004). An increased number of CD patients with isolated colonic disease possessed the IL-6 -174 CC genotype compared to those with nonisolated colonic disease (p= 0.032). CONCLUSION The cytokine gene polymorphisms studied here do not appear to influence IBD susceptibility. There does, however, appear to be an influence on disease phenotype, particularly on CD site.
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Affiliation(s)
- Michael J Cantor
- Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
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