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Wolf M, Lange J, Benndorf D, Welz L, Nikolaus S, Siever LK, Tran F, Schallert K, Hellwig P, Schreiber S, Gunzer M, Rosenstiel P, Reichl U, Adolph T, Jukic A, Aden K, Heyer R. Fecal metaproteomics enables functional characterization of remission in patients with inflammatory bowel disease. J Proteomics 2025; 318:105455. [PMID: 40360052 DOI: 10.1016/j.jprot.2025.105455] [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: 10/21/2024] [Revised: 05/08/2025] [Accepted: 05/09/2025] [Indexed: 05/15/2025]
Abstract
The gut microbiome is an important contributor to the development and the course of inflammatory bowel disease (IBD). While changes in the gut microbiome composition were observed in response to IBD therapy using biologics, studies elucidating human and microbial proteins and pathways in dependence on therapy success are sparse. Fecal samples of a cohort of IBD patients were collected before and after 14 weeks of treatment with three different biologics. Clinical disease activity scores were used to determine the clinical response and remission. Fecal metaproteomes of remitting patients (n = 12) and of non-remitting patients (n = 12) were compared before treatment and changes within both groups were assessed over sampling time to identify functional changes and potential human and microbial biomarkers. The abundance of proteins associated with neutrophilic granulocytes, and immunoglobulins significantly decreased in remitting patients. There were changes in pathways of microbial metabolism in samples from patients with remission after therapy, including an increased butyrate fermentation. Distinct changes of proteins related to gut inflammation and gut microbiome metabolism showed whether IBD remission was achieved or not. This suggests that metaproteomics could be a useful tool for monitoring remission in IBD therapies. SIGNIFICANCE: IBD is rising in incidence, especially in newly industrialized countries, and the microbiome is an important contributor to its pathogenesis. Despite manifold therapeutical options, achieving remission is often ineffective, and choosing new alternative drugs remains often empirical. Therefore, efficient tools for monitoring therapeutic response and assessing the effectiveness of drugs in specific patients are mandatory. In the present study, we show that the use of metaproteomics is a promising avenue to address these challenges. We observed the amelioration of inflammation and restoration of a healthy microbiome in remitting patients in contrast to non-remitting patients. Therefore, metaproteomics is a valuable tool for monitoring the therapy success in IBD.
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Affiliation(s)
- Maximilian Wolf
- Multidimensional Omics Analyses group, Faculty of Technology, Bielefeld University, Universitätsstrasse 25, 33615 Bielefeld, Germany; Graduate School DILS, Bielefeld Institute for Bioinformatics Infrastructure (BIBI), Bielefeld University, Universitätsstrasse 25, 33615 Bielefeld, Germany.
| | - Julian Lange
- Bioprocess Engineering, Otto-von-Guericke University Magdeburg, Universitätsplatz 2, 39106 Magdeburg, Germany
| | - Dirk Benndorf
- Applied Biosciences and Process Engineering, Anhalt University of Applied Science, Bernburger Straße 56, 06366 Koethen, Germany
| | - Lina Welz
- Institute of Clinical Molecular Biology, Christian-Albrechts University of Kiel, Rosalind-Franklin-Straße 12, 24105 Kiel, Germany
| | - Susanna Nikolaus
- Institute of Clinical Molecular Biology, Christian-Albrechts University of Kiel, Rosalind-Franklin-Straße 12, 24105 Kiel, Germany
| | - Laura Katharina Siever
- Institute of Clinical Molecular Biology, Christian-Albrechts University of Kiel, Rosalind-Franklin-Straße 12, 24105 Kiel, Germany
| | - Florian Tran
- Institute of Clinical Molecular Biology, Christian-Albrechts University of Kiel, Rosalind-Franklin-Straße 12, 24105 Kiel, Germany
| | - Kay Schallert
- Leibniz-Institut für Analytische Wissenschaften - ISAS - e., Bunsen-Kirchhoff-Str. 11, 44139 Dortmund, Germany
| | - Patrick Hellwig
- Bioprocess Engineering, Otto-von-Guericke University Magdeburg, Universitätsplatz 2, 39106 Magdeburg, Germany; Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstraße 1, 39106 Magdeburg, Germany
| | - Stefan Schreiber
- Institute of Clinical Molecular Biology, Christian-Albrechts University of Kiel, Rosalind-Franklin-Straße 12, 24105 Kiel, Germany
| | - Matthias Gunzer
- Leibniz-Institut für Analytische Wissenschaften - ISAS - e., Bunsen-Kirchhoff-Str. 11, 44139 Dortmund, Germany; Institute for Experimental Immunology and Imaging and Imaging Center Essen, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, Germany
| | - Philip Rosenstiel
- Institute of Clinical Molecular Biology, Christian-Albrechts University of Kiel, Rosalind-Franklin-Straße 12, 24105 Kiel, Germany
| | - Udo Reichl
- Bioprocess Engineering, Otto-von-Guericke University Magdeburg, Universitätsplatz 2, 39106 Magdeburg, Germany; Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstraße 1, 39106 Magdeburg, Germany
| | - Timon Adolph
- Medical University Innsbruck, Christoph-Probst-Platz 1, 6020 Innsbruck, Austria
| | - Almina Jukic
- Medical University Innsbruck, Christoph-Probst-Platz 1, 6020 Innsbruck, Austria
| | - Konrad Aden
- Institute of Clinical Molecular Biology, Christian-Albrechts University of Kiel, Rosalind-Franklin-Straße 12, 24105 Kiel, Germany
| | - Robert Heyer
- Multidimensional Omics Analyses group, Faculty of Technology, Bielefeld University, Universitätsstrasse 25, 33615 Bielefeld, Germany; Leibniz-Institut für Analytische Wissenschaften - ISAS - e., Bunsen-Kirchhoff-Str. 11, 44139 Dortmund, Germany
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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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Peruhova M, Stoyanova D, Miteva DG, Kitanova M, Mirchev MB, Velikova T. Genetic factors that predict response and failure of biologic therapy in inflammatory bowel disease. World J Exp Med 2025; 15:97404. [PMID: 40115750 PMCID: PMC11718585 DOI: 10.5493/wjem.v15.i1.97404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Revised: 10/09/2024] [Accepted: 11/14/2024] [Indexed: 12/26/2024] Open
Abstract
Inflammatory bowel disease (IBD) represents a significant disease burden marked by chronic inflammation and complications that adversely affect patients' quality of life. Effective diagnostic strategies involve clinical assessments, endoscopic evaluations, imaging studies, and biomarker testing, where early diagnosis is essential for effective management and prevention of long-term complications, highlighting the need for continual advancements in diagnostic methods. The intricate interplay between genetic factors and the outcomes of biological therapy is of critical importance. Unraveling the genetic determinants that influence responses and failures to biological therapy holds significant promise for optimizing treatment strategies for patients with IBD on biologics. Through an in-depth examination of current literature, this review article synthesizes critical genetic markers associated with therapeutic efficacy and resistance in IBD. Understanding these genetic actors paves the way for personalized approaches, informing clinicians on predicting, tailoring, and enhancing the effectiveness of biological therapies for improved outcomes in patients with IBD.
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Affiliation(s)
- Milena Peruhova
- Department of Gastroenterology, University Hospital Heart and Brain, Burgas 1000, Bulgaria
| | - Daniela Stoyanova
- Department of Gastroenterology, Military Medical Academy, Sofia 1606, Bulgaria
| | | | - Meglena Kitanova
- Department of Genetics, Faculty of Biology, Sofia University St. Kliment Ohridski, Sofia 1164, Bulgaria
| | | | - Tsvetelina Velikova
- Department of Medical Faculty, Sofia University St. Kliment Ohridski, Sofia 1407, Bulgaria
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Rottura M, Pirrotta I, Giorgi DA, Irrera N, Arcoraci V, Mannino F, Campisi R, Bivacqua C, Patanè L, Costantino G, Pallio S, Fries W, Viola A, Pallio G. Genetic Polymorphisms on TNFA, TNFRSF1A, and TNFRSF1B Genes Predict the Effectiveness of Anti-TNF-α Treatment in Inflammatory Bowel Disease Patients. Biomedicines 2025; 13:669. [PMID: 40149645 PMCID: PMC11939863 DOI: 10.3390/biomedicines13030669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 02/28/2025] [Accepted: 03/05/2025] [Indexed: 03/29/2025] Open
Abstract
Background/Objectives: Tumor necrosis factor alpha (TNF-α) is the key inflammatory cytokine involved in the pathogenesis of inflammatory bowel diseases (IBDs). Anti-TNF-α therapy has been successfully used for IBD treatment, although the therapeutic response differs among patients due to the genetic background. The aim of this study was to investigate whether the presence of single nucleotide polymorphisms (SNPs) on TNFA, TNFRSF1A, and TNFRSF1B genes could affect anti-TNF-α treatment effectiveness in IBD patients. Methods: In this prospective cohort study, 83 European IBD patients treated with infliximab or adalimumab (with or without steroid bridge therapy) as first-line therapy were enrolled. Genomic DNA was extracted from peripheral blood, and TNF-α (rs1800629, rs361525, rs1799724), TNFRSF1A (rs767455), and TNFRSF1B (rs1061622, rs1061624, rs3397, rs976881) SNPs were assessed. Steroid-free remission (SFR) (clinical remission together with steroid interruption) and anti-TNF-α therapy persistence after 12 months of follow-up were evaluated. Patients who stopped anti-TNF-α therapy before the end of follow-up, due to side effects or treatment failure, were defined as discontinuers. Results: A higher frequency of the G/G genotype in rs1800629 and the A/A genotype in rs1061624 was observed in the SFR group compared to non-SFR (97.7% vs. 82.8%; p = 0.025 and 32.6% vs. 10.3%; p = 0.029, respectively). Moreover, carriers of the A/A genotype in rs361525 and the C/C genotype in rs767455 had a lower probability of achieving SFR than wild-type patients (OR = 0.14; 95% CI= 0.03-0.69; p = 0.016 and OR = 0.10; 95% CI = 0.02-0.60; p = 0.012, respectively). Furthermore, an increased frequency of rs1800629 A allele was observed in patients who discontinued treatment compared to completers (27.3% vs. 6.9%; p = 0.033), as well as a high risk of interrupting therapy (HR = 6.47; 95% CI = 1.15-36.38). Conclusions: These results suggest that the evaluation of SNPs in TNF-α, TNFR1A, and TNFR1B genes could improve the management of IBD, leading to more effective, individualized treatment plans and a reduction in healthcare costs associated with ineffective therapies and disease complications.
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Affiliation(s)
- Michelangelo Rottura
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (M.R.); (I.P.); (D.A.G.); (N.I.); (V.A.); (C.B.); (L.P.); (S.P.); (W.F.)
| | - Igor Pirrotta
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (M.R.); (I.P.); (D.A.G.); (N.I.); (V.A.); (C.B.); (L.P.); (S.P.); (W.F.)
| | - Domenico Antonio Giorgi
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (M.R.); (I.P.); (D.A.G.); (N.I.); (V.A.); (C.B.); (L.P.); (S.P.); (W.F.)
| | - Natasha Irrera
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (M.R.); (I.P.); (D.A.G.); (N.I.); (V.A.); (C.B.); (L.P.); (S.P.); (W.F.)
| | - Vincenzo Arcoraci
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (M.R.); (I.P.); (D.A.G.); (N.I.); (V.A.); (C.B.); (L.P.); (S.P.); (W.F.)
| | - Federica Mannino
- Department of Medicine and Surgery, University of Enna “Kore”, Contrada Santa Panasia, 94100 Enna, Italy;
| | - Rosario Campisi
- Department of Biomedical and Dental Sciences and Morphological and Functional Imaging, University of Messina, Via C. Valeria, 98125 Messina, Italy; (R.C.); (G.P.)
| | - Chiara Bivacqua
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (M.R.); (I.P.); (D.A.G.); (N.I.); (V.A.); (C.B.); (L.P.); (S.P.); (W.F.)
- Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, Gastroenterology & Hepatology Unit, University of Palermo, Piazza delle Cliniche, 90127 Palermo, Italy
| | - Laura Patanè
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (M.R.); (I.P.); (D.A.G.); (N.I.); (V.A.); (C.B.); (L.P.); (S.P.); (W.F.)
- Department of Health Promotion, Mother & Child Care, Internal Medicine & Medical Specialties, Gastroenterology & Hepatology Unit, University of Palermo, Piazza delle Cliniche, 90127 Palermo, Italy
| | - Giuseppe Costantino
- IBD-Unit, University Hospital Gaetano Martino, Via C. Valeria, 98125 Messina, Italy;
| | - Socrate Pallio
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (M.R.); (I.P.); (D.A.G.); (N.I.); (V.A.); (C.B.); (L.P.); (S.P.); (W.F.)
| | - Walter Fries
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (M.R.); (I.P.); (D.A.G.); (N.I.); (V.A.); (C.B.); (L.P.); (S.P.); (W.F.)
| | - Anna Viola
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (M.R.); (I.P.); (D.A.G.); (N.I.); (V.A.); (C.B.); (L.P.); (S.P.); (W.F.)
| | - Giovanni Pallio
- Department of Biomedical and Dental Sciences and Morphological and Functional Imaging, University of Messina, Via C. Valeria, 98125 Messina, Italy; (R.C.); (G.P.)
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Ballesta-López O, Gil-Candel M, Centelles-Oria M, Megías-Vericat JE, Solana-Altabella A, Ribes-Artero H, Nos-Mateu P, García-Pellicer J, Poveda-Andrés JL. Pharmacogenetics in Response to Biological Agents in Inflammatory Bowel Disease: A Systematic Review. Int J Mol Sci 2025; 26:1760. [PMID: 40004223 PMCID: PMC11855474 DOI: 10.3390/ijms26041760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Revised: 02/07/2025] [Accepted: 02/13/2025] [Indexed: 02/27/2025] Open
Abstract
Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders influenced by microbial, environmental, genetic, and immune factors. The introduction of biological agents has transformed IBD therapy, improving symptoms, reducing complications, and enhancing patients' quality of life. However, approximately 30% of patients exhibit primary non-response, and 50% experience a loss of response over time. Genetic and non-genetic factors contribute to variability in treatment outcomes. This systematic review aims to thoroughly analyze and assess existing studies exploring the relationships between genetic variations and individual responses to biologic drugs, in order to identify genetic markers that are predictive of treatment efficacy, risk of adverse effects, or drug toxicity, thereby informing clinical practice and guiding future research. PubMed and EMBASE papers were reviewed by three independent reviewers according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses [PRISMA] guidelines. Of the 883 records screened, 99 met the inclusion criteria. The findings of this review represent an initial step toward personalized medicine in IBD, with the potential to improve clinical outcomes in biological therapy.
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Affiliation(s)
- Octavio Ballesta-López
- Pharmacy Department, Hospital Universitari i Politècnic La Fe, Av. Fernando Abril Martorell 106, 46026 Valencia, Spain; (O.B.-L.)
- Accredited Research Group on Pharmacy, Instituto de Investigación Sanitaria La Fe (IISLAFE), Av. Fernando Abril Martorell 106, 46026 Valencia, Spain
| | - Mayte Gil-Candel
- Pharmacy Department, Hospital Universitari i Politècnic La Fe, Av. Fernando Abril Martorell 106, 46026 Valencia, Spain; (O.B.-L.)
- Accredited Research Group on Pharmacy, Instituto de Investigación Sanitaria La Fe (IISLAFE), Av. Fernando Abril Martorell 106, 46026 Valencia, Spain
| | - María Centelles-Oria
- Pharmacy Department, Hospital Universitari i Politècnic La Fe, Av. Fernando Abril Martorell 106, 46026 Valencia, Spain; (O.B.-L.)
- Accredited Research Group on Pharmacy, Instituto de Investigación Sanitaria La Fe (IISLAFE), Av. Fernando Abril Martorell 106, 46026 Valencia, Spain
| | - Juan Eduardo Megías-Vericat
- Pharmacy Department, Hospital Universitari i Politècnic La Fe, Av. Fernando Abril Martorell 106, 46026 Valencia, Spain; (O.B.-L.)
- Accredited Research Group on Pharmacy, Instituto de Investigación Sanitaria La Fe (IISLAFE), Av. Fernando Abril Martorell 106, 46026 Valencia, Spain
| | - Antonio Solana-Altabella
- Pharmacy Department, Hospital Universitari i Politècnic La Fe, Av. Fernando Abril Martorell 106, 46026 Valencia, Spain; (O.B.-L.)
- Accredited Research Group on Pharmacy, Instituto de Investigación Sanitaria La Fe (IISLAFE), Av. Fernando Abril Martorell 106, 46026 Valencia, Spain
- Accredited Research Group on Hematology, Instituto de Investigación Sanitaria La Fe (IISLAFE), Av. Fernando Abril Martorell 106, 46026 Valencia, Spain
| | - Hugo Ribes-Artero
- Pharmacy Department, Hospital Universitari i Politècnic La Fe, Av. Fernando Abril Martorell 106, 46026 Valencia, Spain; (O.B.-L.)
- Accredited Research Group on Pharmacy, Instituto de Investigación Sanitaria La Fe (IISLAFE), Av. Fernando Abril Martorell 106, 46026 Valencia, Spain
| | - Pilar Nos-Mateu
- Inflammatory Bowel Disease Unit, Gastroenterology Department, Hospital Universitari i Politècnic La Fe, Av. Fernando Abril Martorell 106, 46026 Valencia, Spain
| | - Javier García-Pellicer
- Pharmacy Department, Hospital Universitari i Politècnic La Fe, Av. Fernando Abril Martorell 106, 46026 Valencia, Spain; (O.B.-L.)
- Accredited Research Group on Pharmacy, Instituto de Investigación Sanitaria La Fe (IISLAFE), Av. Fernando Abril Martorell 106, 46026 Valencia, Spain
| | - José Luis Poveda-Andrés
- Pharmacy Department, Hospital Universitari i Politècnic La Fe, Av. Fernando Abril Martorell 106, 46026 Valencia, Spain; (O.B.-L.)
- Accredited Research Group on Pharmacy, Instituto de Investigación Sanitaria La Fe (IISLAFE), Av. Fernando Abril Martorell 106, 46026 Valencia, Spain
- Management Department, Hospital Universitari i Politècnic La Fe, Av. Fernando Abril Martorell 106, 46026 Valencia, Spain
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Babiker-Mohamed MH, Bhandari S, Ranganathan P. Pharmacogenetics of therapies in rheumatoid arthritis: An update. Best Pract Res Clin Rheumatol 2024; 38:101974. [PMID: 39034216 DOI: 10.1016/j.berh.2024.101974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 07/15/2024] [Accepted: 07/15/2024] [Indexed: 07/23/2024]
Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune inflammatory arthritis. Despite many treatment advances, achieving remission or low-disease activity in RA remains challenging, often requiring trial and error approaches with numerous medications. Precision medicine, particularly pharmacogenomics, explores how genetic factors influence drug response in individual patients, and incorporates such factors to develop personalized treatments for individual patients. Genetic variations in drug-metabolizing enzymes, transporters, and targets may contribute to inter-individual differences in drug efficacy and toxicity. Advancements in molecular sequencing have allowed rapid identification of such variants, including single nucleotide polymorphisms (SNPs). This review highlights recent major findings in the pharmacogenetics of therapies in RA, focusing on key genes and SNPs to provide insights into current trends and developments in this field.
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Affiliation(s)
- Mohamed H Babiker-Mohamed
- Division of Rheumatology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | - Sambhawana Bhandari
- Division of Rheumatology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA
| | - Prabha Ranganathan
- Division of Rheumatology, Department of Medicine, School of Medicine, Washington University in St. Louis, St. Louis, MO, USA.
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7
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Kosorínová D, Suchá P, Havlíčeková Z, Pršo M, Dvoran P, Bánovčin P. Pharmacogenetics in personalized treatment in pediatric patients with inflammatory bowel disease (IBD). ČESKO-SLOVENSKÁ PEDIATRIE 2024; 79:213-219. [DOI: 10.55095/cspediatrie2024/008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Peruhova M, Miteva D, Kokudeva M, Banova S, Velikova T. Cytokine Signatures in Inflamed Mucosa of IBD Patients: State-of-the-Art. GASTROENTEROLOGY INSIGHTS 2024; 15:471-485. [DOI: 10.3390/gastroent15020034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2024] Open
Abstract
The process of development, recurrence, and exacerbation of the inflammatory process depends on the cytokine levels in IBD. For that reason, many cytokine therapies have been developed for treating IBD patients. Researchers employ various techniques and methodologies for cytokine profiling to identify cytokine signatures in inflamed mucosa. These include enzyme-linked immunosorbent assays (ELISA), multiplex immunoassays, flow cytometry, and gene expression analysis techniques (i.e., microarray, RNA-seq, single-cell RNA-seq (scRNA-seq), mass cytometry (CyTOF), Luminex). Research knowledge so far can give us some insights into the cytokine milieu associated with mucosal inflammation by quantifying cytokine levels in mucosal tissues or biological fluids such as serum or stool. The review is aimed at presenting state-of-the-art techniques for cytokine profiling and the various biomarkers for follow-up and treatment.
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Affiliation(s)
- Milena Peruhova
- Division of Gastroenterology, University Hospital “Heart and Brain”, Zdrave Str. 1, 8000 Burgas, Bulgaria
| | - Dimitrina Miteva
- Department of Genetics, Faculty of Biology, Sofia University “St. Kliment Ohridski”, 8 Dragan Tzankov Str., 1164 Sofia, Bulgaria
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str, 1407 Sofia, Bulgaria
| | - Maria Kokudeva
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Medical University of Sofia, ul. Dunav 2, 1000 Sofia, Bulgaria
| | - Sonya Banova
- Division of Gastroenterology, University Hospital “Heart and Brain”, Zdrave Str. 1, 8000 Burgas, Bulgaria
| | - Tsvetelina Velikova
- Medical Faculty, Sofia University St. Kliment Ohridski, 1 Kozyak Str, 1407 Sofia, Bulgaria
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9
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Al-Sofi RF, Bergmann MS, Nielsen CH, Andersen V, Skov L, Loft N. The Association between Genetics and Response to Treatment with Biologics in Patients with Psoriasis, Psoriatic Arthritis, Rheumatoid Arthritis, and Inflammatory Bowel Diseases: A Systematic Review and Meta-Analysis. Int J Mol Sci 2024; 25:5793. [PMID: 38891983 PMCID: PMC11171831 DOI: 10.3390/ijms25115793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 05/13/2024] [Accepted: 05/22/2024] [Indexed: 06/21/2024] Open
Abstract
Genetic biomarkers could potentially lower the risk of treatment failure in chronic inflammatory diseases (CID) like psoriasis, psoriatic arthritis (PsA), rheumatoid arthritis (RA), and inflammatory bowel disease (IBD). We performed a systematic review and meta-analysis assessing the association between single nucleotide polymorphisms (SNPs) and response to biologics. Odds ratio (OR) with 95% confidence interval (CI) meta-analyses were performed. In total, 185 studies examining 62,774 individuals were included. For the diseases combined, the minor allele of MYD88 (rs7744) was associated with good response to TNFi (OR: 1.24 [1.02-1.51], 6 studies, 3158 patients with psoriasis or RA) and the minor alleles of NLRP3 (rs4612666) (OR: 0.71 [0.58-0.87], 5 studies, 3819 patients with RA or IBD), TNF-308 (rs1800629) (OR: 0.71 [0.55-0.92], 25 studies, 4341 patients with psoriasis, RA, or IBD), FCGR3A (rs396991) (OR: 0.77 [0.65-0.93], 18 studies, 2562 patients with psoriasis, PsA, RA, or IBD), and TNF-238 (rs361525) (OR: 0.57 [0.34-0.96]), 7 studies, 818 patients with psoriasis, RA, or IBD) were associated with poor response to TNFi together or infliximab alone. Genetic variants in TNFα, NLRP3, MYD88, and FcRγ genes are associated with response to TNFi across several inflammatory diseases. Most other genetic variants associated with response were observed in a few studies, and further validation is needed.
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Affiliation(s)
- Rownaq Fares Al-Sofi
- Department of Dermatology and Allergy, Copenhagen University Hospital—Herlev and Gentofte, 1165 Copenhagen, Denmark
- Copenhagen Research Group for Inflammatory Skin, Herlev and Gentofte Hospital, 2730 Herlev, Denmark
| | - Mie Siewertsen Bergmann
- Department of Dermatology and Allergy, Copenhagen University Hospital—Herlev and Gentofte, 1165 Copenhagen, Denmark
- Copenhagen Research Group for Inflammatory Skin, Herlev and Gentofte Hospital, 2730 Herlev, Denmark
| | - Claus Henrik Nielsen
- Center for Rheumatology and Spine Diseases, Institute for Inflammation Research, Copenhagen University Hospital Rigshospitalet, 2100 Copenhagen, Denmark
| | - Vibeke Andersen
- Institute of Regional Health Research, University of Southern Denmark, 5230 Odense, Denmark
- Molecular Diagnostics and Clinical Research Unit, Department of Internal Medicine, University Hospital of Southern Denmark, 6200 Aabenraa, Denmark
- Institute of Molecular Medicine, University of Southern Denmark, 5230 Odense, Denmark
| | - Lone Skov
- Department of Dermatology and Allergy, Copenhagen University Hospital—Herlev and Gentofte, 1165 Copenhagen, Denmark
- Copenhagen Research Group for Inflammatory Skin, Herlev and Gentofte Hospital, 2730 Herlev, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 1172 Copenhagen, Denmark
| | - Nikolai Loft
- Department of Dermatology and Allergy, Copenhagen University Hospital—Herlev and Gentofte, 1165 Copenhagen, Denmark
- Copenhagen Research Group for Inflammatory Skin, Herlev and Gentofte Hospital, 2730 Herlev, Denmark
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10
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Kumar M, Murugesan S, Ibrahim N, Elawad M, Al Khodor S. Predictive biomarkers for anti-TNF alpha therapy in IBD patients. J Transl Med 2024; 22:284. [PMID: 38493113 PMCID: PMC10943853 DOI: 10.1186/s12967-024-05058-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Accepted: 03/04/2024] [Indexed: 03/18/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic gastrointestinal condition characterized by severe gut inflammation, commonly presenting as Crohn's disease, ulcerative colitis or categorized as IBD- unclassified. While various treatments have demonstrated efficacy in adult IBD patients, the advent of anti-TNF therapies has significantly revolutionized treatment outcomes and clinical management. These therapies have played a pivotal role in achieving clinical and endoscopic remission, promoting mucosal healing, averting disease progression, and diminishing the necessity for surgery. Nevertheless, not all patients exhibit positive responses to these therapies, and some may experience a loss of responsiveness over time. This review aims to present a comprehensive examination of predictive biomarkers for monitoring the therapeutic response to anti-TNF therapy in IBD patients. It will explore their limitations and clinical utilities, paving the way for a more personalized and effective therapeutic approach.
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Affiliation(s)
- Manoj Kumar
- Research Department, Sidra Medicine, Doha, Qatar
| | | | - Nazira Ibrahim
- Division of Gastroenterology, Hepatology and Nutrition, Sidra Medicine, Doha, Qatar
| | - Mamoun Elawad
- Division of Gastroenterology, Hepatology and Nutrition, Sidra Medicine, Doha, Qatar
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11
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Zeng Z, Jiang M, Li X, Yuan J, Zhang H. Precision medicine in inflammatory bowel disease. PRECISION CLINICAL MEDICINE 2023; 6:pbad033. [PMID: 38638127 PMCID: PMC11025389 DOI: 10.1093/pcmedi/pbad033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 12/13/2023] [Indexed: 04/20/2024] Open
Abstract
Inflammatory bowel disease (IBD) is an incurable disease characterized by remission-relapse cycles throughout its course. Both Crohn's disease (CD) and ulcerative colitis (UC), the two main forms of IBD, exhibit tendency to develop complications and substantial heterogeneity in terms of frequency and severity of relapse, thus posing great challenges to the clinical management for IBD. Current treatment strategies are effective in different ways in induction and maintenance therapies for IBD. Recent advances in studies of genetics, pharmacogenetics, proteomics and microbiome provide a strong driving force for identifying molecular markers of prognosis and treatment response, which should help clinicians manage IBD patients more effectively, and then, improve clinical outcomes and reduce treatment costs of patients. In this review, we summarize and discuss precision medicine in IBD, focusing on predictive markers of disease course and treatment response, and monitoring indices during therapeutic drug monitoring.
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Affiliation(s)
- Zhen Zeng
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Mingshan Jiang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Xi Li
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
- General Practice Ward/International Medical Center Ward, General Practice Medical Center, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jing Yuan
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Hu Zhang
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu 610041, China
- Centre for Inflammatory Bowel Disease, West China Hospital, Sichuan University, Chengdu 610041, China
- Lab of Inflammatory Bowel Disease, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu 610041, China
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12
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Lykowska-Szuber L, Walczak M, Dobrowolska A, Skrzypczak-Zielinska M. Apoptosis and inflammatory genes variants in primary non-response to anti-TNF therapy in Crohn's disease patients. Eur J Gastroenterol Hepatol 2023; 35:1088-1096. [PMID: 37577818 DOI: 10.1097/meg.0000000000002618] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/15/2023]
Abstract
Anti-TNF therapy has indeed revolutionized the treatment of Crohn's disease, leading to higher rates of response and remission in patients. However, a significant proportion of 20-40% of patients do not respond to the initial therapy, others experience a secondary loss of response with ongoing treatment. Adverse drug reactions also occur in some patients. The effectiveness of anti-TNF treatment may be influenced by genetic variability, including FCGR3A, ADAM17, TNFRSF1A, TNFRSF1B, FAS, FASL, IL1B, CASP9 , and MIF genes. In this article, we provide an overview of the current knowledge and findings in the pharmacogenetics of anti-TNF drugs in CD focusing on the aspect of apoptosis and inflammatory genes variants in primary non-response. Pharmacogenetic investigations have been conducted to identify genetic markers that can predict response to anti-TNF therapy. However, large multi-center validation studies and multi-loci algorithms development are required to effectively prognose the treatment effect. The identification of predictive markers of response to anti-TNF therapy can help clinicians make informed decisions about treatment options and minimize adverse drug reactions in patients.
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Affiliation(s)
- Liliana Lykowska-Szuber
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences
| | - Michal Walczak
- Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
| | - Agnieszka Dobrowolska
- Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences
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13
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Cheli S, Savino D, De Silvestri A, Norsa L, Sansotta N, Penagini F, Dilillo D, Panceri R, Cattaneo D, Clementi E, Zuin G. One year of experience with combined pharmacokinetic/pharmacogenetic monitoring of anti-TNF alpha agents: a retrospective study. THE PHARMACOGENOMICS JOURNAL 2023; 23:112-118. [PMID: 37016150 DOI: 10.1038/s41397-023-00304-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/15/2023] [Accepted: 03/20/2023] [Indexed: 04/06/2023]
Abstract
Anti-tumor necrosis factor alpha (anti-TNFα) inhibitors are used extensively for the management of moderate to severe inflammatory bowel disease (IBD) in both adult and pediatric patients. Unfortunately, not all patients show an optimal response to induction therapy, while others lose their response over time for reasons yet poorly understood. We report on a pharmacokinetic/pharmacogenetic approach to monitor the therapy with anti-TNFα in a real-world cohort of seventy-nine pediatric patients affected by IBD that was analyzed retrospectively. We evaluated plasma concentrations of infliximab, adalimumab, and related anti-drug antibodies (ADAs), and single nucleotide polymorphisms (SNPs) in genes involved in immune processes and inflammation on the anti-TNFα response. We found a significant association between the SNP in TNFα promoter (-308G>A) and clinical remission without steroids in patients on infliximab therapy. Additionally, a potential connection between HLA-DQA1*05 genetic variant carriers and a higher risk of anti-TNFα immunogenicity emerged.
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Affiliation(s)
- Stefania Cheli
- Unit of Clinical Pharmacology, ASST Fatebenefratelli Sacco, University Hospital, Milano, Italy
| | - Diego Savino
- Unit of Clinical Pharmacology, ASST Fatebenefratelli Sacco, University Hospital, Milano, Italy
| | - Annalisa De Silvestri
- Clinical Epidemiology and Biometry Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Lorenzo Norsa
- Pediatric Hepatology, Gastroenterology and Transplantation Unit, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Naire Sansotta
- Pediatric Hepatology, Gastroenterology and Transplantation Unit, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Francesca Penagini
- Pediatric Department, "Vittore Buzzi" Children's Hospital, University of Milan, Milano, Italy
| | - Dario Dilillo
- Pediatric Department, "Vittore Buzzi" Children's Hospital, University of Milan, Milano, Italy
| | - Roberto Panceri
- Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
| | - Dario Cattaneo
- Unit of Clinical Pharmacology, ASST Fatebenefratelli Sacco, University Hospital, Milano, Italy
| | - Emilio Clementi
- Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Italy.
- Clinical Pharmacology Unit, Department of Biomedical and Clinical Sciences, L. Sacco University Hospital, Università degli Studi di Milano, Milan, Italy.
| | - Giovanna Zuin
- Pediatrics, Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy
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14
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Cozzi G, Scagnellato L, Lorenzin M, Savarino E, Zingone F, Ometto F, Favero M, Doria A, Vavricka SR, Ramonda R. Spondyloarthritis with inflammatory bowel disease: the latest on biologic and targeted therapies. Nat Rev Rheumatol 2023:10.1038/s41584-023-00984-8. [PMID: 37386288 DOI: 10.1038/s41584-023-00984-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/19/2023] [Indexed: 07/01/2023]
Abstract
Spondyloarthritis (SpA) encompasses a heterogeneous group of chronic inflammatory diseases that can affect both axial and peripheral joints, tendons and entheses. Among the extra-articular manifestations, inflammatory bowel disease (IBD) is associated with considerable morbidity and effects on quality of life. In everyday clinical practice, treatment of these conditions requires a close collaboration between gastroenterologists and rheumatologists to enable early detection of joint and intestinal manifestations during follow-up and to choose the most effective therapeutic regimen, implementing precision medicine for each patient's subtype of SpA and IBD. The biggest issue in this field is the dearth of drugs that are approved for both diseases, as only TNF inhibitors are currently approved for the treatment of full-spectrum SpA-IBD. Janus tyrosine kinase inhibitors are among the most promising drugs for the treatment of peripheral and axial SpA, as well as for intestinal manifestations. Other therapies such as inhibitors of IL-23 and IL-17, phosphodiesterase 4 inhibitor, α4β7 integrin blockers and faecal microbiota transplantation seem to only be able to control some disease domains, or require further studies. Given the growing interest in the development of novel drugs to treat both conditions, it is important to understand the current state of the art and the unmet needs in the management of SpA-IBD.
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Affiliation(s)
- Giacomo Cozzi
- Rheumatology Unit, Department of Medicine-DIMED, Padova University Hospital, Padova, Italy
| | - Laura Scagnellato
- Rheumatology Unit, Department of Medicine-DIMED, Padova University Hospital, Padova, Italy
| | - Mariagrazia Lorenzin
- Rheumatology Unit, Department of Medicine-DIMED, Padova University Hospital, Padova, Italy
| | - Edoardo Savarino
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padova, Padova, Italy
| | - Fabiana Zingone
- Gastroenterology Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital of Padova, Padova, Italy
| | - Francesca Ometto
- Rheumatology Unit, Department of Medicine-DIMED, Padova University Hospital, Padova, Italy
| | - Marta Favero
- Rheumatology Unit, Department of Medicine-DIMED, Padova University Hospital, Padova, Italy
| | - Andrea Doria
- Rheumatology Unit, Department of Medicine-DIMED, Padova University Hospital, Padova, Italy
| | - Stephan R Vavricka
- Department of Gastroenterology and Hepatology, University Hospital Zürich and Center for Gastroenterology and Hepatology, Zürich, Switzerland
| | - Roberta Ramonda
- Rheumatology Unit, Department of Medicine-DIMED, Padova University Hospital, Padova, Italy.
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15
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Markelova M, Senina A, Khusnutdinova D, Siniagina M, Kupriyanova E, Shakirova G, Odintsova A, Abdulkhakov R, Kolesnikova I, Shagaleeva O, Lyamina S, Abdulkhakov S, Zakharzhevskaya N, Grigoryeva T. Association between Taxonomic Composition of Gut Microbiota and Host Single Nucleotide Polymorphisms in Crohn's Disease Patients from Russia. Int J Mol Sci 2023; 24:ijms24097998. [PMID: 37175705 PMCID: PMC10178390 DOI: 10.3390/ijms24097998] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Revised: 04/25/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
Crohn's disease (CD) is a chronic relapsing inflammatory bowel disease of unknown etiology. Genetic predisposition and dysbiotic gut microbiota are important factors in the pathogenesis of CD. In this study, we analyzed the taxonomic composition of the gut microbiota and genotypes of 24 single nucleotide polymorphisms (SNP) associated with the risk of CD. The studied cohorts included 96 CD patients and 24 healthy volunteers from Russia. Statistically significant differences were found in the allele frequencies for 8 SNPs and taxonomic composition of the gut microbiota in CD patients compared with controls. In addition, two types of gut microbiota communities were identified in CD patients. The main distinguishing driver of bacterial families for the first community type are Bacteroidaceae and unclassified members of the Clostridiales order, and the second type is characterized by increased abundance of Streptococcaceae and Enterobacteriaceae. Differences in the allele frequencies of the rs9858542 (BSN), rs3816769 (STAT3), and rs1793004 (NELL1) were also found between groups of CD patients with different types of microbiota communities. These findings confirm the complex multifactorial nature of CD.
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Affiliation(s)
- Maria Markelova
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Anastasia Senina
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Dilyara Khusnutdinova
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Maria Siniagina
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Elena Kupriyanova
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | | | | | - Rustam Abdulkhakov
- Hospital Therapy Department, Kazan State Medical University, 420012 Kazan, Russia
| | - Irina Kolesnikova
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia
| | - Olga Shagaleeva
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia
| | - Svetlana Lyamina
- Molecular Pathology of Digestion Laboratory, A.I. Yevdokimov Moscow State University of Medicine and Dentistry, 127473 Moscow, Russia
| | - Sayar Abdulkhakov
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Natalia Zakharzhevskaya
- Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, 119435 Moscow, Russia
| | - Tatiana Grigoryeva
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
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16
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Vieujean S, Louis E. Precision medicine and drug optimization in adult inflammatory bowel disease patients. Therap Adv Gastroenterol 2023; 16:17562848231173331. [PMID: 37197397 PMCID: PMC10184262 DOI: 10.1177/17562848231173331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Accepted: 04/16/2023] [Indexed: 05/19/2023] Open
Abstract
Inflammatory bowel diseases (IBD) encompass two main entities including ulcerative colitis and Crohn's disease. Although having a common global pathophysiological mechanism, IBD patients are characterized by a significant interindividual heterogeneity and may differ by their disease type, disease locations, disease behaviours, disease manifestations, disease course as well as treatment needs. Indeed, although the therapeutic armamentarium for these diseases has expanded rapidly in recent years, a proportion of patients remains with a suboptimal response to medical treatment due to primary non-response, secondary loss of response or intolerance to currently available drugs. Identifying, prior to treatment initiation, which patients are likely to respond to a specific drug would improve the disease management, avoid unnecessary side effects and reduce the healthcare expenses. Precision medicine classifies individuals into subpopulations according to clinical and molecular characteristics with the objective to tailor preventative and therapeutic interventions to the characteristics of each patient. Interventions would thus be performed only on those who will benefit, sparing side effects and expense for those who will not. This review aims to summarize clinical factors, biomarkers (genetic, transcriptomic, proteomic, metabolic, radiomic or from the microbiota) and tools that could predict disease progression to guide towards a step-up or top-down strategy. Predictive factors of response or non-response to treatment will then be reviewed, followed by a discussion about the optimal dose of drug required for patients. The time at which these treatments should be administered (or rather can be stopped in case of a deep remission or in the aftermath of a surgery) will also be addressed. IBD remain biologically complex, with multifactorial etiopathology, clinical heterogeneity as well as temporal and therapeutic variabilities, which makes precision medicine especially challenging in this area. Although applied for many years in oncology, it remains an unmet medical need in IBD.
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Affiliation(s)
- Sophie Vieujean
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
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17
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Abstract
PURPOSE OF REVIEW Sarcoidosis is a chronic multisystemic inflammatory disease of unknown aetiology with a wide range of highly variable clinical manifestations and unpredictable disease course. Sarcoidosis patients may present with specific organ-related symptoms involving functional impairments, and less specific symptoms. The decision whether and when to treat a sarcoidosis patient with pharmacotherapy depends on two major factors: risk of organ failure and/or death and impairment of quality of life. This decision is complex and not standardized. RECENT FINDINGS Glucocorticoids (GCs) are recommended as initial treatment, when needed. Subsequent GC-sparing alternatives frequently follow. Comorbidities or adverse drug reactions (ADRs) from drugs used in sarcoidosis treatment are sometimes very hard to differentiate from symptoms associated with the disease itself, which may cause diagnostic dilemmas. An ideal approach to minimalize ADRs would involve genetic screening prior to prescribing certain 'high-risk drugs' and therapeutic drug monitoring during treatment. Pharmacogenomic testing aims to guide appropriate selection of medicines, with the potential of reducing unnecessary polypharmacy while improving clinical outcomes. SUMMARY A multidisciplinary approach to the management of sarcoidosis may avoid unnecessary ADRs. It is important to consider the possibility of drug-induced damage in sarcoidosis, especially if the clinical situation deteriorates after the introduction of a particular drug.
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Affiliation(s)
- Marjolein Drent
- Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Science, Maastricht University, Maastricht
- ILD Center of Excellence, Department of Respiratory Medicine, St. Antonius Hospital, Nieuwegein
- ILD Care Foundation Research Team, Ede
| | - Naomi T. Jessurun
- ILD Care Foundation Research Team, Ede
- Netherlands Pharmacovigilance Centre Lareb, ‘s-Hertogenbosch
| | - Petal A. Wijnen
- ILD Care Foundation Research Team, Ede
- Central Diagnostic Laboratory, Department of Clinical Chemistry, MUMC, Maastricht, The Netherlands
| | - Otto Bekers
- Central Diagnostic Laboratory, Department of Clinical Chemistry, MUMC, Maastricht, The Netherlands
| | - Aalt Bast
- Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Science, Maastricht University, Maastricht
- ILD Care Foundation Research Team, Ede
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18
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Elhag DA, Kumar M, Saadaoui M, Akobeng AK, Al-Mudahka F, Elawad M, Al Khodor S. Inflammatory Bowel Disease Treatments and Predictive Biomarkers of Therapeutic Response. Int J Mol Sci 2022; 23:ijms23136966. [PMID: 35805965 PMCID: PMC9266456 DOI: 10.3390/ijms23136966] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 06/05/2022] [Accepted: 06/06/2022] [Indexed: 02/08/2023] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic immune-mediated inflammation of the gastrointestinal tract with a highly heterogeneous presentation. It has a relapsing and remitting clinical course that necessitates lifelong monitoring and treatment. Although the availability of a variety of effective therapeutic options including immunomodulators and biologics (such as TNF, CAM inhibitors) has led to a paradigm shift in the treatment outcomes and clinical management of IBD patients, some patients still either fail to respond or lose their responsiveness to therapy over time. Therefore, according to the recent Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE-II) recommendations, continuous disease monitoring from symptomatic relief to endoscopic healing along with short- and long-term therapeutic responses are critical for providing IBD patients with a tailored therapy algorithm. Moreover, considering the high unmet need for novel therapeutic approaches for IBD patients, various new modulators of cytokine signaling events (for example, JAK/TYK inhibitors), inhibitors of cytokines (for example IL-12/IL-23, IL-22, IL-36, and IL-6 inhibitors), anti-adhesion and migration strategies (for example, β7 integrin, sphingosine 1-phosphate receptors, and stem cells), as well as microbial-based therapeutics to decolonize the bed buds (for example, fecal microbiota transplantation and bacterial inhibitors) are currently being evaluated in different phases of controlled clinical trials. This review aims to offer a comprehensive overview of available treatment options and emerging therapeutic approaches for IBD patients. Furthermore, predictive biomarkers for monitoring the therapeutic response to different IBD therapies are also discussed.
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Affiliation(s)
- Duaa Ahmed Elhag
- Research Department, Sidra Medicine, Doha 26999, Qatar; (D.A.E.); (M.K.); (M.S.)
| | - Manoj Kumar
- Research Department, Sidra Medicine, Doha 26999, Qatar; (D.A.E.); (M.K.); (M.S.)
| | - Marwa Saadaoui
- Research Department, Sidra Medicine, Doha 26999, Qatar; (D.A.E.); (M.K.); (M.S.)
| | - Anthony K. Akobeng
- Division of Gastroenterology, Hepatology and Nutrition, Sidra Medicine, Doha 26999, Qatar; (A.K.A.); (F.A.-M.); (M.E.)
| | - Fatma Al-Mudahka
- Division of Gastroenterology, Hepatology and Nutrition, Sidra Medicine, Doha 26999, Qatar; (A.K.A.); (F.A.-M.); (M.E.)
| | - Mamoun Elawad
- Division of Gastroenterology, Hepatology and Nutrition, Sidra Medicine, Doha 26999, Qatar; (A.K.A.); (F.A.-M.); (M.E.)
| | - Souhaila Al Khodor
- Research Department, Sidra Medicine, Doha 26999, Qatar; (D.A.E.); (M.K.); (M.S.)
- Correspondence:
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19
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Yoshida A, Kimura K, Morizane T, Ueno F. Predictor of primary response to antitumor necrosis factor-α therapy for inflammatory bowel disease: a single-center observational study. Eur J Gastroenterol Hepatol 2022; 34:640-645. [PMID: 35352693 DOI: 10.1097/meg.0000000000002372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND It is necessary to find reliable and appropriate predictors of primary response to anti-TNFα therapy (infliximab and adalimumab) in inflammatory bowel disease (IBD) so as to avoid treatment failure and select optimal treatment. The aim of this study is to reveal useful predictors of the response to anti-TNFα treatment from baseline to 2 months after initial administration of anti-TNFα for individual IBD patients using our pharmacokinetic and pharmacodynamic (PK/PD) model at the time of second administration. METHODS We retrospectively analyzed 26 IBD patients who received anti-TNFα. In the PK/PD model, inflammation was assumed to be suppressed based on the action of anti-TNFα at the rate constant of Kanti-TNFα (day-1). Kanti-TNFα0 (day-1) is Kanti-TNFα in the absence of anti-TNFα. We expressed inflammation caused by factors not affected by the action of anti-TNFα using the rate constant Kelse (day-1). Using univariate and multivariate linear regressions, we statistically analyzed factors related to the improvement of disease activity index. RESULTS The significant correlation between Kanti-TNFα0/Kelse and the improvement of disease activity index was shown in Crohn's disease patients (univariate: estimated value 2.4; P = 0.003; and multivariate: 1.8; P = 0.012) and ulcerative colitis patients (univariate: 0.12; P = 0.011), and no other factors were significant. CONCLUSION This is the first study to present a useful predictor of primary response to anti-TNFα of individual IBD patients at second administration. The Kanti-TNFα0/Kelse ratio may help to select the optimal therapeutic drug and avoid the improper continuous administration of anti-TNFα in the induction phase.
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Affiliation(s)
- Atsushi Yoshida
- Center for Gastroenterology and Inflammatory Bowel Disease, Ofuna Chuo Hospital, Kamakura
| | - Koji Kimura
- Department of Clinical Evaluation of Drug Efficacy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan
| | - Toshio Morizane
- Center for Gastroenterology and Inflammatory Bowel Disease, Ofuna Chuo Hospital, Kamakura
| | - Fumiaki Ueno
- Center for Gastroenterology and Inflammatory Bowel Disease, Ofuna Chuo Hospital, Kamakura
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20
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Wang Z, Kong L, Zhang H, Sun F, Guo Z, Zhang R, Dou Y. Tumor Necrosis Factor Alpha -308G/A Gene Polymorphisms Combined with Neutrophil-to-Lymphocyte and Platelet-to-Lymphocyte Ratio Predicts the Efficacy and Safety of Anti-TNF-α Therapy in Patients with Ankylosing Spondylitis, Rheumatoid Arthritis, and Psoriasis Arthritis. Front Pharmacol 2022; 12:811719. [PMID: 35126146 PMCID: PMC8814446 DOI: 10.3389/fphar.2021.811719] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Accepted: 12/30/2021] [Indexed: 01/04/2023] Open
Abstract
Background: TNF-α has been reported to be closely associated with autoimmune inflammatory diseases. This study aims to investigate the role of TNF-α -308(rs1800629) G/A gene polymorphisms as well as neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in predicting the efficacy and safety of TNF inhibitors (TNFi) in patients with ankylosing spondylitis (AS), rheumatoid arthritis (RA), and psoriasis arthritis (PsA). Methods: A total of 515 subjects (181 AS, 144 RA, 48 PsA, 10 hyperbilirubinemia, 10 hyperlipidemia and 122 healthy control) were recruited in this study. The accuracy of RT-PCR methods for identifying individual TNF-α -308 genotypes was assessed using sequencing as the gold standard. Baseline NLR and PLR of patients with AS, RA and PsA and healthy controls (HC) were calculated and compared. Meanwhile, differences between responders and non-responders to TNFi treatment as well as between individuals with and without adverse effects (AE) among responders were compared. Results: The RT-PCR method is stable and reliable for TNF-α -308G/A gene polymorphism analysis, independent of sample status. The GG genotype was overwhelmingly represented, with relatively few GA genotype, whilst the AA genotype was not detected in this study. There was no observed association between TNF-α-308G/A polymorphism and susceptibility in AS, RA or PsA patients. Patients with AS, RA, and PsA had a higher NLR, compared to the HC group. Apart from PsA patients, AS and RA patients had a higher PLR, compared to the HC group. NLR was positively correlated with PLR. Furthermore, a lack of response was more frequently observed in AS and RA patients that carrying the GA genotype than the GG genotype. AS and RA patients with AE had higher NLR and PLR, compared with the non-AE group. Conclusion: Our study preliminarily shown that combining TNF-α -308G/A polymorphisms with NLR and PLR can predict the responsiveness and safety of anti-TNF therapy in patients with AS or RA.
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Affiliation(s)
- Ziran Wang
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Lingjun Kong
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Han Zhang
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Fengchun Sun
- Department of Clinical Laboratory, Affiliated Hospital of Jining Medical University, Jining, China
| | - Zijian Guo
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Rui Zhang
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Yaling Dou
- Department of Clinical Laboratory, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
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21
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Gasparetto M, Strisciuglio C, Assa A, Gerasimidis K, Giachero F, Novak J, Robinson P, Tél B, Zilbauer M, Jenke A. Making Research Flourish Through ESPGHAN: A Position Paper From the ESPGHAN Special Interest Group for Basic and Translational Research. J Pediatr Gastroenterol Nutr 2022; 74:301-312. [PMID: 34310437 DOI: 10.1097/mpg.0000000000003250] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
ABSTRACT Recent research breakthroughs have emerged from applied basic research throughout all scientific areas, including adult and paediatric gastroenterology, hepatology and nutrition (PGHAN). The research landscape within the European Society of Paediatric Gastroenterology and Nutrition (ESPGHAN) is also inevitably changing from clinical research to studies involving applied laboratory research. This position paper aims to depict the current status quo of basic science and translational research within ESPGHAN, and to delineate how the society could invest in research in the present and future time. The paper also explores which research areas in the field of PGHAN represent the current and future priorities, and what type of support is needed across the ESPGHAN working groups (WGs) and special interest groups (SIGs) to fulfil their research goals.
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Affiliation(s)
- Marco Gasparetto
- Royal London Children's Hospital, Barts Health NHS Trust, London, UK
| | - Caterina Strisciuglio
- Department of Woman, Child and General and Specialist Surgery, University of Campania "Luigi Vanvitelli", Naples, Italy
| | - Amit Assa
- Department of Pediatrics, Assuta Ashdod University Hospital, Ashdod, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
| | | | - Federica Giachero
- Clinical, Molecular, Genetics and Epigenetics Faculty of Health, Center for Biochemical Education and Research (ZBAF), Witten-Herdecke University, Witten; Evangelisches Krankenhaus Oberhausen, Children's Hospital, Paediatrics, Oberhausen, Germany
| | - Jan Novak
- Department of Pediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Philip Robinson
- Wellcome Sanger Institute, Cambridge; Department of Paediatrics, University of Cambridge, Cambridge, UK
| | - Bálint Tél
- Semmelweis University, 1st Department of Paediatrics, Budapest, Hungary
| | - Matthias Zilbauer
- University Department of Paediatrics, University of Cambridge, Cambridge, UK
| | - Andreas Jenke
- Children's Hospital Kassel, Witten/Herdecke University, Kassel, Germany
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22
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Miler M, Nikolac Gabaj N, Ćelap I, Grazio S, Tomašić V, Bišćanin A, Mitrović J, Đerek L, Morović-Vergles J, Vrkić N, Štefanović M. Association of polymorphisms in promoter region of TNF-α -238 and -308 with clinical outcomes in patients with immune-mediated inflammatory diseases on anti-TNF therapy. Rheumatol Int 2021; 41:2195-2203. [PMID: 34623480 DOI: 10.1007/s00296-021-05016-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 09/27/2021] [Indexed: 10/20/2022]
Abstract
The hypothesis of the study was that polymorphisms in promoter regions -238 and -308 of TNF-α could be associated with different clinical outcomes in inflammatory bowel diseases (IBD) and immune-mediated rheumatic diseases (IMRD). The aim was to examine the possible association of both polymorphisms with concentration of C-reactive protein (CRP) and fecal calprotectin (fCAL), onset of the remission and development of the ADA in patients on therapy with anti-TNF inhibitors. The prospective study was done in patients with IBD and IMRD on infliximab (IFX) or adalimumab (ADM). Patients were genotyped for TNF-α -238 and -308 polymorphisms. The concentration of CRP, fCAL, IFX or ADM and antibodies to drugs were measured according to manufacturer's instructions and followed-up for 6 or 12 months. Out of all patients (N = 112), number of patients in remission did not differ according to genotypes (for IBD patients P = 0.509 vs 0.223; for IMRD patients P = 0.541 vs 0.132 for TNF-α -238 and -308, respectively). Initial CRP concentration was higher in IBD patients with TNF-α -308 GG than GA/AA genotypes in patients who failed to achieve remission [11.8 (4.4-39.6) vs 3.1 (1.5-6.5), P = 0.033]. In IBD patients with remission, fCAL concentration after at least 6 months of therapy was higher in TNF-α-308 GG than in GA genotype [52 (25-552) vs 20 (20-20) µg/g, P = 0.041]. Our results showed the association of TNF-α -308 GG genotype with a higher concentration of CRP and fecal calprotectin in patients with inflammatory bowel diseases on IFX or ADM therapy. Clinical remission and development of antibodies to anti-TNF drugs were not associated with TNF-α -238 and -308 polymorphisms.
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Affiliation(s)
- Marijana Miler
- Department of Clinical Chemistry, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia.
| | - Nora Nikolac Gabaj
- Department of Clinical Chemistry, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
- Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
| | - Ivana Ćelap
- Department of Clinical Chemistry, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
| | - Simeon Grazio
- Department for Rheumatology, Physical and Rehabilitation Medicine, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
| | - Vedran Tomašić
- Department of Gastroenterology and Hepatology, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
| | - Alen Bišćanin
- Department of Gastroenterology and Hepatology, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
| | - Joško Mitrović
- Department of Clinical Immunology, Allergology and Rheumatology, Department of Internal Medicine, School of Medicine, University of Zagreb, University Hospital Dubrava, Zagreb, Croatia
| | - Lovorka Đerek
- Clinical Department of Laboratory Diagnostics, University Hospital Dubrava, Zagreb, Croatia
| | - Jadranka Morović-Vergles
- Division of Cl Immunology, Allergology and Rheumatology, Department of Internal Medicine, School of Medicine, University of Zagreb, University Hospital Dubrava, Zagreb, Croatia
| | - Nada Vrkić
- Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
| | - Mario Štefanović
- Department of Clinical Chemistry, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
- Faculty of Pharmacy and Biochemistry, University of Zagreb, Zagreb, Croatia
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23
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Lauro R, Mannino F, Irrera N, Squadrito F, Altavilla D, Squadrito G, Pallio G, Bitto A. Pharmacogenetics of Biological Agents Used in Inflammatory Bowel Disease: A Systematic Review. Biomedicines 2021; 9:1748. [PMID: 34944563 PMCID: PMC8699014 DOI: 10.3390/biomedicines9121748] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/19/2021] [Accepted: 11/19/2021] [Indexed: 12/12/2022] Open
Abstract
Inflammatory Bowel Disease (IBD) comprises a group of disorders, in particular Crohn's disease (CD) and ulcerative colitis (UC), characterized by chronic inflammation affecting the gastrointestinal tract. The treatment of these conditions is primarily based on anti-inflammatory drugs, although the use of biological drugs with lower side effects quickly increased in the last decade. However, the presence of certain polymorphisms in the population may determine a different outcome in response to therapy, reflecting the heterogeneity of the efficacy in patients. Considering that several studies showed important correlations between genetic polymorphisms and response to biological treatments in IBD patients, this systematic review aims to summarize the pharmacogenetics of biologicals approved for IBD, thus highlighting a possible association between some polymorphisms and drug response. With this purpose, we reviewed PubMed papers published over the past 21 years (2000-2021), using as the search term "drug name and IBD or CD or UC and polymorphisms" to underline the role of pharmacogenetic tests in approaching the disease with a targeted therapy.
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Affiliation(s)
- Rita Lauro
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (R.L.); (F.M.); (N.I.); (F.S.); (G.S.); (A.B.)
| | - Federica Mannino
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (R.L.); (F.M.); (N.I.); (F.S.); (G.S.); (A.B.)
| | - Natasha Irrera
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (R.L.); (F.M.); (N.I.); (F.S.); (G.S.); (A.B.)
- SunNutraPharma, Academic Spin-Off Company of the University of Messina, Via C. Valeria, 98125 Messina, Italy;
| | - Francesco Squadrito
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (R.L.); (F.M.); (N.I.); (F.S.); (G.S.); (A.B.)
- SunNutraPharma, Academic Spin-Off Company of the University of Messina, Via C. Valeria, 98125 Messina, Italy;
| | - Domenica Altavilla
- SunNutraPharma, Academic Spin-Off Company of the University of Messina, Via C. Valeria, 98125 Messina, Italy;
- Department of Biomedical, Dental, Morphological and Functional Imaging Sciences, University of Messina, Via C. Valeria, 98125 Messina, Italy
| | - Giovanni Squadrito
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (R.L.); (F.M.); (N.I.); (F.S.); (G.S.); (A.B.)
| | - Giovanni Pallio
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (R.L.); (F.M.); (N.I.); (F.S.); (G.S.); (A.B.)
| | - Alessandra Bitto
- Department of Clinical and Experimental Medicine, University of Messina, Via C. Valeria, 98125 Messina, Italy; (R.L.); (F.M.); (N.I.); (F.S.); (G.S.); (A.B.)
- SunNutraPharma, Academic Spin-Off Company of the University of Messina, Via C. Valeria, 98125 Messina, Italy;
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24
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Curci D, Lucafò M, Cifù A, Fabris M, Bramuzzo M, Martelossi S, Franca R, Decorti G, Stocco G. Pharmacogenetic variants of infliximab response in young patients with inflammatory bowel disease. Clin Transl Sci 2021; 14:2184-2192. [PMID: 34145770 PMCID: PMC8604212 DOI: 10.1111/cts.13075] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 04/05/2021] [Accepted: 04/22/2021] [Indexed: 02/02/2023] Open
Abstract
Infliximab is commonly used in inflammatory bowel disease (IBD), however, differences in clinical response among patients are common. Several studies have considered the possibility that these differences are caused by genetic variability even if no unique marker has been yet identified in pediatric patients. We evaluated the impact of two candidate single-nucleotide polymorphisms (SNPs) rs396991 in FCGR3A and rs1800629 in TNFα genes on infliximab response in an Italian cohort of 76 pediatric patients with IBD. Results showed that patients with the variant FCGR3A allele had a reduced clinical response at the end of induction (p value = 0.004), at 22 weeks (p value = 0.001), and at 52 weeks of treatment (p value = 0.01). A significant association between the FCGR3A variant and median infliximab levels measured during maintenance therapy was also observed: patients with wild type genotype had higher infliximab levels compared to patient with variant allele. Furthermore, patients with the variant allele had a higher probability to produce antidrug antibodies (ADAs). No association was found among the TNFα SNP, clinical response, and infliximab levels. This study addressed for the first time in pediatric patients with IBD, the association of FCGR3A SNP, infliximab response, and ADA production.
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Affiliation(s)
- Debora Curci
- Institute for Maternal and Child Health‐IRCCS "Burlo Garofolo"TriesteItaly
| | - Marianna Lucafò
- Institute for Maternal and Child Health‐IRCCS "Burlo Garofolo"TriesteItaly
| | - Adriana Cifù
- Department of Laboratory Medicine, S. Maria della Misericordia University HospitalUdineItaly
| | - Martina Fabris
- Department of Laboratory Medicine, S. Maria della Misericordia University HospitalUdineItaly
| | - Matteo Bramuzzo
- Institute for Maternal and Child Health‐IRCCS "Burlo Garofolo"TriesteItaly
| | | | - Raffaella Franca
- Department of Medicine, Surgery and Health Sciences, University of TriesteTriesteItaly
| | - Giuliana Decorti
- Institute for Maternal and Child Health‐IRCCS "Burlo Garofolo"TriesteItaly
- Department of Medicine, Surgery and Health Sciences, University of TriesteTriesteItaly
| | - Gabriele Stocco
- Department of Life SciencesUniversity of TriesteTriesteItaly
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25
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Crohn's disease-related single nucleotide polymorphisms are associated with ileal pouch afferent limb stenosis. J Gastrointest Surg 2021; 25:2377-2386. [PMID: 33443688 DOI: 10.1007/s11605-020-04884-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Accepted: 11/12/2020] [Indexed: 01/31/2023]
Abstract
BACKGROUND Ileal pouch-anal anastomosis (IPAA) is a common surgical treatment for ulcerative colitis. Afferent limb stenosis is an infrequent complication following IPAA, suggesting underlying Crohn's disease (CD). We hypothesized that CD-related single nucleotide polymorphisms (SNPs) are associated with afferent limb stenosis. METHODS Afferent limb stenosis and CD control group patients were recruited from a prospective institutional inflammatory bowel disease database and associated biobank. Patient demographics, Montreal classification, and medication use were recorded. Ten SNPs associated with stricturing Crohn's disease were examined in genomic DNA and compared among afferent limb stenosis, stricturing CD, and non-stricturing CD controls. RESULTS Twenty-seven afferent limb stenosis and 162 CD control group patients (108 stricturing, 54 non-stricturing) were identified. Patients were gender and race matched. Afferent limb stenosis and stricturing CD controls were younger at diagnosis (Montreal A1/A2 vs. A3) compared to non-stricturing CD controls (both p < 0.05). The majority of afferent limb stenosis patients were non-smokers compared to CD controls (74% vs. 36%, p < 0.01) and did not use biologic therapies (4% vs. 37%, p < 0.001). The FUT2 G allele was more frequent in afferent limb stenosis and stricturing CD controls compared to non-stricturing CD controls (both p < 0.05). The NOD2 T allele was more frequent in stricturing CD controls compared to afferent limb stenosis and non-stricturing CD controls (both p < 0.05). CONCLUSION Afferent limb stenosis patients are phenotypically similar to stricturing CD controls, but differ with lower smoking rates and lower NOD2 allele frequency. Such differences could contribute to the presentation delay with a stricturing phenotype. Selective SNP assessment may help categorize patients likely to develop afferent limb stenosis.
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26
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Antonatos C, Stavrou EF, Evangelou E, Vasilopoulos Y. Exploring pharmacogenetic variants for predicting response to anti-TNF therapy in autoimmune diseases: a meta-analysis. Pharmacogenomics 2021; 22:435-445. [PMID: 33887993 DOI: 10.2217/pgs-2021-0019] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Aim: The aim of this study is to explore how SNPs may affect the response to anti-TNF-α therapy in the major autoimmune diseases, such as psoriasis, rheumatoid arthritis, inflammatory bowel diseases and Spondyloarthritis. Methodology: We conducted a systematic overview on the field, by assessing all studies that examined the association between polymorphisms and response to anti-TNF-α therapy in participants of European descent. Results: In total, six independent SNPs located in FCGR2A, FCGR3A, TNF-α and TNFRSF1B genes were significantly associated with response to TNF-α blockers, found mainly in disease-subgroup analyses. Conclusion: No common pharmacogenetic variant was identified for all autoimmune diseases under study, suggesting the requirement of more studies in the field in order to capture such predictive variants that will aid treatment selection.
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Affiliation(s)
- Charalabos Antonatos
- Department of Biology, Laboratory of Genetics, University of Patras, Patras, Greece
| | - Eleana F Stavrou
- Department of Biology, Laboratory of Genetics, University of Patras, Patras, Greece
| | - Evangelos Evangelou
- Department of Hygiene & Epidemiology, Medical School, University of Ioannina, Ioannina, Greece.,Institute of Biosciences, University Research Center of loannina, Ioannina, Greece.,Department of Epidemiology & Biostatistics, MRC Centre for Environment and Health, School of Public Health, Faculty of Medicine, Imperial College London, St Mary's Campus, Norfolk Place, London, W2 1PG, UK
| | - Yiannis Vasilopoulos
- Department of Biology, Laboratory of Genetics, University of Patras, Patras, Greece
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27
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Mahajna H, Ben-Horin S. Novel bio-genetic predictors of response to biologic treatment in inflammatory bowel diseases. Curr Opin Pharmacol 2020; 55:132-140. [PMID: 33249396 DOI: 10.1016/j.coph.2020.10.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 09/29/2020] [Accepted: 10/11/2020] [Indexed: 02/07/2023]
Abstract
Despite the evolving therapeutic armamentarium, the treatment of IBD patients remains challenging and many patients fail to respond to biologic agents. With the limited yield of clinical factors to predict the outcome of biologic treatments, studies have focused on identifying genetic alterations and circulating or tissue biomarkers to identify patients who are likely to respond to therapy. In this review, we examine the current knowledge and status of genetic, expression biomarkers, and microbiome predictors. The search for genetic predictors has yielded many genetic loci variants, but few were reproducible. Expression studies of putative biomarkers show promising results, especially with TREM1, oncostatin M and TNF biomarkers, but confirmatory studies are warranted. Finally, the microbiome is emerging as an important player with specific taxa and functional pathways differentially abundant and enriched in responders versus non-responders to certain biologics. Integrating different factors into a robust predictive model, which is both reproducible, accurate and affordable, remains the main challenge before these individualized strategies can reach clinical use.
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Affiliation(s)
- Hussein Mahajna
- Gastroenterology Department, Sheba Medical Center, Affiliated to Tel-Aviv University, Tel-Aviv, Israel.
| | - Shomron Ben-Horin
- Gastroenterology Department, Sheba Medical Center, Affiliated to Tel-Aviv University, Tel-Aviv, Israel
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28
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Atreya R, Neurath MF, Siegmund B. Personalizing Treatment in IBD: Hype or Reality in 2020? Can We Predict Response to Anti-TNF? Front Med (Lausanne) 2020; 7:517. [PMID: 32984386 PMCID: PMC7492550 DOI: 10.3389/fmed.2020.00517] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 07/27/2020] [Indexed: 12/12/2022] Open
Abstract
The advent of anti-TNF agents as the first approved targeted therapy in the treatment of inflammatory bowel disease (IBD) patients has made a major impact on our existing therapeutic algorithms. They have not only been approved for induction and maintenance treatment in IBD patients, but have also enabled us to define and achieve novel therapeutic outcomes, such as combination of clinical symptom control and endoscopic remission, as well as mucosal healing. Nevertheless, approximately one third of treated patients do not respond to initiated anti-TNF therapy and these treatments are associated with sometimes severe systemic side-effects. There is therefore the currently unmet clinical need do establish predictive markers of response to identify the subgroup of IBD patients, that have a heightened probability of response. There have so far been approaches from different fields of IBD research, to descry markers that would empower us to apply TNF-inhibitors in a more rational manner. These markers encompass findings from disease-related and clinical factors, pharmacokinetics, biochemical markers, blood and stool derived parameters, pharmacogenomics, microbial species, metabolic compounds, and mucosal factors. Furthermore, changes in the intestinal immune cell composition in response to therapeutic pressure of anti-TNF treatment have recently been implicated in the process of molecular resistance to these drugs. Insights into factors that determine resistance to anti-TNF therapy give reasonable hope, that a more targeted approach can then be utilized in these non-responders. Here, IL-23 could be identified as one of the key factors determining resistance to TNF-inhibitors. Growing insights into the molecular mechanism of action of TNF-inhibitors might also enable us to derive critical molecular markers that not only mediate the clinical effects of anti-TNF therapy, but which level of expression might also correlate with its therapeutic efficacy. In this narrative review, we present an overview of currently identified possible predictive markers for successful anti-TNF therapy and discuss identified molecular pathways that drive resistance to these substances. We will also point out the necessity and difficulty of developing and validating a diagnostic marker concerning clinically relevant outcome parameters, before they can finally enter daily clinical practice and enable a more personalized therapeutic approach.
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Affiliation(s)
- Raja Atreya
- Department of Medicine, Medical Clinic 1, University Hospital Erlangen, University of Erlangen-Nürnberg Erlangen, Erlangen, Germany.,Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany.,The Transregio 241 IBDome Consortium, Erlangen, Germany
| | - Markus F Neurath
- Department of Medicine, Medical Clinic 1, University Hospital Erlangen, University of Erlangen-Nürnberg Erlangen, Erlangen, Germany.,Deutsches Zentrum Immuntherapie (DZI), Erlangen, Germany
| | - Britta Siegmund
- The Transregio 241 IBDome Consortium, Berlin, Germany.,Medizinische Klinik m. S. Gastroenterologie, Infektiologie und Rheumatologie, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany.,Berlin Institute of Health, Berlin, Germany
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29
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Khalaf K, Janowicz K, Dyszkiewicz-Konwińska M, Hutchings G, Dompe C, Moncrieff L, Jankowski M, Machnik M, Oleksiewicz U, Kocherova I, Petitte J, Mozdziak P, Shibli JA, Iżycki D, Józkowiak M, Piotrowska-Kempisty H, Skowroński MT, Antosik P, Kempisty B. CRISPR/Cas9 in Cancer Immunotherapy: Animal Models and Human Clinical Trials. Genes (Basel) 2020; 11:E921. [PMID: 32796761 PMCID: PMC7463827 DOI: 10.3390/genes11080921] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 07/29/2020] [Accepted: 08/10/2020] [Indexed: 12/18/2022] Open
Abstract
Even though chemotherapy and immunotherapy emerged to limit continual and unregulated proliferation of cancer cells, currently available therapeutic agents are associated with high toxicity levels and low success rates. Additionally, ongoing multi-targeted therapies are limited only for few carcinogenesis pathways, due to continually emerging and evolving mutations of proto-oncogenes and tumor-suppressive genes. CRISPR/Cas9, as a specific gene-editing tool, is used to correct causative mutations with minimal toxicity, but is also employed as an adjuvant to immunotherapy to achieve a more robust immunological response. Some of the most critical limitations of the CRISPR/Cas9 technology include off-target mutations, resulting in nonspecific restrictions of DNA upstream of the Protospacer Adjacent Motifs (PAM), ethical agreements, and the lack of a scientific consensus aiming at risk evaluation. Currently, CRISPR/Cas9 is tested on animal models to enhance genome editing specificity and induce a stronger anti-tumor response. Moreover, ongoing clinical trials use the CRISPR/Cas9 system in immune cells to modify genomes in a target-specific manner. Recently, error-free in vitro systems have been engineered to overcome limitations of this gene-editing system. The aim of the article is to present the knowledge concerning the use of CRISPR Cas9 technique in targeting treatment-resistant cancers. Additionally, the use of CRISPR/Cas9 is aided as an emerging supplementation of immunotherapy, currently used in experimental oncology. Demonstrating further, applications and advances of the CRISPR/Cas9 technique are presented in animal models and human clinical trials. Concluding, an overview of the limitations of the gene-editing tool is proffered.
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Affiliation(s)
- Khalil Khalaf
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznań, Poland; (K.K.); (K.J.); (M.D.-K.); (G.H.); (M.J.); (I.K.)
| | - Krzysztof Janowicz
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznań, Poland; (K.K.); (K.J.); (M.D.-K.); (G.H.); (M.J.); (I.K.)
- The School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK; (C.D.); (L.M.)
| | - Marta Dyszkiewicz-Konwińska
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznań, Poland; (K.K.); (K.J.); (M.D.-K.); (G.H.); (M.J.); (I.K.)
- Department of Biomaterials and Experimental Dentistry, Poznan University of Medical Sciences, 60-812 Poznań, Poland
| | - Greg Hutchings
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznań, Poland; (K.K.); (K.J.); (M.D.-K.); (G.H.); (M.J.); (I.K.)
- The School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK; (C.D.); (L.M.)
| | - Claudia Dompe
- The School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK; (C.D.); (L.M.)
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznań, Poland
| | - Lisa Moncrieff
- The School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK; (C.D.); (L.M.)
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznań, Poland
| | - Maurycy Jankowski
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznań, Poland; (K.K.); (K.J.); (M.D.-K.); (G.H.); (M.J.); (I.K.)
| | - Marta Machnik
- Department of Cancer Immunology, Poznan University of Medical Sciences, 60-408 Poznan, Poland; (M.M.); (U.O.); (D.I.)
- Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Centre, 61-866 Poznan, Poland
| | - Urszula Oleksiewicz
- Department of Cancer Immunology, Poznan University of Medical Sciences, 60-408 Poznan, Poland; (M.M.); (U.O.); (D.I.)
- Department of Cancer Diagnostics and Immunology, Greater Poland Cancer Centre, 61-866 Poznan, Poland
| | - Ievgeniia Kocherova
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznań, Poland; (K.K.); (K.J.); (M.D.-K.); (G.H.); (M.J.); (I.K.)
| | - Jim Petitte
- Prestage Department of Poultry Science, North Carolina State University, Raleigh, NC 27695, USA;
| | - Paul Mozdziak
- Physiology Graduate Program, North Carolina State University, Raleigh, NC 27695, USA;
| | - Jamil A. Shibli
- Department of Periodontology and Oral Implantology, Dental Research Division, University of Guarulhos, Guarulhos 07023-070, Brazil;
| | - Dariusz Iżycki
- Department of Cancer Immunology, Poznan University of Medical Sciences, 60-408 Poznan, Poland; (M.M.); (U.O.); (D.I.)
| | - Małgorzata Józkowiak
- Department of Toxicology, Poznan University of Medical Sciences, 61-631 Poznań, Poland; (M.J.); (H.P.-K.)
| | - Hanna Piotrowska-Kempisty
- Department of Toxicology, Poznan University of Medical Sciences, 61-631 Poznań, Poland; (M.J.); (H.P.-K.)
| | - Mariusz T. Skowroński
- Department of Basic and Preclinical Sciences, Institute of Veterinary Medicine, Nicolaus Copernicus University in Torun, 87-100 Toruń, Poland;
| | - Paweł Antosik
- Department of Veterinary Surgery, Nicolaus Copernicus University in Torun, 87-100 Toruń, Poland;
| | - Bartosz Kempisty
- Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznań, Poland; (K.K.); (K.J.); (M.D.-K.); (G.H.); (M.J.); (I.K.)
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznań, Poland
- Department of Veterinary Surgery, Nicolaus Copernicus University in Torun, 87-100 Toruń, Poland;
- Department of Obstetrics and Gynecology, University Hospital and Masaryk University, 601 77 Brno, Czech Republic
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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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31
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Hu L, Tan H, Cao Q, Yuan G, Huang C, Su G, Kijlstra A, Yang P. Weak association of a TNFRSF1A polymorphism with Behcet's disease in Chinese Han. Exp Eye Res 2020; 196:108045. [PMID: 32389622 DOI: 10.1016/j.exer.2020.108045] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 04/20/2020] [Accepted: 04/26/2020] [Indexed: 11/17/2022]
Abstract
The purpose of this study was to investigate whether single nucleotide polymorphisms (SNPs) of the tumor necrosis factor receptor superfamily (TNFRSF) and their ligand (TNFSF) gene are associated with susceptibility to Behcet's Disease (BD) in Chinese Han. A two-phase case-control study was performed in 1055 BD patients and 1829 healthy controls. A total of 27 SNPs was tested using MassARRAY iPLEX® technology. Data were analyzed using a Chi-square (χ2) test and Fisher's exact calibration test. The Bonferroni correction was applied for multiple testing. A statistically significant higher frequency of the A allele and a lower frequency of the G allele of rs1800692 was found in BD (Pc = 0.013, OR = 1.233, 95% CI = 1.103-1.379: Pc = 0.013, OR = 0.811, 95% CI = 0.725-0.907, respectively). Our findings indicate that TNFRSF1A might confer genetic susceptibility to BD in a Chinese Han population.
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Affiliation(s)
- Lili Hu
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, People's Republic of China.
| | - Handan Tan
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, People's Republic of China.
| | - Qingfeng Cao
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, People's Republic of China.
| | - Gangxiang Yuan
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, People's Republic of China.
| | - Changwei Huang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, People's Republic of China.
| | - Guannan Su
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, People's Republic of China.
| | - Aize Kijlstra
- University Eye Clinic Maastricht, Maastricht, the Netherlands.
| | - Peizeng Yang
- The First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Ophthalmology and Chongqing Eye Institute, Chongqing, People's Republic of China.
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Actis GC, Pellicano R, Fagoonee S, Ribaldone DG. History of Inflammatory Bowel Diseases. J Clin Med 2019; 8:1970. [PMID: 31739460 PMCID: PMC6912289 DOI: 10.3390/jcm8111970] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Revised: 11/02/2019] [Accepted: 11/12/2019] [Indexed: 12/19/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are characterized by chronic inflammation of the intestinal mucosa and unknown etiology. In this review, we identified three main eras in the IBD history. Between the 19th and the 20th century, the primary task had been the definition of the diagnostic criteria in order to differentiate the new entity from intestinal tuberculosis. In the 20th century, an intense and prolific therapeutic research prevailed, culminating in the introduction of biological drugs in the clinical setting. Since the beginning of the 21st century, traditional definition criteria have been challenged by holistic criteria in an effort to seek a still unattained cure. Centuries of worldwide efforts on IBD etiology and therapy search have culminated in this novel strategy.
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Affiliation(s)
| | | | - Sharmila Fagoonee
- Institute of Biostructures and Bioimaging (CNR) c/o Molecular Biotechnology Center, 10126 Turin, Italy;
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33
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Wang C, Baer HM, Gaya DR, Nibbs RJB, Milling S. Can molecular stratification improve the treatment of inflammatory bowel disease? Pharmacol Res 2019; 148:104442. [PMID: 31491469 PMCID: PMC6902263 DOI: 10.1016/j.phrs.2019.104442] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 09/02/2019] [Accepted: 09/02/2019] [Indexed: 02/07/2023]
Abstract
Inflammatory bowel disease (IBD) is a debilitating chronic inflammatory disease of the gastrointestinal (GI) tract. It affects more than 3.5 million people in the western world and places a huge financial burden on healthcare systems. IBD is highly heterogeneous; disease severity and outcomes in IBD are highly variable, and patients may experience episodes of relapse and remission. However, treatment often follows a step-up model whereby the patients start with anti-inflammatory agents (corticosteroids or immunosuppressants) and step-up to monoclonal anti-tumour necrosis factor-α (TNFα) antibodies and then other biologics if the initial drugs cannot control disease. Unfortunately, many patients do not respond to the costly biologics, and thus often still require gut-resective surgery, which decreases quality of life. In order to decrease rates of surgery and ineffective treatments, it is important to identify markers that accurately predict disease progression and treatment responses, to inform decisions about the best choice of therapeutics. Here we examine molecular approaches to patient stratification that aim to increase the effectiveness of treatments and potentially reduce healthcare costs. In the future, it may become possible to stratify patients based on their suitability for specific molecular-targeted therapeutic agents, and eventually use molecular stratification for personalised medicine in IBD.
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Affiliation(s)
- Claire Wang
- Institute of Infection, Inflammation & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Hannah M Baer
- Institute of Infection, Inflammation & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Daniel R Gaya
- Gastroenterology Unit, Glasgow Royal Infirmary, Glasgow, UK
| | - Robert J B Nibbs
- Institute of Infection, Inflammation & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK
| | - Simon Milling
- Institute of Infection, Inflammation & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
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Zhao M, Burisch J. Impact of Genes and the Environment on the Pathogenesis and Disease Course of Inflammatory Bowel Disease. Dig Dis Sci 2019; 64:1759-1769. [PMID: 31073736 DOI: 10.1007/s10620-019-05648-w] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Crohn's disease and ulcerative colitis constitute two major subgroups of inflammatory bowel diseases (IBD), a group of complex polygenic diseases characterized by chronic and progressive inflammation in the gastrointestinal tract. In recent years, methodological advances in genetic analysis have greatly expanded our understanding of the genetic background of IBD. So far, more than 240 genetic risk loci have been identified for IBD. However, these risk alleles explain less than 30% of the susceptibility to disease development, suggesting that environmental factors contribute considerably. The increasing occurrence of IBD in Eastern countries following their 'westernization', as well as the increased risk of disease among those who migrate to high-incidence regions, also suggest that the environment is key in the pathogenesis of IBD. In this review, we summarize the current evidence on the role of genetic and environmental factors in the susceptibility to, and disease course of, IBD, and we suggest how these findings might be applied to clinical practice.
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Affiliation(s)
- Mirabella Zhao
- Gastro Unit, Hvidovre University Hospital, Kettegaard Alle 30, 2650, Hvidovre, Denmark
| | - Johan Burisch
- Gastro Unit, Hvidovre University Hospital, Kettegaard Alle 30, 2650, Hvidovre, Denmark.
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35
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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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Lucafò M, Franca R, Selvestrel D, Curci D, Pugnetti L, Decorti G, Stocco G. Pharmacogenetics of treatments for inflammatory bowel disease. Expert Opin Drug Metab Toxicol 2018; 14:1209-1223. [PMID: 30465611 DOI: 10.1080/17425255.2018.1551876] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2018] [Accepted: 11/20/2018] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel disease is a chronic inflammation of the gut whose pathogenesis is still unclear. Although no curative therapy is currently available, a number of drugs are used in induction and maintenance therapy; however, for most of these drugs, a high inter-individual variability in response is observed. Among the factors of this variability, genetics plays an important role. Areas covered: This review summarizes the results of pharmacogenetic studies, considering the most important drugs used and in particular aminosalycilates, glucocorticoids, thiopurines, monoclonal antibodies and thalidomide. Most studies used a candidate gene approach, even if significant breakthroughs have been obtained recently from applying genome-wide studies. When available, also investigations considering epigenetics and pharmacogenetic dosing guidelines have been included. Expert opinion: Only for thiopurines, genetic markers identified as predictors of efficacy or adverse events have allowed the development of dosing guidelines. For the other drugs, encouraging results are available and great expectations rely on the study of epigenetics and integration with pharmacokinetic information, especially useful for biologics. However, to improve therapy of IBD patients with these drugs, for implementation in the clinics of pharmacogenetics, informatic clinical decision support systems and training about pharmacogenetics of health providers are needed.
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Affiliation(s)
- Marianna Lucafò
- a Experimental and Clinical Pharmacology Unit , National Cancer Institute - Centro di Riferimento Oncologico , Aviano , Italy
- b Institute for Maternal and Child Health IRCCS Burlo Garofolo , Diagnostics Department Trieste , Italy
| | - Raffaella Franca
- b Institute for Maternal and Child Health IRCCS Burlo Garofolo , Diagnostics Department Trieste , Italy
- c Department of Medical, Surgical and Health Sciences , University of Trieste , Trieste , Italy
| | - Davide Selvestrel
- d PhD School in Science of Reproduction and Development , University of Trieste , Trieste , Italy
| | - Debora Curci
- d PhD School in Science of Reproduction and Development , University of Trieste , Trieste , Italy
| | - Letizia Pugnetti
- d PhD School in Science of Reproduction and Development , University of Trieste , Trieste , Italy
| | - Giuliana Decorti
- b Institute for Maternal and Child Health IRCCS Burlo Garofolo , Diagnostics Department Trieste , Italy
- c Department of Medical, Surgical and Health Sciences , University of Trieste , Trieste , Italy
| | - Gabriele Stocco
- e Department of Life Sciences , University of Trieste , Trieste , Italy
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Stevens TW, Matheeuwsen M, Lönnkvist MH, Parker CE, Wildenberg ME, Gecse KB, D'Haens GR. Systematic review: predictive biomarkers of therapeutic response in inflammatory bowel disease-personalised medicine in its infancy. Aliment Pharmacol Ther 2018; 48:1213-1231. [PMID: 30378142 DOI: 10.1111/apt.15033] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 07/19/2018] [Accepted: 09/29/2018] [Indexed: 12/17/2022]
Abstract
BACKGROUND Inflammatory bowel disease (IBD) is characterised by substantial heterogeneity in treatment response. With an expanding number of therapeutic agents, identifying optimal treatment at the patient level remains a major challenge. AIM To systematically review the available literature on predictive biomarkers of therapeutic response in IBD. METHODS An electronic literature search was performed on 30 January 2018 using MEDLINE, EMBASE and the Cochrane Library. Retrospective, prospective, uncontrolled and controlled studies reporting on biomarkers predicting therapeutic response in paediatric and adult IBD populations were eligible for inclusion. The methodological quality of the included studies was assessed using the QUIPS tool. Due to anticipated heterogeneity and limited data, a qualitative, rather than quantitative, assessment was planned. RESULTS Of the 10 638 citations identified, 92 articles met the inclusion criteria. Several potential DNA, mRNA and protein markers were evaluated as predictive biomarkers. Most studies focused on predicting response to anti-TNF agents. Substantial between-study heterogeneity was identified with respect to both the biomarkers studied and the definition of response. None of the included studies received a low risk of bias rating for all six domains. Currently, none of the biomarkers is sufficiently predictive for clinical use. CONCLUSIONS The search for predictive biomarkers is still in its infancy and current evidence is limited. Future research efforts should take into account the high patient heterogeneity within prospective trials with objective response assessment. Predictive models will most likely comprise a combination of several molecular markers from integrated omics-levels and clinical characteristics.
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Affiliation(s)
- Toer W Stevens
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Mijntje Matheeuwsen
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Maria H Lönnkvist
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | | | - Manon E Wildenberg
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.,Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, Amsterdam, The Netherlands
| | - Krisztina B Gecse
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Geert R D'Haens
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
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