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Evaluation of anti-TNF therapeutic response in patients with inflammatory bowel disease: Current and novel biomarkers.

ABSTRACT: Neutralizing tumour necrosis factor (TNF) antibodies have been widely used to treat inflammatory bowel disease (IBD) in the clinical practice. In this review, the principal biomarker analysis revealed that faecal calprotectin, C-reactive protein, serum or mucosal concentrations of anti-TNF monoclonal antibodies (mAbs) and antibodies to anti-TNF mAbs are commonly used as current biomarkers in the evaluation of anti-TNF therapeutic efficacy. However, mucosal cytokine transcripts. microRNAs, proteomics and faecal and mucosal gut microbiota profile and mucosal histological features are reported to be novel candidates of biomarkers with high clinical utility in the evaluation of anti-TNF therapeutic efficacy in patients with IBD. Therefore, a robust validation of novel promising biomarkers and comparison studies between current used and novel biomarkers are urgently required to improve their value in the evaluation of therapeutic efficacy and optimization of personalized medicine and identification of IBD candidates for anti-TNF therapy in future clinical practice.

SUBMITTER: Cui G

PROVIDER: S-EPMC8054158 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Evaluation of anti-TNF therapeutic response in patients with inflammatory bowel disease: Current and novel biomarkers.

Cui Guanglin G Fan Qingbo Q Li Zhenfeng Z Goll Rasmus R Florholmen Jon J

EBioMedicine 20210413

Neutralizing tumour necrosis factor (TNF) antibodies have been widely used to treat inflammatory bowel disease (IBD) in the clinical practice. In this review, the principal biomarker analysis revealed that faecal calprotectin, C-reactive protein, serum or mucosal concentrations of anti-TNF monoclonal antibodies (mAbs) and antibodies to anti-TNF mAbs are commonly used as current biomarkers in the evaluation of anti-TNF therapeutic efficacy. However, mucosal cytokine transcripts. microRNAs, proteo ...[more]

PMID: 33862588

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Project description:BackgroundPersonalised 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.AimTo 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.MethodsWe 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.ResultsA 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.ConclusionsThere 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.

Project description:ObjectivesInterleukin-23 (IL-23) has emerged as a new therapeutic target for the treatment of inflammatory bowel disease (IBD). As biomarkers of disease state and treatment efficacy are becoming increasingly important in drug development, we sought to identify efficacy biomarkers for anti-IL-23 therapy in Crohn's disease (CD).MethodsCandidate IL-23 biomarkers, downstream of IL-23 signaling, were identified using shotgun proteomic analysis of feces and colon lavages obtained from a short-term mouse IBD model (anti-CD40 Rag2(-/-)) treated preventively with monoclonal antibodies (mAbs) to the IL-23 receptor (IL-23R). The biomarkers were then measured in an IBD T-cell transfer model treated therapeutically with a mAb to IL-23 (p19), confirming their association with IBD. To assess the clinical relevance of these markers, we assessed their concentrations in clinical serum, colon tissue, and feces from CD patients.ResultsWe identified 57 proteins up or downregulated in diseased animals that returned to control values when the mice were treated with mAbs to IL-23R. Among those, S100A8, S100A9, regenerating protein 3β (REG), REG3γ, lipocalin 2 (LCN2), deleted in malignant tumor 1 (DMBT1), and macrophage migration inhibitory factor (MIF) mRNA levels correlated with disease score and dose titration of mAbs to IL-23R or IL-23(p19). All biomarkers, except DMBT1, were also downregulated after therapeutic administration of mAbs to IL-23(p19) in a T-cell transfer IBD mouse model. In sera from CD patients, we confirmed a significant upregulation of S100A8/A9 (43%), MIF (138%), pancreatitis-associated protein (PAP, human homolog of REG3β/γ; 49%), LCN2 (520%), and CCL20 (1280%), compared with control samples, as well as a significant upregulation of S100A8/A9 (887%), PAP (401%), and LCN2 (783%) in human feces from CD patients compared with normal controls.ConclusionsThese studies identify multiple protein biomarkers downstream of IL-23 that could be valuable tools to assess the efficacy of this new therapeutic agent.Clinical and Translational Gastroenterology (2012) 3, e10; doi:10.1038/ctg.2012.2; published online 16 February 2012.

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Evaluation of anti-TNF therapeutic response in patients with inflammatory bowel disease: Current and novel biomarkers.

Publications

Evaluation of anti-TNF therapeutic response in patients with inflammatory bowel disease: Current and novel biomarkers.

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