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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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2
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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] [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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Genaro LM, Carron J, de Castro MM, Franceschini APMDF, Lourenço GJ, da Cruz CKNV, Reis GFSR, Pascoal LB, Mello JDC, Pereira IM, Nascimento ML, Oliveira PDSP, Corona LP, Ayrizono MDLS, Lima CSP, Leal RF. Therapeutic drug monitoring and immunogenetic factors associated with the use of adalimumab in Crohn's disease patients. Int J Immunopathol Pharmacol 2025; 39:3946320251319379. [PMID: 39959979 PMCID: PMC11831650 DOI: 10.1177/03946320251319379] [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] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 01/24/2025] [Indexed: 02/20/2025] Open
Abstract
Crohn's disease (CD) involves immune system interactions with intestinal tissue, driven by pro-inflammatory cytokines like Tumor Necrosis Factor (TNF-α). Adalimumab, targeting TNF-α, regulates associated inflammatory responses. Despite being humanized, it may induce immunogenic processes, affecting treatment effectiveness. Thus, monitoring serum adalimumab and anti-drug antibody (ADA) levels can optimize therapy. Understanding genetic factors influencing adalimumab response can enhance personalized treatment and improve patient quality of life. We aimed to quantify adalimumab serum levels, assess test interchangeability, detect ADA, examine immune complex formation, and investigate genetic phenotypes related to immunogenicity in CD patients. Seventy CD patients in the maintenance phase with adalimumab were classified into active (CDA) and remission (CDR) groups. Adalimumab concentration was determined via enzyme-linked immunosorbent assay (ELISA-Promonitor) and lateral flow assay (Quantum Blue), with assay interchangeability assessed statistically. ADA and immune complex formation were quantified using ELISA assays. DNA was genotyped for the genes ATG16L1, CD96, and CD155. No significant differences in adalimumab serum concentrations were observed between groups, regardless of the assay. However, a statistical difference between the tests indicated measurement disparity (P = 0.003), with moderate agreement (Lin's correlation of 0.247). ADA was detected in 4 of 27 of the patients with infratherapeutic levels, 3 in the CDA group and 1 in the CDR group. Analysis of immune complexes revealed significantly higher concentrations in the CDA group (P = 0.0125). The genotypic evaluation revealed significant associations for the CD96 CC (wild-type) genotype with higher CRP levels, colonic involvement, and infratherapeutic levels of adalimumab. ATG16L1 CC genotype was associated with higher CDEIS and fecal calprotectin values, while the variant (TT) genotype had lower platelet counts. The effectiveness of treatment with adalimumab was not directly related to higher medication levels in this cohort. The disparity between tests indicates the need to use only one test in patient follow-up to ensure accuracy in therapeutic monitoring. Genotypic differences highlight the correlation between the wild genotype for CD96 and ATG16L1 with unfavorable laboratory and endoscopic response to adalimumab. Finally, the more significant levels of immune complexes in the CDA group indicate an association with a worse response to adalimumab.
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Affiliation(s)
- Livia Moreira Genaro
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Juliana Carron
- Laboratory of Cancer Genetics (Lageca), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Marina Moreira de Castro
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Ana Paula Menezes de Freitas Franceschini
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Gustavo Jacob Lourenço
- Laboratory of Cancer Genetics (Lageca), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | | | | | - Livia Bitencourt Pascoal
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Juliana Delgado Campos Mello
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Isabela Machado Pereira
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Millene Leal Nascimento
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Priscilla De Sene Portel Oliveira
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Ligiana Pires Corona
- Nutritional Epidemiology Laboratory, School of Applied Sciences, University of Campinas (Unicamp), Limeira, São Paulo, Brazil
| | - Maria de Lourdes Setsuko Ayrizono
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Carmen Silvia Passos Lima
- Laboratory of Cancer Genetics (Lageca), School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
| | - Raquel Franco Leal
- Inflammatory Bowel Disease Research Laboratory (LabDII), Gastrocenter, Colorectal Surgery Unit, Surgery Department, School of Medical Sciences, University of Campinas (Unicamp), Campinas, São Paulo, Brazil
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Lee YM, Vucic D. The role of autophagy in RIP1 mediated cell death and intestinal inflammation. Adv Immunol 2024; 163:1-20. [PMID: 39271257 DOI: 10.1016/bs.ai.2024.07.003] [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] [Indexed: 09/15/2024]
Abstract
Autophagy, a highly conserved catabolic process that targets various types of cellular cargoes to lysosomal degradation, is one of the most important biological mechanisms critical for cellular homeostasis. Components of these cellular cargoes can range from individual proteins to invading pathogens, and degrading these materials is important for maintaining organismal health and survival. The process of autophagy is carried out by complex molecular mechanisms, and a growing body of evidence indicates that these mechanisms intersect with those involved in the cell death pathways. In this review, we examine several emerging studies elucidating the role of autophagy in RIP1-mediated cell death signaling, with particular emphasis on impaired autophagy caused by ATG16L1 deficiency. We also discuss how autophagy in RIP1-mediated cell death affects intestinal homeostasis in preclinical models, and the implications of the intersection between RIP1 and autophagy for understanding the intestinal pathologies associated with inflammatory bowel disease (IBD). Finally, we highlight the potential benefits of therapeutic targeting of RIP1 and autophagy proteins, while also proposing areas of research that will likely elucidate new links between autophagy and cell death signaling.
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Affiliation(s)
| | - Domagoj Vucic
- Immunology Discovery, Genentech, South San Francisco, CA, United States.
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Minea H, Singeap AM, Minea M, Juncu S, Muzica C, Sfarti CV, Girleanu I, Chiriac S, Miftode ID, Stanciu C, Trifan A. The Contribution of Genetic and Epigenetic Factors: An Emerging Concept in the Assessment and Prognosis of Inflammatory Bowel Diseases. Int J Mol Sci 2024; 25:8420. [PMID: 39125988 PMCID: PMC11313574 DOI: 10.3390/ijms25158420] [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: 07/03/2024] [Revised: 07/25/2024] [Accepted: 07/27/2024] [Indexed: 08/12/2024] Open
Abstract
Inflammatory bowel disease (IBD) represents heterogeneous and relapsing intestinal conditions with a severe impact on the quality of life of individuals and a continuously increasing prevalence. In recent years, the development of sequencing technology has provided new means of exploring the complex pathogenesis of IBD. An ideal solution is represented by the approach of precision medicine that investigates multiple cellular and molecular interactions, which are tools that perform a holistic, systematic, and impartial analysis of the genomic, transcriptomic, proteomic, metabolomic, and microbiomics sets. Hence, it has led to the orientation of current research towards the identification of new biomarkers that could be successfully used in the management of IBD patients. Multi-omics explores the dimension of variation in the characteristics of these diseases, offering the advantage of understanding the cellular and molecular mechanisms that affect intestinal homeostasis for a much better prediction of disease development and choice of treatment. This review focuses on the progress made in the field of prognostic and predictive biomarkers, highlighting the limitations, challenges, and also the opportunities associated with the application of genomics and epigenomics technologies in clinical practice.
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Affiliation(s)
- Horia Minea
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania; (H.M.); (S.J.); (C.V.S.); (I.G.); (S.C.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Ana-Maria Singeap
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania; (H.M.); (S.J.); (C.V.S.); (I.G.); (S.C.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Manuela Minea
- Department of Microbiology, The National Institute of Public Health, 700464 Iasi, Romania;
| | - Simona Juncu
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania; (H.M.); (S.J.); (C.V.S.); (I.G.); (S.C.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Cristina Muzica
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania; (H.M.); (S.J.); (C.V.S.); (I.G.); (S.C.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Catalin Victor Sfarti
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania; (H.M.); (S.J.); (C.V.S.); (I.G.); (S.C.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Irina Girleanu
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania; (H.M.); (S.J.); (C.V.S.); (I.G.); (S.C.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Stefan Chiriac
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania; (H.M.); (S.J.); (C.V.S.); (I.G.); (S.C.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Ioana Diandra Miftode
- Department of Radiology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania;
- Department of Radiology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Carol Stanciu
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania; (H.M.); (S.J.); (C.V.S.); (I.G.); (S.C.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
| | - Anca Trifan
- Department of Gastroenterology, Grigore T. Popa University of Medicine and Pharmacy, 700115 Iasi, Romania; (H.M.); (S.J.); (C.V.S.); (I.G.); (S.C.); (C.S.); (A.T.)
- Institute of Gastroenterology and Hepatology, “St. Spiridon” University Hospital, 700111 Iasi, Romania
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Gorenjak M, Gole B, Goričan L, Jezernik G, Prosenc Zmrzljak U, Pernat C, Skok P, Potočnik U. Single-Cell Transcriptomic and Targeted Genomic Profiling Adjusted for Inflammation and Therapy Bias Reveal CRTAM and PLCB1 as Novel Hub Genes for Anti-Tumor Necrosis Factor Alpha Therapy Response in Crohn's Disease. Pharmaceutics 2024; 16:835. [PMID: 38931955 PMCID: PMC11207411 DOI: 10.3390/pharmaceutics16060835] [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: 05/10/2024] [Revised: 06/11/2024] [Accepted: 06/17/2024] [Indexed: 06/28/2024] Open
Abstract
BACKGROUND The lack of reliable biomarkers in response to anti-TNFα biologicals hinders personalized therapy for Crohn's disease (CD) patients. The motivation behind our study is to shift the paradigm of anti-TNFα biomarker discovery toward specific immune cell sub-populations using single-cell RNA sequencing and an innovative approach designed to uncover PBMCs gene expression signals, which may be masked due to the treatment or ongoing inflammation; Methods: The single-cell RNA sequencing was performed on PBMC samples from CD patients either naïve to biological therapy, in remission while on adalimumab, or while on ustekinumab but previously non-responsive to adalimumab. Sieves for stringent downstream gene selection consisted of gene ontology and independent cohort genomic profiling. Replication and meta-analyses were performed using publicly available raw RNA sequencing files of sorted immune cells and an association analysis summary. Machine learning, Mendelian randomization, and oligogenic risk score methods were deployed to validate DEGs highly relevant to anti-TNFα therapy response; Results: This study found PLCB1 in CD4+ T cells and CRTAM in double-negative T cells, which met the stringent statistical thresholds throughout the analyses. An additional assessment proved causal inference of both genes in response to anti-TNFα therapy; Conclusions: This study, jointly with an innovative design, uncovered novel candidate genes in the anti-TNFα response landscape of CD, potentially obscured by therapy or inflammation.
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Affiliation(s)
- Mario Gorenjak
- Centre for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska ulica 8, SI-2000 Maribor, Slovenia; (B.G.); (L.G.); (G.J.); (U.P.)
| | - Boris Gole
- Centre for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska ulica 8, SI-2000 Maribor, Slovenia; (B.G.); (L.G.); (G.J.); (U.P.)
| | - Larisa Goričan
- Centre for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska ulica 8, SI-2000 Maribor, Slovenia; (B.G.); (L.G.); (G.J.); (U.P.)
| | - Gregor Jezernik
- Centre for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska ulica 8, SI-2000 Maribor, Slovenia; (B.G.); (L.G.); (G.J.); (U.P.)
| | | | - Cvetka Pernat
- Department of Gastroenterology, Division of Internal Medicine, Maribor University Medical Centre, Ljubljanska ulica 5, SI-2000 Maribor, Slovenia; (C.P.); (P.S.)
| | - Pavel Skok
- Department of Gastroenterology, Division of Internal Medicine, Maribor University Medical Centre, Ljubljanska ulica 5, SI-2000 Maribor, Slovenia; (C.P.); (P.S.)
| | - Uroš Potočnik
- Centre for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor, Taborska ulica 8, SI-2000 Maribor, Slovenia; (B.G.); (L.G.); (G.J.); (U.P.)
- Laboratory for Biochemistry, Molecular Biology and Genomics, Faculty for Chemistry and Chemical Engineering, University of Maribor, Smetanova ulica 17, SI-2000 Maribor, Slovenia
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7
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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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8
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Plaza J, Mínguez A, Bastida G, Marqués R, Nos P, Poveda JL, Moret-Tatay I. Genetic Variants Associated with Biological Treatment Response in Inflammatory Bowel Disease: A Systematic Review. Int J Mol Sci 2024; 25:3717. [PMID: 38612528 PMCID: PMC11012229 DOI: 10.3390/ijms25073717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 03/05/2024] [Accepted: 03/21/2024] [Indexed: 04/14/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the digestive tract usually characterized by diarrhea, rectal bleeding, and abdominal pain. IBD includes Crohn's disease and ulcerative colitis as the main entities. IBD is a debilitating condition that can lead to life-threatening complications, involving possible malignancy and surgery. The available therapies aim to achieve long-term remission and prevent disease progression. Biologics are bioengineered therapeutic drugs that mainly target proteins. Although they have revolutionized the treatment of IBD, their potential therapeutic benefits are limited due to large interindividual variability in clinical response in terms of efficacy and toxicity, resulting in high rates of long-term therapeutic failure. It is therefore important to find biomarkers that provide tailor-made treatment strategies that allow for patient stratification to maximize treatment benefits and minimize adverse events. Pharmacogenetics has the potential to optimize biologics selection in IBD by identifying genetic variants, specifically single nucleotide polymorphisms (SNPs), which are the underlying factors associated with an individual's drug response. This review analyzes the current knowledge of genetic variants associated with biological agent response (infliximab, adalimumab, ustekinumab, and vedolizumab) in IBD. An online literature search in various databases was conducted. After applying the inclusion and exclusion criteria, 28 reports from the 1685 results were employed for the review. The most significant SNPs potentially useful as predictive biomarkers of treatment response are linked to immunity, cytokine production, and immunorecognition.
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Affiliation(s)
- Javier Plaza
- Inflammatory Bowel Disease Research Group, Health Research Institute La Fe (IIS La Fe), 46026 Valencia, Spain; (J.P.); (A.M.)
- Department of Pharmacy and Pharmaceutical Technology and Parasitology, University of Valencia, 46100 Valencia, Spain
| | - Alejandro Mínguez
- Inflammatory Bowel Disease Research Group, Health Research Institute La Fe (IIS La Fe), 46026 Valencia, Spain; (J.P.); (A.M.)
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain; (G.B.); (P.N.)
| | - Guillermo Bastida
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain; (G.B.); (P.N.)
| | - Remedios Marqués
- Pharmacy Department, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain; (R.M.); (J.L.P.)
| | - Pilar Nos
- Inflammatory Bowel Disease Unit, Gastroenterology Department, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain; (G.B.); (P.N.)
| | - Jose Luis Poveda
- Pharmacy Department, La Fe University and Polytechnic Hospital, 46026 Valencia, Spain; (R.M.); (J.L.P.)
| | - Inés Moret-Tatay
- Inflammatory Bowel Disease Research Group, Health Research Institute La Fe (IIS La Fe), 46026 Valencia, Spain; (J.P.); (A.M.)
- General Directorate of Public Health, Council of Healthcare, 46021 Valencia, Spain
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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: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [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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10
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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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11
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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: 0] [Impact Index Per Article: 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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12
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Wang LF, Chen PR, He SK, Duan SH, Zhang Y. Predictors and optimal management of tumor necrosis factor antagonist nonresponse in inflammatory bowel disease: A literature review. World J Gastroenterol 2023; 29:4481-4498. [PMID: 37621757 PMCID: PMC10445007 DOI: 10.3748/wjg.v29.i29.4481] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 06/28/2023] [Accepted: 07/17/2023] [Indexed: 08/02/2023] Open
Abstract
Tumor necrosis factor-α (TNF-α) antagonists, the first biologics approved for treating patients with inflammatory bowel disease (IBD), are effective for the induction and maintenance of remission and significantly improving prognosis. However, up to one-third of treated patients show primary nonresponse (PNR) to anti-TNF-α therapies, and 23%-50% of IBD patients experience loss of response (LOR) to these biologics during subsequent treatment. There is still no recognized predictor for evaluating the efficacy of anti-TNF drugs. This review summarizes the existing predictors of PNR and LOR to anti-TNF in IBD patients. Most predictors remain controversial, and only previous surgical history, disease manifestations, drug concentrations, antidrug antibodies, serum albumin, some biologic markers, and some genetic markers may be potentially predictive. In addition, we also discuss the next steps of treatment for patients with PNR or LOR to TNF antagonists. Therapeutic drug monitoring plays an important role in treatment selection. Dose escalation, combination therapy, switching to a different anti-TNF drug, or switching to a biologic with a different mechanism of action can be selected based on the concentration of the drug and/or antidrug antibodies.
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Affiliation(s)
- Liang-Fang Wang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Ping-Run Chen
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Si-Ke He
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Shi-Hao Duan
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
| | - Yan Zhang
- Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
- West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province, China
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13
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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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Kriger-Sharabi OA, Kopylov U. Harnessing the Power of Precision Medicine and Novel Biomarkers to Treat Crohn’s Disease. J Clin Med 2023; 12:jcm12072696. [PMID: 37048779 PMCID: PMC10094767 DOI: 10.3390/jcm12072696] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 03/11/2023] [Accepted: 03/21/2023] [Indexed: 04/08/2023] Open
Abstract
Crohn’s disease (CD) is a chronic inflammatory condition that affects the gastrointestinal tract. It is part of a spectrum of inflammatory Bowel Diseases (IBD). The disease is complex, characterized by significant inter and intra-individual heterogeneity, which contributes to a diverse and multifaceted portrayal of the disease. Consequently, applying specific and accurate treatment is challenging, and therapeutic success rates remain disappointing and insufficient. In recent years, significant advances in the therapeutic potential of CD have been made. Hope has been provided by these developments in the form of an expanding treatment toolkit. However, even with these beneficial adjustments, patients are frequently treated using an ineffective “one size fits all” treatment protocol, ultimately leading to a plateau in drug effectiveness and a decline in overall treatment success rates. Furthermore, with the advancement in the genome-wide association study, in combination with significant bioinformatic developments, the world of medicine has moved in the direction of personalized, tailored-treatment medicine, and this trend has not escaped the world of IBDs. Prediction models, novel biomarkers, and complex algorithms are emerging and inspiring optimism that CD patients will be treated with “precision medicine” in the near future, meaning that their treatments will be selected based on the patient’s various unique features. In this review, we will outline the current diagnostic and therapeutic limitations that lead to a glass ceiling effect and thus send us in pursuit of discovering novel biomarkers. We will illustrate the challenges and difficulties in discovering relevant and innovative biomarkers and implementing them into everyday clinical practice. We will also heighten the progress made in practicing personalized medicine for CD patients and shed light on future directions and horizons.
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Affiliation(s)
- Ofra Aviva Kriger-Sharabi
- Department of Gatsroenterology, Assuta Ashdod Medical Center, Affiliated to The Ben-Gurion University (BGU) Medical School, Ashdod 7747629, Israel
| | - Uri Kopylov
- Department of Gastroenterology, Sheba Medical Center, Tel Hashomer, Affliated to Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
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15
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Jezernik G, Gorenjak M, Potočnik U. MIF Variant rs755622 Is Associated with Severe Crohn's Disease and Better Response to Anti-TNF Adalimumab Therapy. Genes (Basel) 2023; 14:452. [PMID: 36833379 PMCID: PMC9957382 DOI: 10.3390/genes14020452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 02/02/2023] [Accepted: 02/07/2023] [Indexed: 02/12/2023] Open
Abstract
Crohn's disease (CD), rheumatoid arthritis, psoriatic arthritis and other inflammatory diseases comprise a group of chronic diseases with immune-mediated pathogenesis which share common pathological pathways, as well as treatment strategies including anti-TNF biologic therapy. However, the response rate to anti-TNF therapy among those diseases varies, and approximately one third of patients do not respond. Since pharmacogenetic studies for anti-TNF therapy have been more frequent for other related diseases and are rare in CD, the aim of our study was to further explore markers associated with anti-TNF response in other inflammatory diseases in Slovenian CD patients treated with the anti-TNF drug adalimumab (ADA). We enrolled 102 CD patients on ADA, for which the response was defined after 4, 12, 20 and 30 weeks of treatment, using an IBDQ questionnaire and blood CRP value. We genotyped 41 SNPs significantly associated with response to anti-TNF treatment in other diseases. We found novel pharmacogenetic association between SNP rs755622 in the gene MIF (macrophage migration inhibitory factor) and SNP rs3740691 in the gene ARFGAP2 in CD patients treated with ADA. The strongest and most consistent association with treatment response was found for the variant rs2275913 in gene IL17A (p = 9.73 × 10-3).
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Affiliation(s)
- Gregor Jezernik
- Faculty of Medicine, University of Maribor, Taborska Ulica 8, 2000 Maribor, Slovenia
| | - Mario Gorenjak
- Faculty of Medicine, University of Maribor, Taborska Ulica 8, 2000 Maribor, Slovenia
| | - Uroš Potočnik
- Faculty of Medicine, University of Maribor, Taborska Ulica 8, 2000 Maribor, Slovenia
- Faculty of Chemistry and Chemical Engineering, University of Maribor, Smetanova Ulica 17, 2000 Maribor, Slovenia
- Department for Science and Research, University Medical Centre Maribor, Ljubljanska Ulica 5, 2000 Maribor, Slovenia
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16
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Zhu K, Ding X, Chen Z, Xi Q, Pang X, Chen W, Miao L. Association between genetic variants and development of antibodies to infliximab: A cross-sectional study in Chinese patients with Crohn's disease. Front Pharmacol 2023; 14:1096816. [PMID: 36726584 PMCID: PMC9885127 DOI: 10.3389/fphar.2023.1096816] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2022] [Accepted: 01/03/2023] [Indexed: 01/18/2023] Open
Abstract
Aims: Genetic variants increase the susceptibility to anti-drug antibodies (ADA) in response to anti-TNF therapy in chronic inflammatory diseases. However, little is known about genetic variants in Chinese populations. This study aimed to identify genetic variants contributing to the risk of the development of antibodies to infliximab (ATI) in Chinese patients with Crohn's disease (CD). Methods: CD patients (n = 104) treated with infliximab (IFX) during the maintenance therapy were enrolled in this cross-sectional study. ATI was assessed by an in-house developed drug-tolerant ELISA method. ATI titers of 1:20 and ≥1:60 were considered a low titer and a high titer, respectively. Thirteen types of single nucleotide polymorphisms (SNPs) within 13 genes involved in the immune process, the susceptibility to chronic inflammatory diseases, cytokines and apoptosis pathways were investigated. Results: The median trough levels of infliximab (TLI) in patients with clinical remission (CR) were higher than those in patients without CR (3.80 vs. 1.50 μg/mL, p < .001). The median TLI in patients with high-titer ATI was significantly lower than that in ATI-negative patients (1.15 vs. 4.48 μg/mL, p < .001) or those with low-titer ATI (1.15 vs. 2.95 μg/mL, p = .03). The HLA-DQA1*05 rs2097432 GG and GA genotypes were more frequent in patients with ATI (GG and AG vs. AA, 27/38 = 71.05% vs. 29/66 = 43.94%, OR 2.94, 95% CI 1.19-7.30, p = .02). Patients carrying the CC and AC genotypes of rs396991 in FCGR3A were associated with a higher frequency of ATI formation (CC and AC vs. AA, 37/57 = 64.91% vs. 19/47 = 40.43%, OR 2.94, 95% CI 1.24-6.96, p = .01). According to the number of variants in rs2097432 and rs393991, patients with two variants had a higher proportion of producing ATI (two variants vs. no variant, 17/21 = 80.95% vs. 9/30 = 30.00%, OR 9.92, 95% CI 2.59-37.87, p = .001; single variant vs. no variant, 30/53 = 56.60% vs. 9/30 = 30.00%, OR 3.04, 95% CI 1.18-7.88, p = .02). No association was found between other SNPs and ATI production. Conclusion: Rs2097432 in HLA-DQA1*05 and rs396991 in FCGR3A are associated with ATI production in Chinese patients with CD. A pharmacogenomic strategy could help with the clinical management of CD.
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Affiliation(s)
- Kouzhu Zhu
- Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, China,College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Xiaoliang Ding
- Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, China,Institute for Interdisciplinary Drug Research and Translational Sciences, Soochow University, Suzhou, China
| | - Zhiyao Chen
- Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Qinhua Xi
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Xueqin Pang
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Weichang Chen
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China,*Correspondence: Weichang Chen, ; Liyan Miao,
| | - Liyan Miao
- Department of Pharmacy, The First Affiliated Hospital of Soochow University, Suzhou, China,College of Pharmaceutical Sciences, Soochow University, Suzhou, China,Institute for Interdisciplinary Drug Research and Translational Sciences, Soochow University, Suzhou, China,National Clinical Research Center for Hematologic Diseases, The First Affiliated Hospital of Soochow University, Suzhou, China,*Correspondence: Weichang Chen, ; Liyan Miao,
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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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18
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Identification of Novel Loci Involved in Adalimumab Response in Crohn’s Disease Patients Using Integration of Genome Profiling and Isoform-Level Immune-Cell Deconvoluted Transcriptome Profiling of Colon Tissue. Pharmaceutics 2022; 14:pharmaceutics14091893. [PMID: 36145641 PMCID: PMC9500628 DOI: 10.3390/pharmaceutics14091893] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 08/25/2022] [Accepted: 09/02/2022] [Indexed: 11/17/2022] Open
Abstract
Crohn’s disease is a consequence of dysregulated inflammatory response to the host’s microbiota. Although anti-TNF treatment improves the quality of the patient’s life, a large proportion of patients lose response to the treatment. The past decade of research has led to a continuum of studies showcasing the heterogeneity of anti-TNF response; thus, the aim of the present study was to dissect transcriptome-wide findings to transcript isoform specific levels and combine the analyses with refined information of immune cell landscapes in colon tissue, and subsequently select promising candidates using gene ontology and genomic integration. We enrolled Slovenian Crohn’s disease patients who were naïve with respect to adalimumab treatment. We performed colon tissue RNA sequencing and peripheral blood mononuclear cell DNA genotyping with a subsequent contemporary integrative approach to combine immune cell deconvoluted isoform transcript specific transcriptome analysis, gene ontology layering and genomic data. We identified nine genes (MACF1, CTSE, HDLBP, HSPA9, HLA-DMB, TAP2, LGMN, ANAPC11, ACP5) with 15 transcripts and 16 variants involved in the adalimumab response. Our study identified loci, some of which were previously shown to contribute to inflammatory bowel disease susceptibility, as novel loci involved in adalimumab response in Crohn’s disease patients.
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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: 50] [Impact Index Per Article: 16.7] [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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Development of a Machine Learning Model to Predict Non-Durable Response to Anti-TNF Therapy in Crohn’s Disease Using Transcriptome Imputed from Genotypes. J Pers Med 2022; 12:jpm12060947. [PMID: 35743732 PMCID: PMC9224874 DOI: 10.3390/jpm12060947] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 06/05/2022] [Accepted: 06/08/2022] [Indexed: 11/25/2022] Open
Abstract
Almost half of patients show no primary or secondary response to monoclonal anti-tumor necrosis factor α (anti-TNF) antibody treatment for inflammatory bowel disease (IBD). Thus, the exact mechanisms of a non-durable response (NDR) remain inadequately defined. We used our genome-wide genotype data to impute expression values as features in training machine learning models to predict a NDR. Blood samples from various IBD cohorts were used for genotyping with the Korea Biobank Array. A total of 234 patients with Crohn’s disease (CD) who received their first anti-TNF therapy were enrolled. The expression profiles of 6294 genes in whole-blood tissue imputed from the genotype data were combined with clinical parameters to train a logistic model to predict the NDR. The top two and three most significant features were genetic features (DPY19L3, GSTT1, and NUCB1), not clinical features. The logistic regression of the NDR vs. DR status in our cohort by the imputed expression levels showed that the β coefficients were positive for DPY19L3 and GSTT1, and negative for NUCB1, concordant with the known eQTL information. Machine learning models using imputed gene expression features effectively predicted NDR to anti-TNF agents in patients with CD.
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21
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Ahsan T, Sajib AA. Missense variants in the TNFA epitopes and their effects on interaction with therapeutic antibodies-in silico analysis. J Genet Eng Biotechnol 2022; 20:7. [PMID: 35006391 PMCID: PMC8748575 DOI: 10.1186/s43141-021-00288-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2021] [Accepted: 12/13/2021] [Indexed: 11/10/2022]
Abstract
BACKGROUND Tumor necrosis factor alpha (TNFA) is an important cytokine that influences multiple biological processes. It is one of the key mediators of acute and chronic systemic inflammatory reactions and plays a central role in several autoimmune diseases. A number of approved monoclonal antibodies (mAbs) are widely used to subside these autoimmune diseases. However, there is a high rate of non-responsiveness to treatments with these mAbs. Therefore, it is important to be able to predict responses of the patients in an individualistic manner to these therapeutic antibodies before administration. In the present study, we used in silico tools to explore the effects of missense variants in the respective epitopes of four therapeutic anti-TNFA mAbs-adalimumab (ADA), certolizumab pegol (CZP), golimumab (GLM), and infliximab (IFX)-on their interactions with TNFA. RESULTS The binding affinities of CZP and ADA to corresponding epitopes appear to be reduced by four (TNFAR131Q, TNFAE135G, TNFAR138Q, and TNFAR138W) and two (TNFAG66C and TNFAG66S) variants, respectively. The binding of GLM and IFX appears to be affected by TNFAR141S and TNFAR138W, respectively. TNFAG66C and TNFAG66S may be associated with autoimmune diseases, whereas TNFAE135G, TNFAR138W, and TNFAR141S may be pathogenic per se. CONCLUSION These variants may contribute to the observed inter-individual variability in response to anti-TNFA mAbs treatments and be used as markers to predict responses, and thus optimize therapeutic benefits to the patients.
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Affiliation(s)
- Tamim Ahsan
- Molecular Biotechnology Division, National Institute of Biotechnology, Dhaka, 1349 Bangladesh
| | - Abu Ashfaqur Sajib
- Department of Genetic Engineering & Biotechnology, University of Dhaka, Dhaka, 1000 Bangladesh
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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: 17] [Impact Index Per Article: 4.3] [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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Omics data integration identifies ELOVL7 and MMD gene regions as novel loci for adalimumab response in patients with Crohn's disease. Sci Rep 2021; 11:5449. [PMID: 33750834 PMCID: PMC7970911 DOI: 10.1038/s41598-021-84909-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 02/22/2021] [Indexed: 12/13/2022] Open
Abstract
Response to anti-TNF therapy is of pivotal importance in patients with Crohn’s disease (CD). Here we integrated our and previously reported PBMC derived transcriptomic and genomic data for identification of biomarkers for discrimination between responders and non-responders to anti-TNF therapy. CD patients, who were naïve with respect to the treatment with biologicals, were enrolled in the study. DNA and RNA were extracted from peripheral blood mononuclear cells. RNA-seq was performed using BGISEQ-500. Genotyping was performed using Infinium Global Screening Array. Association regressions were carried out with 12 week response to adalimumab as an outcome variable. RNA-seq analysis confirmed 7 out of 65 previously suggested genes involved in anti-TNF response. Subsequently, analysis of single nucleotide variants in regions of confirmed genes identified 5 variants near MMD and two in ELOVL7 intronic regions associated with treatment response to anti-TNF. Functional analysis has shown that rs1465352, rs4422035 and rs78620886 are listed at H3K9ac_Pro histone modification epigenetic mark. The present study confirmed MMD and ELOVL7 involvement in anti-TNF response and revealed that the regulation of MMD and ELOVL7 gene regions in ADA response may be a part of a complex interplay extending from genetic to epigenetic and to transcriptomic level.
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Dalal RS, Ananthakrishnan AN, Hamilton MJ, Winter RW. Two Strikes but Not Out: Deep Remission of Ulcerative Colitis with Ustekinumab After Primary Non-response to Infliximab and Vedolizumab. Dig Dis Sci 2021; 66:733-737. [PMID: 33569666 DOI: 10.1007/s10620-021-06852-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/12/2021] [Indexed: 12/20/2022]
Affiliation(s)
- Rahul S Dalal
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA.,Crohn's and Colitis Center, Brigham and Women's Hospital, Boston, MA, 02467, USA
| | - Ashwin N Ananthakrishnan
- Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Matthew J Hamilton
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA.,Crohn's and Colitis Center, Brigham and Women's Hospital, Boston, MA, 02467, USA
| | - Rachel W Winter
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, MA, USA. .,Harvard Medical School, Boston, MA, USA. .,Crohn's and Colitis Center, Brigham and Women's Hospital, Boston, MA, 02467, USA.
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25
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Predictors and Early Markers of Response to Biological Therapies in Inflammatory Bowel Diseases. J Clin Med 2021; 10:jcm10040853. [PMID: 33669579 PMCID: PMC7922976 DOI: 10.3390/jcm10040853] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 02/10/2021] [Accepted: 02/11/2021] [Indexed: 12/22/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are chronic conditions that primarily affect the gastrointestinal tract, with a complex pathogenesis; they are characterized by a significant heterogeneity of clinical presentations and of inflammatory pathways that sustain intestinal damage. After the introduction of the first biological therapies, the pipeline of therapies for IBD has been constantly expanding, and a significant number of new molecules is expected in the next few years. Evidence from clinical trials and real-life experiences has taught us that up to 40% of patients do not respond to a specific drug. Unfortunately, to date, clinicians lack a valid tool that can predict each patient’s response to therapies and that could help them in choosing what drug to administer. Several candidate biomarkers have been investigated so far, with conflicting results: clinical, genetic, immunological, pharmacokinetic and microbial markers have been tested, but no ideal marker has been identified so far. Based on recent evidence, multiparametric models seemingly hold the greatest potential for predicting response to therapy. In this narrative review, we aim to summarize the current knowledge on predictors and early markers of response to biological therapies in IBD.
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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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27
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Tamargo-Gómez I, Fernández ÁF, Mariño G. Pathogenic Single Nucleotide Polymorphisms on Autophagy-Related Genes. Int J Mol Sci 2020; 21:ijms21218196. [PMID: 33147747 PMCID: PMC7672651 DOI: 10.3390/ijms21218196] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2020] [Revised: 10/28/2020] [Accepted: 10/30/2020] [Indexed: 02/06/2023] Open
Abstract
In recent years, the study of single nucleotide polymorphisms (SNPs) has gained increasing importance in biomedical research, as they can either be at the molecular origin of a determined disorder or directly affect the efficiency of a given treatment. In this regard, sequence variations in genes involved in pro-survival cellular pathways are commonly associated with pathologies, as the alteration of these routes compromises cellular homeostasis. This is the case of autophagy, an evolutionarily conserved pathway that counteracts extracellular and intracellular stressors by mediating the turnover of cytosolic components through lysosomal degradation. Accordingly, autophagy dysregulation has been extensively described in a wide range of human pathologies, including cancer, neurodegeneration, or inflammatory alterations. Thus, it is not surprising that pathogenic gene variants in genes encoding crucial effectors of the autophagosome/lysosome axis are increasingly being identified. In this review, we present a comprehensive list of clinically relevant SNPs in autophagy-related genes, highlighting the scope and relevance of autophagy alterations in human disease.
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Affiliation(s)
- Isaac Tamargo-Gómez
- Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain;
- Departamento de Biología Funcional, Universidad de Oviedo, 33011 Oviedo, Spain
| | - Álvaro F. Fernández
- Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain;
- Departamento de Biología Funcional, Universidad de Oviedo, 33011 Oviedo, Spain
- Correspondence: (Á.F.F.); (G.M.); Tel.: +34-985652416 (G.M.)
| | - Guillermo Mariño
- Instituto de Investigación Sanitaria del Principado de Asturias, 33011 Oviedo, Spain;
- Departamento de Biología Funcional, Universidad de Oviedo, 33011 Oviedo, Spain
- Correspondence: (Á.F.F.); (G.M.); Tel.: +34-985652416 (G.M.)
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28
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Genetic Predictors of Long-term Response to Antitumor Necrosis Factor Agents in Pediatric Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr 2020; 71:508-515. [PMID: 32773718 DOI: 10.1097/mpg.0000000000002840] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Inflammatory bowel disease (IBD) is more complex in children and they will have to live with the disease for much longer. For this reason, it is necessary to optimize treatment. The polymorphisms associated with the response to anti-tumor necrosis factor (TNF) drugs in adults with IBD have not been analyzed in children. The aim of the study was to identify genetic variants associated with the long-term response to anti-TNF drugs in children with IBD. METHODS An observational, longitudinal, ambispective cohort's study was conducted. We recruited 209 anti-TNF-treated children diagnosed with IBD and genotyped 21 polymorphisms previously studied in adults with Crohn disease (CD) using real-time PCR. The association between single-nucleotide polymorphisms (SNPs) and time-to-failure was analyzed using the log-rank test. RESULTS After multivariate analysis, 3 SNPs in IL10, IL17A and IL6 were significantly associated with response to anti-TNF treatment among patients diagnosed with CD (rs1800872-HR, 4.749 (95% confidence interval [CI] 1.156-19.517), P value < 0.05; rs2275913-HR, 0.320 [95% CI 0.111-0.920], P value < 0.05; and rs10499563-HR, 0.210 [95% CI 0.047-0.947], P value 0.05, respectively). None of these SNPs were associated with response to infliximab in adults diagnosed with CD. Among patients diagnosed with ulcerative colitis (UC), 1 SNP in LY96 was significantly associated with response to anti-TNF treatment (rs-11465996-HR, 10.220 [95% CI 1.849-56.504] P value < 0.05). CONCLUSIONS Genotyping of these DNA variants before starting treatment may help to identify children who are long-term responders to anti-TNF drugs, and thus tailor treatment of pediatric IBD.
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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: 84] [Impact Index Per Article: 16.8] [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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30
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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: 164] [Impact Index Per Article: 32.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Inflammatory bowel diseases [IBD]-ulcerative colitis and Crohn's disease-are commonly treated with biologic drugs. However, only approximately two-thirds of patients have an initial response to these therapies. Personalised medicine has the potential to optimise efficacy, decrease the risk of adverse drug events, and reduce costs by establishing the most suitable therapy for a selected patient. AIM The present study reviews the potential predictors of short-term primary response to biologic treatment, including not only anti-tumour necrosis factor [TNF] agents [such as infliximab, adalimumab, certolizumab, and golimumab] but also vedolizumab and ustekinumab. METHODS We performed a systematic bibliographical search to identify studies investigating predictive factors of response to biologic therapy. RESULTS For anti-TNF agents, most of the evaluated factors have not demonstrated usefulness, and many others are still controversial. Thus, only a few factors may have a potential role in the prediction of the response, including disease behaviour/phenotype, disease severity, C-reactive protein, albumin, cytokine expression in serum, previous anti-TNF therapy, some proteomic markers, and some colorectal mucosa markers. For vedolizumab, the availability of useful predictive markers seems to be even lower, with only some factors showing a limited value, such as the expression of α4β7 integrin in blood, the faecal microbiota, some proteomic markers, and some colorectal mucosa markers. Finally, in the case of ustekinumab, no predictive factor has been reported yet to be helpful in clinical practice. CONCLUSION In summary, currently no single marker fulfils all criteria for being an appropriate prognostic indicator of response to any biologic treatment in IBD.
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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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Gole B, Potočnik U. Pre-Treatment Biomarkers of Anti-Tumour Necrosis Factor Therapy Response in Crohn's Disease-A Systematic Review and Gene Ontology Analysis. Cells 2019; 8:cells8060515. [PMID: 31141991 PMCID: PMC6628089 DOI: 10.3390/cells8060515] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 05/24/2019] [Accepted: 05/25/2019] [Indexed: 12/15/2022] Open
Abstract
The most prominent treatment for the serious cases of Crohn’s disease (CD) are biological tumour necrosis factor (TNF) inhibitors. Unfortunately, therapy nonresponse is still a serious issue in ~1/3 of CD patients. Accurate prediction of responsiveness prior to therapy start would therefore be of great value. Clinical predictors have, however, proved insufficient. Here, we integrate genomic and expression data on potential pre-treatment biomarkers of anti-TNF nonresponse. We show that there is almost no overlap between genomic (annotated with tissue-specific expression quantitative trait loci data) and transcription (RNA and protein data) biomarkers. Furthermore, using interaction networks we demonstrate there is little direct interaction between the proposed biomarkers, though a majority do have common interactors connecting them into networks. Our gene ontology analysis shows that these networks have roles in apoptotic signalling, response to oxidative stress and inflammation pathways. We conclude that a more systematic approach with genome-wide search of genomic and expression biomarkers in the same patients is needed in future studies.
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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] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION 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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Zhang H, Zeng Z, Mukherjee A, Shen B. Molecular diagnosis and classification of inflammatory bowel disease. Expert Rev Mol Diagn 2018; 18:867-886. [PMID: 30152711 DOI: 10.1080/14737159.2018.1516549] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Traditional diagnosis and classification of inflammatory bowel diseases (IBDs) have been based on clinical evaluation, laboratory testing, endoscopy, imaging, and histological examinations. With the advancement of medical technology, an increasing number of molecular surrogates are playing a key role in diagnosis, differential diagnosis, assessment of disease activity, prediction of clinical course, and therapeutic response of IBD. Areas covered: The authors review roles of both existing and emerging surrogates including genetic, serological, histologic, and fecal markers in diagnosis and classification of IBD. Comparisons in advantages and disadvantages of different markers have also been discussed. In addition, this review underscores controversial and unclear aspects which need further study. Expert commentary: IBD is characteristic of chronicity, relapse-remission and destructiveness. It is of great importance for clinicians to make an accurate diagnosis and classification. Current and new molecular markers perform well with acceptable sensitivity and specificity. The use of molecular markers in clinical practice needs to be further explored and then generalized. More work is warranted to identify novel useful markers and elucidate how to apply them together with current markers in clinical settings.
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Affiliation(s)
- Hu Zhang
- a Center for Inflammatory Bowel Disease & Department of Gastroenterology , West China Hospital, Sichuan University , Chengdu , China
| | - Zhen Zeng
- a Center for Inflammatory Bowel Disease & Department of Gastroenterology , West China Hospital, Sichuan University , Chengdu , China
| | - Arjudeb Mukherjee
- b West China School of Medicine , Sichuan University , Chengdu , China
| | - Bo Shen
- c Center for Inflammatory Bowel Disease, Digestive Disease and Surgery Institute, The Cleveland Clinic Foundation , Cleveland , Ohio , USA
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Burke KE, Khalili H, Garber JJ, Haritunians T, McGovern DPB, Xavier RJ, Ananthakrishnan AN. Genetic Markers Predict Primary Nonresponse and Durable Response to Anti-Tumor Necrosis Factor Therapy in Ulcerative Colitis. Inflamm Bowel Dis 2018; 24:1840-1848. [PMID: 29718226 PMCID: PMC6128143 DOI: 10.1093/ibd/izy083] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Despite a high nonresponse rate, predictors of response to anti-tumor necrosis factor (anti-TNF) therapy in ulcerative colitis (UC) remain limited. We aim to determine clinical and genetic predictors of primary nonresponse (PNR) and durable response (DR) to anti-TNF therapy in a large prospective UC cohort. METHODS Using the Illumina Immunochip, candidate polymorphisms associated with clinical outcomes of PNR and DR were separately evaluated and combined into weighted genetic risk scores. Combined genetic and clinical multivariable models for PNR and DR were compared with clinical predictive models using area under the receiver operating characteristic (AUROC) curves. Models were internally (DR) or externally (PNR) validated. Multivariable logistic regression was utilized to assess the association of genetic risk scores with infliximab levels and antibodies. RESULTS Of 231 patients, 28 (12%) experienced PNR and 120 (52%) experienced DR. There was no significant difference in clinical features between primary nonresponders and responders. Eight alleles were associated with PNR. A combined clinical-genetic model (AUROC, 0.87) more accurately predicted PNR compared with a clinical-only model (AUROC, 0.57; P < 0.0001). In an external cohort of 131 patients, increasing tertiles of PNR genetic risk score correlated with increased risk of PNR (P = 0.052). Twelve candidate loci were associated with DR. Genetic risk score quartiles for DR demonstrated a strong dose-response relationship in predicting treatment duration. Genetic risk scores for PNR and DR were not associated with infliximab levels or antibody formation. CONCLUSION Genetic polymorphisms enhance prediction of PNR and DR to anti-TNF therapy in patients with UC.
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Affiliation(s)
- Kristin E Burke
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts,Harvard Medical School, Boston, Massachusetts
| | - Hamed Khalili
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts,Harvard Medical School, Boston, Massachusetts
| | - John J Garber
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts,Harvard Medical School, Boston, Massachusetts
| | - Talin Haritunians
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Dermot P B McGovern
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Ramnik J Xavier
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts,Harvard Medical School, Boston, Massachusetts
| | - Ashwin N Ananthakrishnan
- Inflammatory Bowel Disease Center, Division of Gastroenterology, Massachusetts General Hospital, Boston, Massachusetts,Harvard Medical School, Boston, Massachusetts,Address correspondence to: Ashwin N. Ananthakrishnan, Massachusetts General Hospital Crohn’s and Colitis Center, 165 Cambridge Street, Boston, MA 02114 ()
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DNA polymorphisms predict time to progression from uncomplicated to complicated Crohn's disease. Eur J Gastroenterol Hepatol 2018; 30:447-455. [PMID: 29293112 DOI: 10.1097/meg.0000000000001055] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE Most patients with Crohn's disease (CD) are diagnosed with the uncomplicated inflammatory form of the disease (Montreal stage B1). However, the majority of them will progress to complicated stricturing (B2) and penetrating (B3) CD during their lifetimes. The aim of our study was to identify the genetic factors associated with time to progression from uncomplicated to complicated CD. PATIENTS AND METHODS Patients with an inflammatory phenotype at diagnosis were followed up for 10 years. Genotyping was carried out using Illumina ImmunoChip. After quality control, association analyses, Bonferroni's adjustments, linear and Cox's regression, and Kaplan-Meier analysis were carried out for 111 patients and Manhattan plots were constructed. RESULTS Ten years after diagnosis, 39.1% of the patients still had the inflammatory form and 60.9% progressed to complicated disease, with an average time to progression of 5.91 years. Ileal and ileocolonic locations were associated with the complicated CD (P=1.08E-03). We found that patients with the AA genotype at single-nucleotide polymorphism rs16857259 near the gene CACNA1E progressed to the complicated form later (8.80 years) compared with patients with the AC (5.11 years) or CC (2.00 years) genotypes (P=3.82E-07). In addition, nine single-nucleotide polymorphisms (near the genes RASGRP1, SULF2, XPO1, ZBTB44, HLA DOA/BRD2, HLA DRB1/HLA DQA1, PPARA, PUDP, and KIAA1614) showed a suggestive association with disease progression (P<10). Multivariate Cox's regression analysis on the basis of clinical and genetic data confirmed the association of the selected model with disease progression (P=5.73E-16). CONCLUSION Our study confirmed the association between the locus on chromosome 1 near the gene CACNA1E with time to progression from inflammatory to stricturing or penetrating CD. Predicting the time to progression is useful to the clinician in terms of individualizing patients' management.
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Pernat Drobež C, Ferkolj I, Potočnik U, Repnik K. Crohn's Disease Candidate Gene Alleles Predict Time to Progression from Inflammatory B1 to Stricturing B2, or Penetrating B3 Phenotype. Genet Test Mol Biomarkers 2018; 22:143-151. [PMID: 29446656 DOI: 10.1089/gtmb.2017.0210] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM Crohn's disease (CD) patients are mostly diagnosed with the uncomplicated inflammatory form of disease; however, the majority will progress to complicated stricturing or penetrating disease over time. It is important to identify patients at risk for disease progression at an early stage. The aim of our study was to examine the role of 33 candidate CD genes as possible predictors of disease progression and their influence on time to progression from an inflammatory to a stricturing or penetrating phenotype. METHODS Patients with an inflammatory phenotype at diagnosis were followed for 10 years and 33 CD-associated polymorphisms were genotyped. To test for association with CD, 449 healthy individuals were analyzed as the control group. RESULTS Ten years after diagnosis, 39.1% of patients had not progressed beyond an inflammatory phenotype, but 60.9% had progressed to complicated disease, with average time to progression being 5.91 years. Association analyses of selected single nucleotide polymorphisms (SNPs) confirmed associations with CD for 12 SNPs. Furthermore, seven loci were associated with disease progression, out of which SNP rs4263839 in the gene TNFSF15 showed the strongest association with disease progression and the frameshift mutation rs2066847 in the gene NOD2 showed the strongest association with time to progression. CONCLUSIONS The results of our study identified specific genetic biomarkers as useful predictors of both disease progression and speed of disease progression in patients with CD.
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Affiliation(s)
- Cvetka Pernat Drobež
- 1 Department of Gastroenterology, University Medical Centre Maribor , Maribor, Slovenia
| | - Ivan Ferkolj
- 2 Department of Gastroenterology, Division of Internal Medicine, University Medical Centre Ljubljana , Ljubljana, Slovenia
| | - Uroš Potočnik
- 3 Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor , Maribor, Slovenia .,4 Laboratory for Biochemistry, Molecular Biology and Genomics, Faculty for Chemistry and Chemical Engineering, University of Maribor , Maribor, Slovenia
| | - Katja Repnik
- 3 Center for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor , Maribor, Slovenia .,4 Laboratory for Biochemistry, Molecular Biology and Genomics, Faculty for Chemistry and Chemical Engineering, University of Maribor , Maribor, Slovenia
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van Hoeve K, Hoffman I, Vermeire S. Therapeutic drug monitoring of anti-TNF therapy in children with inflammatory bowel disease. Expert Opin Drug Saf 2017; 17:185-196. [PMID: 29202588 DOI: 10.1080/14740338.2018.1413090] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Karen van Hoeve
- Department of Pediatric Gastroenterology, University Hospitals Leuven, Leuven, Belgium
| | - Ilse Hoffman
- Department of Pediatric Gastroenterology, University Hospitals Leuven, Leuven, Belgium
| | - Severine Vermeire
- Department of Gastroenterology & Hepatology, University Hospitals Leuven, Leuven, Belgium
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de Bruyn M, Vermeire S. NOD2 and bacterial recognition as therapeutic targets for Crohn’s disease. Expert Opin Ther Targets 2017; 21:1123-1139. [DOI: 10.1080/14728222.2017.1397627] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Affiliation(s)
- Magali de Bruyn
- Translational Research in GastroIntestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
| | - Séverine Vermeire
- Translational Research in GastroIntestinal Disorders, Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium
- University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium
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Netz U, Carter JV, Eichenberger MR, Dryden GW, Pan J, Rai SN, Galandiuk S. Genetic polymorphisms predict response to anti-tumor necrosis factor treatment in Crohn’s disease. World J Gastroenterol 2017; 23:4958-4967. [PMID: 28785150 PMCID: PMC5526766 DOI: 10.3748/wjg.v23.i27.4958] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 04/05/2017] [Accepted: 05/04/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate genetic factors that might help define which Crohn’s disease (CD) patients are likely to benefit from anti-tumor necrosis factor (TNF) therapy.
METHODS This was a prospective cohort study. Patients were recruited from a university digestive disease practice database. We included CD patients who received anti-TNF therapy, had available medical records (with information on treatment duration and efficacy) and who consented to participation. Patients with allergic reactions were excluded. Patients were grouped as ever-responders or non-responders. Genomic DNA was extracted from peripheral blood, and 7 single nucleotide polymorphisms (SNPs) were assessed. The main outcome measure (following exposure to the drug) was response to therapy. The patient genotypes were assessed as the predictors of outcome. Possible confounders and effect modifiers included age, gender, race, and socioeconomic status disease, as well as disease characteristics (such as Montreal criteria).
RESULTS 121 patients were included. Twenty-one were non-responders, and 100 were ever-responders. Fas ligand SNP (rs763110) genotype frequencies, TNF gene -308 SNP (rs1800629) genotype frequencies, and their combination, were significantly different between groups on multivariable analysis controlling for Montreal disease behavior and perianal disease. The odds of a patient with a Fas ligand CC genotype being a non-responder were four-fold higher as compared to a TC or TT genotype (P = 0.009, OR = 4.30, 95%CI: 1.45-12.80). The presence of the A (minor) TNF gene -308 allele correlated with three-fold higher odds of being a non-responder (P = 0.049, OR = 2.88, 95%CI: 1.01-8.22). Patients with the combination of the Fas ligand CC genotype and the TNF -308 A allele had nearly five-fold higher odds of being a non-responder (P = 0.015, OR = 4.76, 95%CI: 1.35-16.77). No difference was seen for the remaining SNPs.
CONCLUSION The Fas-ligand SNP and TNF gene -308 SNP are associated with anti-TNF treatment response in CD and may help select patients likely to benefit from therapy.
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Rufini S, Ciccacci C, Novelli G, Borgiani P. Pharmacogenetics of inflammatory bowel disease: a focus on Crohn's disease. Pharmacogenomics 2017; 18:1095-1114. [PMID: 28686143 DOI: 10.2217/pgs-2017-0068] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Crohn's disease is an inflammatory bowel disease showing a high heterogeneity in phenotype and a strong genetic component. The treatment is complex, due to different severity of clinical parameters and to the fact that therapies only permit to control symptoms and to induce remission for short periods. Moreover, all categories of drugs present a great interindividual variability both in terms of efficacy and side effects appearance. For this reason, the identification of specific genomic biomarkers involved in drugs response will be of great clinical utility in order to foresee drug's efficacy and to prevent adverse reactions, permitting a more personalized therapeutic approach. In this review, we focus the attention on the pharmacogenetic studies regarding drugs commonly utilized in Crohn's disease treatment.
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Affiliation(s)
- Sara Rufini
- Department of Biomedicine & Prevention, Genetics Unit, University of Rome "Tor Vergata", Rome, Italy
| | - Cinzia Ciccacci
- Department of Biomedicine & Prevention, Genetics Unit, University of Rome "Tor Vergata", Rome, Italy
| | - Giuseppe Novelli
- Department of Biomedicine & Prevention, Genetics Unit, University of Rome "Tor Vergata", Rome, Italy
| | - Paola Borgiani
- Department of Biomedicine & Prevention, Genetics Unit, University of Rome "Tor Vergata", Rome, Italy
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Pharmacogenetic biomarkers of response in Crohn’s disease. THE PHARMACOGENOMICS JOURNAL 2017. [DOI: 10.1038/tpj.2017.27] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Yamamoto-Furusho JK. Pharmacogenetics in inflammatory bowel disease: understanding treatment response and personalizing therapeutic strategies. Pharmgenomics Pers Med 2017; 10:197-204. [PMID: 28603427 PMCID: PMC5457182 DOI: 10.2147/pgpm.s109648] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic and heterogeneous disorder characterized by remitting and relapsing periods of activity. Pharmacogenetics refers to the study of the effect of inheritance on individual variation in drug responses. Several drug-related markers in IBD patients have been identified in order to predict the response to medical treatment including biological therapy as well as the reduction of adverse events. In the future, the treatment of IBD should be personalized in its specific profile to provide the most efficacious treatment with lack of adverse events.
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Affiliation(s)
- Jesús K Yamamoto-Furusho
- Inflammatory Bowel Disease Clinic, Department of Gastroenterology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Tlalpan, Mexico
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Optimizing adalimumab treatment in psoriasis with concomitant methotrexate (OPTIMAP): study protocol for a pragmatic, single-blinded, investigator-initiated randomized controlled trial. Trials 2017; 18:52. [PMID: 28148280 PMCID: PMC5288945 DOI: 10.1186/s13063-017-1777-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Accepted: 01/02/2017] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The introduction of anti-tumor necrosis factor medications has revolutionized the treatment of psoriasis with achievement of treatment goals (Psoriasis Area and Severity Index score 75, remission) that are not usually met with conventional systemics. Nevertheless, some patients continue to experience persistent disease activity or treatment failure over time. Strategies to optimize treatment outcomes include the use of concomitant methotrexate, which has demonstrated beneficial effects on pharmacokinetics and treatment efficacy in psoriasis and other inflammatory diseases. METHODS This is an investigator-initiated, multicenter randomized controlled trial (RCT) designed to compare the combination treatment of adalimumab and methotrexate with adalimumab monotherapy in patients with psoriasis. The primary outcome is adalimumab drug survival at week 49. Other outcomes include improvement in disease severity and quality of life, tolerability, and safety. Moreover, anti-adalimumab antibodies and adalimumab serum concentrations will be measured and correlations between genotypes and clinical outcomes will be assessed. Patient recruitment started in March 2014. Up to now, 36 patients have been randomized. Many more patients have been (pre)screened. A total of 93 patients is desired to meet an adequate sample size. In our experience, the main limitation for recruitment is prior adalimumab therapy and intolerability or toxicity for methotrexate in the past. DISCUSSION OPTIMAP is the first RCT to examine combination therapy with adalimumab and methotrexate in a psoriasis population. With data derived from this study we expect to provide valuable clinical data on long-term treatment outcomes. These data will be supported by assessment of the impact of concomitant methotrexate on adalimumab pharmacokinetics. Furthermore, the influence of several single nucleotide polymorphisms on adalimumab response will be analyzed in order to support the development of a more personalized approach for this targeted therapy. TRIAL REGISTRATION NTR4499 . Registered on 7 April 2014.
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Stappenbeck TS, McGovern DP. Paneth Cell Alterations in the Development and Phenotype of Crohn's Disease. Gastroenterology 2017; 152:322-326. [PMID: 27729212 PMCID: PMC5209278 DOI: 10.1053/j.gastro.2016.10.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2016] [Revised: 10/03/2016] [Accepted: 10/05/2016] [Indexed: 12/17/2022]
Abstract
Pathogenesis of Crohn's disease (CD) involves immune and microbial dysregulation, induced by environmental factors in genetically susceptible individuals. There are believed to be multiple subtypes of CD, which contributes to its observed clinical heterogeneity. This concept has been reinforced by recognition of the complexity of the genetic, microbial, immune, and environmental factors that affect risk for CD. Paneth cells mediate immunity and maintain the small intestinal epithelium; defects in activities of these cells have been observed in high proportions of patients with CD, and are associated with a more aggressive CD phenotype. Paneth cells integrate complex genetic, immune, and environmental signals, therefore alterations in their function could lead to different subtypes of CD, as observed in studies in cohorts of primarily European descent. Subtypes of CD associated with Paneth cell function have been observed even among patients from different genetic backgrounds. We discuss genetic susceptibility loci for CD and how these affect Paneth cell activity.
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Affiliation(s)
| | - Dermot P.B. McGovern
- The F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
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Barber GE, Yajnik V, Khalili H, Giallourakis C, Garber J, Xavier R, Ananthakrishnan AN. Genetic Markers Predict Primary Non-Response and Durable Response To Anti-TNF Biologic Therapies in Crohn's Disease. Am J Gastroenterol 2016; 111:1816-1822. [PMID: 27596696 PMCID: PMC5143156 DOI: 10.1038/ajg.2016.408] [Citation(s) in RCA: 74] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Accepted: 08/03/2016] [Indexed: 12/11/2022]
Abstract
OBJECTIVES One-fifth of patients with Crohn's disease (CD) are primary non-responders to anti-tumor necrosis factor (anti-TNF) therapy, and an estimated 10-15% will fail therapy annually. Little is known about the genetics of response to anti-TNF therapy. The aim of our study was to identify genetic factors associated with primary non-response (PNR) and loss of response to anti-TNFs in CD. METHODS From a prospective registry, we characterized the response of 427 CD patients to their first anti-TNF therapy. Patients were designated as achieving primary response, durable response, and non-durable response based on clinical, endoscopic, and radiologic criteria. Genotyping was performed on the Illumina Immunochip. Separate genetic scores based on presence of predictive genetic alleles were calculated for PNR and durable response and performance of clinical and genetics models were compared. RESULTS From 359 patients, 36 were adjudged to have PNR (10%), 200 had durable response, and 74 had non-durable response. PNRs had longer disease duration and were more likely to be smokers. Fifteen risk alleles were associated with PNR. Patients with PNR had a significantly higher genetic risk score (GRS) (P =8 × 10-12). A combined clinical-genetic model more accurately predicted PNR when compared with a clinical only model (0.93 vs. 0.70, P <0.001). Sixteen distinct single nucleotide polymorphisms predicted durable response with a higher GRS (P =7 × 10-13). The GRSs for PNR and durable response were not mutually correlated, suggesting distinct mechanisms. CONCLUSIONS Genetic risk alleles can predict primary non-response and durable response to anti-TNF therapy in CD.
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Affiliation(s)
- Grant E Barber
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School
| | - Vijay Yajnik
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School
| | - Hamed Khalili
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School
| | - Cosmas Giallourakis
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School
| | - John Garber
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School
| | - Ramnik Xavier
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School
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Bek S, Nielsen JV, Bojesen AB, Franke A, Bank S, Vogel U, Andersen V. Systematic review: genetic biomarkers associated with anti-TNF treatment response in inflammatory bowel diseases. Aliment Pharmacol Ther 2016; 44:554-67. [PMID: 27417569 PMCID: PMC5113857 DOI: 10.1111/apt.13736] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 03/20/2016] [Accepted: 06/29/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND Personalised medicine, including biomarkers for treatment selection, may provide new algorithms for more effective treatment of patients. Genetic variation may impact drug response and genetic markers could help selecting the best treatment strategy for the individual patient. AIM To identify polymorphisms and candidate genes from the literature that are associated with anti-tumour necrosis factor (TNF) treatment response in patients with inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis. METHODS We performed a PubMed literature search and retrieved studies reporting original data on association between polymorphisms and anti-TNF treatment response and conducted a meta-analysis. RESULTS A functional polymorphism in FCGR3A was significantly associated with anti-TNF treatment response among CD patients using biological response criterion (decrease in C-reactive protein, levels). Meta-analyses showed that polymorphisms in TLR2 (rs3804099, OR (95% CI) = 2.17 (1.35-3.47)], rs11938228 [OR = 0.64 (0.43-0.96)], TLR4 (rs5030728) [OR = 3.18 (1.63-6.21)], TLR9 (rs352139) [OR = 0.43 (0.21-0.88)], TNFRSF1A (rs4149570) [OR = 2.06 (1.02-4.17)], IFNG (rs2430561) [OR = 1.66 (1.05-2.63)], IL6 (rs10499563) [OR = 1.65 (1.04-2.63)] and IL1B (rs4848306) [OR = 1.88 (1.05-3.35)] were significantly associated with response among IBD patients using clinical response criteria. A positive predictive value of 0.96 was achieved by combining five genetic markers in an explorative analysis. CONCLUSIONS There are no genetic markers currently available which are adequately predictive of anti-TNF response for use in the clinic. Genetic markers bear the advantage that they do not change over time. Therefore, hypothesis-free approaches, testing a large number of polymorphisms in large, well-characterised cohorts, are required in order to identify genetic profiles with larger effect sizes, which could be employed as biomarkers for treatment selection in clinical settings.
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Affiliation(s)
- S. Bek
- Molecular and Diagnostic Research UnitHospital of Southern JutlandAabenraaDenmark
| | - J. V. Nielsen
- Molecular and Diagnostic Research UnitHospital of Southern JutlandAabenraaDenmark
| | - A. B. Bojesen
- Research Unit for E‐mental HealthMental Health Services in the Region of Southern OdenseOdenseDenmark
| | - A. Franke
- Institute of Clinical Molecular BiologyChristian‐Albrechts‐University of KielKielGermany
| | - S. Bank
- Molecular and Diagnostic Research UnitHospital of Southern JutlandAabenraaDenmark
| | - U. Vogel
- National Research Centre for the Working EnvironmentCopenhagenDenmark
| | - V. Andersen
- Molecular and Diagnostic Research UnitHospital of Southern JutlandAabenraaDenmark,Institute of Molecular MedicineUniversity of Southern DenmarkOdenseDenmark,Institute of Regional Health ResearchUniversity of Southern DenmarkOdenseDenmark,OPENUniversity of Southern DenmarkOdenseDenmark
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Kopylov U, Seidman E. Predicting durable response or resistance to antitumor necrosis factor therapy in inflammatory bowel disease. Therap Adv Gastroenterol 2016; 9:513-26. [PMID: 27366220 PMCID: PMC4913332 DOI: 10.1177/1756283x16638833] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023] Open
Abstract
Monoclonal antibodies to tumor necrosis factor (TNF) have become a mainstay of the therapeutic armamentarium in inflammatory bowel disease (IBD) over the last 15 years. Although highly effective, primary and secondary nonresponse are common and associated with poor clinical outcomes and significant costs. Multiple clinical, genetic and immunopharmacological factors may impact the response to anti-TNFs. Early stratification of IBD patients by the expected risk of therapeutic failure during the induction and maintenance phases of treatment may allow for treatment optimization and potentially optimal short- and long-term outcomes. The aim of this review is to summarize the current data concerning the potential predictors of therapeutic success and failure of anti-TNFs in IBD.
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Affiliation(s)
- Uri Kopylov
- Division of Gastroenterology, Sheba Medical Center, Tel Hashomer and Sackler Faculty of Medicine, Tel Aviv, Israel
| | - Ernest Seidman
- Professor of Medicine and Pediatrics McGill University, Director, IBD Center of Excellence at McGill, Bruce Kaufman Endowed Chair in IBD at McGill, Canada Research Chair in Immune Mediated Gastrointestinal Disorders, Digestive Lab Research Institute of the McGill University Health Centre, 1650 Cedar Avenue C10.145, Montreal, QC H3G 1A4, Canada
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49
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Repnik K, Koder S, Skok P, Ferkolj I, Potočnik U. Transferrin Level Before Treatment and Genetic Polymorphism in HFE Gene as Predictive Markers for Response to Adalimumab in Crohn’s Disease Patients. Biochem Genet 2016; 54:476-486. [DOI: 10.1007/s10528-016-9734-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Accepted: 04/13/2016] [Indexed: 12/19/2022]
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50
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Deželak M, Repnik K, Koder S, Ferkolj I, Potočnik U. A Prospective Pharmacogenomic Study of Crohn's Disease Patients during Routine Therapy with Anti-TNF-α Drug Adalimumab: Contribution of ATG5, NFKB1, and CRP Genes to Pharmacodynamic Variability. OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY 2016; 20:296-309. [PMID: 27096233 DOI: 10.1089/omi.2016.0005] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Crohn's disease is often treated with the anti-tumor necrosis factor-α drug adalimumab. However, about 20%-40% of patients do not display adequate therapeutic response. We prospectively evaluated, during a routine therapy of Crohn's disease patients, the candidate autophagy-related genes ATG12 and ATG5 and the inflammation-related genes NFKB1, NFKBIA, and CRP as potential predictors of adalimumab treatment response (pharmacodynamics). The associations of haplotypes and SNPs in these genes with response to drug therapy, biochemical parameters, and body mass were determined at baseline and after 4, 12, 20, and 30 weeks of therapy. Association analysis showed that haplotypes defined with the SNPs rs9373839 and rs510432 in ATG5 gene were significantly associated with positive response to therapy (p < 0.002). In addition, allele C and genotypes CC and CT of the rs1130864 in the CRP gene were positively associated with therapeutic response (p < 0.002). To the best of our knowledge, this is the first report that supports the association of SNPs in ATG5 and CRP genes with response to adalimumab therapy in Crohn's disease. Further study of these biological pathways in larger and independent clinical samples is warranted as novel streams of research on precision medicine and diagnostics for Crohn's disease.
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Affiliation(s)
- Matjaž Deželak
- 1 Centre for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor , Maribor, Slovenia
| | - Katja Repnik
- 1 Centre for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor , Maribor, Slovenia .,2 Laboratory for Biochemistry, Molecular Biology and Genomics, Faculty for Chemistry and Chemical Engineering, University of Maribor , Maribor, Slovenia
| | - Silvo Koder
- 3 University Medical Centre Maribor , Maribor, Slovenia
| | - Ivan Ferkolj
- 4 University Medical Centre Ljubljana , Ljubljana, Slovenia
| | - Uroš Potočnik
- 1 Centre for Human Molecular Genetics and Pharmacogenomics, Faculty of Medicine, University of Maribor , Maribor, Slovenia .,2 Laboratory for Biochemistry, Molecular Biology and Genomics, Faculty for Chemistry and Chemical Engineering, University of Maribor , Maribor, Slovenia
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