• genetic testing
• genetic variants
• inflammatory bowel disease (IBD)
• personalized treatment
• single nucleotide polymorphisms (SNPs)

• Lotteries Health Research
• Otago Medical Research Foundation
• Maurice Wilkins Centre for Molecular Biodiscovery
• Southland Medical Foundation
• Health Research Council of New Zealand

• Crohn's disease
• adalimumab
• certolizumab
• inflammatory bowel disease
• infliximab
• precision medicine
• tofacitinib
• ulcerative colitis
• ustekinumab
• vedolizumab

• Humans
• Inflammatory Bowel Diseases/drug therapy
• Inflammatory Bowel Diseases/genetics
• Inflammatory Bowel Diseases/therapy
• Inflammatory Bowel Diseases/microbiology
• Inflammatory Bowel Diseases/diagnosis
• Metabolomics/methods
• Biomarkers/analysis
• Biomarkers/metabolism
• Treatment Outcome
• Genomics/methods
• Proteomics/methods
• Biological Products/therapeutic use
• Precision Medicine/methods
• Adult
• Transcriptome
• Multiomics

• 82270579 National Natural Science Foundation of China
• 82370551 National Natural Science Foundation of China
• 2024GXNSFFA010009 Natural Science Foundation of Guangxi Zhuang Autonomous Region
• 2023YFC2507300 National Key Research and Development Program of China
• National Natural Science Foundation of China
• Natural Science Foundation of Guangxi Zhuang Autonomous Region
• National Key Research and Development Program of China

• Crohn’s disease
• adalimumab
• inflammatory bowel disease
• infliximab
• polymorphism
• ulcerative colitis
• ustekinumab
• vedolizumab

• Humans
• Inflammatory Bowel Diseases/drug therapy
• Inflammatory Bowel Diseases/genetics
• Pharmacogenetics/methods
• Biological Factors/therapeutic use
• Precision Medicine
• Treatment Outcome

• Crohn’s disease
• NOD2/CARD15
• genetic factors

• Humans
• Crohn Disease/genetics
• Crohn Disease/epidemiology
• Crohn Disease/diagnosis
• Crohn Disease/therapy
• Nod2 Signaling Adaptor Protein/genetics
• Genetic Predisposition to Disease

• biologic therapy
• drug resistance
• inflammatory bowel disease
• non-response
• therapeutic failure

• Crohn’s disease
• artificial intelligence
• inflammatory bowel disease
• multi-omics
• network medicine
• omics
• systems biology
• ulcerative colitis

• Humans
• Multiomics
• Artificial Intelligence
• Cross-Sectional Studies
• Prospective Studies
• Retrospective Studies
• Inflammatory Bowel Diseases/diagnosis
• Inflammatory Bowel Diseases/genetics

• Inflammatory bowel disease
• Management
• Predictor
• Primary nonresponse
• Secondary nonresponse
• Tumor necrosis factor antagonist

• Humans
• Tumor Necrosis Factor Inhibitors/therapeutic use
• Antibodies
• Combined Modality Therapy
• Inflammatory Bowel Diseases/drug therapy
• Biological Products/adverse effects

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.

• Crohn’s disease
• Inflammatory Bowel Disease
• adalimumab
• infliximab
• polymorphism
• ulcerative colitis
• ustekinumab
• vedolizumab

• Crohn's disease
• Genetics and genomics
• Myeloid cells
• Personalised therapeutics
• Stromal cells
• anti-TNF therapy

During the last decades, a better understanding of the mechanisms sustaining the pathogenic process in inflammatory bowel diseases (IBD) has contributed to expand the therapeutic armamentarium for patients with these disorders. Alongside with traditional therapies, monoclonal antibodies against tumor necrosis factor-α, the interleukin (IL)-12/IL-23 p40 subunit and the α4β7 integrin, and tofacitinib, a small molecule inhibiting intracellular pathways downstream to cytokine receptors, have entered into the clinic. However, these drugs are not effective in all patients and some responders can lose response over time. Such a therapeutic failure is, at least in part, dependent on the fact that, in IBD, the tissue damage is driven by simultaneous activation of multiple and distinct immune-inflammatory signals and the detrimental mucosal immune response changes over time even in the same patient. Therefore, personalized approaches aimed at identifying which patient should be treated with a specific drug at a precise time point are worth pursuing. A such approach has the advantage to improve efficacy of the drug and limit adverse reactions, thereby improving quality of the life of the patients and reducing costs. In this review, we summarize all the available evidence about the possible role of precision medicine in IBD.

• IBD
• anti-TNF
• crohn’s disease
• personalized medicine
• ulcerative colitis

• HLA
• TPMT gene
• adverse drug reactions
• antitumor necrosis factor treatment
• genome-wide association study
• inflammatory bowel disease
• pharmacogenetics
• thiopurines

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.

• anti-TNF
• inflammatory bowel diseases
• personalized medicine
• prediction
• response

• Adalimumab
• Crohn’s disease
• anti-TNF
• biologics
• certolizumab
• golimumab
• inflammatory bowel disease
• infliximab
• predictive
• response
• ulcerative colitis
• ustekinumab
• vedolizumab

• IBD
• Oncostatin M
• biomarker
• diagnostic
• prognostic
• therapeutic

• Anti-TNF response
• genetics
• inflammatory bowel disease

• Crohn’s disease
• Environment
• Genetics
• Inflammatory bowel disease
• Pathogenesis
• Risk factors
• Ulcerative colitis

• genetics
• inflammatory bowel disease
• molecular profiling
• transcriptomics

• Antibodies, Bacterial/blood
• CD8-Positive T-Lymphocytes/cytology
• CD8-Positive T-Lymphocytes/immunology
• CD8-Positive T-Lymphocytes/metabolism
• Clinical Decision-Making
• Forkhead Box Protein O3/genetics
• Genome-Wide Association Study
• Humans
• Inflammatory Bowel Diseases/diagnosis
• Inflammatory Bowel Diseases/genetics
• Inflammatory Bowel Diseases/metabolism
• Mesalamine/adverse effects
• Risk Factors
• Transcriptome

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.

• Crohn’s disease
• adalimumab
• anti-tumour necrosis factor
• biomarker
• certolizumab pegol
• inflammatory bowel disease
• infliximab
• therapy response

• Biomarkers/blood
• Biomarkers/metabolism
• Crohn Disease/blood
• Crohn Disease/drug therapy
• Crohn Disease/genetics
• Gene Ontology
• Genome, Human
• Humans
• Polymorphism, Single Nucleotide/genetics
• RNA/genetics
• RNA/metabolism
• Tumor Necrosis Factor-alpha/antagonists & inhibitors
• Tumor Necrosis Factor-alpha/metabolism

The pathogenesis of inflammatory bowel disease (IBD) is not well-understood; however, increased and persistent intestinal inflammation, due to inappropriate immune responses that are caused by interactions between genetic factors, gut microbiota, and environmental factors, are thought to lead to IBD. Various studies have identified more than 240 genetic variants related to IBD. These genetic variants are involved in innate and adaptive immunity, autophagy, defective bacterial handing, interleukin-23 and 10 signaling, and so on. According to several epidemiological and clinical studies, the phenotypes and clinical course of IBD differ between Asians and Europeans. Although the risk loci for IBD typically overlap between Asians and Westerners, genetic heterogeneity has been detected in many loci/genes, such as NOD2/CARD15, TNFSF15 and human leukocyte antigen, contributing to the risk of IBD. Thus, although common pathways exist between Westerners and Asians in the development of IBD, their significance may differ for individual pathways. Although genetic studies are not universally applicable in the clinical field, they may be useful for diagnosing and categorizing IBD, predicting therapeutic responses and toxicity to drugs, and assessing prognosis by risk modeling, thereby enabling precision medicine for individual patients.

• Crohn’s disease
• genetics
• inflammatory bowel disease
• ulcerative colitis

• NOD2
• Crohn disease
• anti-TNF trough level
• drug monitoring
• inflammatory bowel diseases

• Ulcerative colitis
• clinical phenotype
• crohn’s disease
• differential diagnosis
• disease activity
• marker
• molecular diagnosis
• response to therapy

• Biological therapy
• Crohn’s disease
• cytokines
• drug monitoring
• markers
• ulcerative colitis

• Antibodies, Monoclonal/therapeutic use
• Biological Therapy
• Gastrointestinal Agents/therapeutic use
• Humans
• Inflammatory Bowel Diseases/drug therapy
• Patient Selection
• Prognosis
• Treatment Outcome
• Tumor Necrosis Factor-alpha/antagonists & inhibitors

• Crohn’s disease
• anti-TNF-α
• biologics
• inflammatory bowel disease
• long-term efficacy
• predictors
• short-term efficacy
• ulcerative colitis

• Age Factors
• Anti-Inflammatory Agents/pharmacology
• Anti-Inflammatory Agents/therapeutic use
• Antibodies, Monoclonal/pharmacology
• Antibodies, Monoclonal/therapeutic use
• Humans
• Inflammatory Bowel Diseases/diagnosis
• Inflammatory Bowel Diseases/drug therapy
• Prognosis
• Sex Factors
• Time Factors
• Treatment Outcome
• Tumor Necrosis Factor-alpha/antagonists & inhibitors

• anti-tnf
• pharmacogenomics
• loss of response
• infliximab
• crohn’s
• genetics
• adalimumab
• non-response

• CARD14
• Crohn’s disease
• Monoclonal
• NOD2
• Polymorphism

• Adalimumab/therapeutic use
• Adult
• Anti-Inflammatory Agents/therapeutic use
• Crohn Disease/drug therapy
• Crohn Disease/epidemiology
• Crohn Disease/genetics
• Female
• Humans
• Infliximab/therapeutic use
• Male
• Nod2 Signaling Adaptor Protein/genetics
• Polymorphism, Genetic/genetics

• Adult
• Anti-Inflammatory Agents/therapeutic use
• Colitis, Ulcerative/diagnosis
• Colitis, Ulcerative/drug therapy
• Colitis, Ulcerative/genetics
• Crohn Disease/diagnosis
• Crohn Disease/drug therapy
• Female
• Genetic Association Studies
• Genetic Markers
• Genetic Variation
• Humans
• Inflammatory Bowel Diseases/diagnosis
• Inflammatory Bowel Diseases/drug therapy
• Inflammatory Bowel Diseases/genetics
• Polymorphism, Genetic
• Tumor Necrosis Factor-alpha/antagonists & inhibitors

• anti-TNF agents
• inflammatory bowel disease
• therapeutic drug monitoring

• Anti-TNF
• Crohn's disease
• Diffusion-weighted MRI
• Predictive factor

• Algorithms
• Antibodies, Monoclonal/therapeutic use
• Crohn Disease/drug therapy
• Crohn Disease/epidemiology
• Crohn Disease/physiopathology
• Disease Management
• Dose-Response Relationship, Drug
• Drug Monitoring
• Humans
• Incidence
• Prevalence
• Severity of Illness Index
• Treatment Failure
• Tumor Necrosis Factor-alpha/immunology
• Tumor Necrosis Factor-alpha/therapeutic use

• Anti-TNF
• Crohn’s disease
• primary non-response

In recent years, the incidence of inflammatory bowel disease (IBD) has been on the rise, extending to countries where it was infrequent in the past. As a result, the gap between high and low incidence countries is decreasing. The disease, therefore, has an important economic impact on the healthcare system. Advances in recent years in pharmacogenetics and clinical pharmacology have allowed for the development of treatment strategies adjusted to the patient profile. Concurrently, new drugs aimed at inflammatory targets have been developed that may expand future treatment options. This review examines advances in the optimization of existing drug treatments and the development of novel treatment options for IBD.

• Inflammatory bowel disease
• Future directions
• Pharmacogenetic
• Pharmacokinetics
• New drugs

• Animals
• Anti-Inflammatory Agents/pharmacokinetics
• Anti-Inflammatory Agents/therapeutic use
• Drug Discovery/trends
• Forecasting
• Gastrointestinal Agents/pharmacokinetics
• Gastrointestinal Agents/therapeutic use
• Humans
• Incidence
• Inflammatory Bowel Diseases/diagnosis
• Inflammatory Bowel Diseases/drug therapy
• Inflammatory Bowel Diseases/epidemiology
• Molecular Targeted Therapy/trends
• Pharmacogenetics/trends

• Crohn's disease
• adalimumab
• biological drugs
• pharmacogenomics
• single nucleotide polymorphism

• Adalimumab/therapeutic use
• Adult
• Autophagy-Related Proteins
• C-Reactive Protein/metabolism
• Carrier Proteins/genetics
• Crohn Disease/genetics
• Crohn Disease/therapy
• Female
• Genetic Association Studies
• Genetic Markers
• Genotype
• Humans
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Slovenia
• Treatment Outcome
• Tumor Necrosis Factor-alpha/antagonists & inhibitors

• Crohn's disease
• Epidemiology
• Genotype
• Phenotype
• Ulcerative colitis

• Gastroenterology
• Personalized Medicine
• Pharmacogenetics

• Crohn’s disease
• clinical genetic predictors
• response to therapy

• biological therapy
• biomarker
• disease heterogeneity
• tumor necrosis factor-α

• crohn’s disease
• ulcerative colitis
• genetics
• complications
• surgery

Influence of genetic variants in the NOD2 gene may play a more important role in disease activity, behaviour and treatment of pediatric- than adult-onset Crohn’s disease (CD).

85 pediatric- and 117 adult-onset CD patients were tested for the three main NOD2 CD-associated variants (p.R702W, p.G908R and p.10007fs) and clinical data of at least two years of follow-up were compared regarding disease behaviour and activity, response to therapy and bone mineral density (BMD).

Chronic active and moderate to severe course of CD is associated in patients with pediatric-onset (p=0.0001) and NOD2 variant alleles (p=0.0001). In pediatric-onset CD the average PCDAI-Score was significantly higher in patients carrying NOD2 variants (p=0.0008). In addition, underweight during course of the disease (p=0.012) was associated with NOD2 variants. Interestingly, osteoporosis was found more frequently in patients carrying NOD2 variant alleles (p=0.033), especially in pediatric-onset CD patients with homozygous NOD2 variants (p=0.037). Accordingly, low BMD in pediatric-onset CD is associated with a higher PCDAI (p=0.0092), chronic active disease (p=0.0148), underweight at diagnosis (p=0.0271) and during follow-up (p=0.0109). Furthermore, pediatric-onset CD patients with NOD2 variants are more frequently steroid-dependent or refractory (p=0.048) and need long-term immunosuppressive therapy (p=0.0213).

These data suggests that the presence of any of the main NOD2 variants in CD is associated with osteoporosis and an age of onset dependent influence towards underweight, higher disease activity and a more intensive immunosuppressive therapy. This observation supports the idea for an early intensive treatment strategy in children and adolescent CD patients with NOD2 gene variants.

AIM: To investigate genetic differences between Crohn’s disease (CD) patients with a sustained remission vs relapsers after discontinuing infliximab while in corticosteroid-free remission.

METHODS: Forty-eight CD patients received infliximab and were in full corticosteroid-free clinical remission but then discontinued infliximab for reasons other than a loss of response, were identified by review of an electronic database and charts. Infliximab-associated remission was defined as corticosteroid-free plus normalization of clinical disease activity [CD activity index (CDAI) < 150] during follow-up visits based on physician global assessments. A CD relapse (loss of infliximab-induced remission) was clinically defined as a physician visit for symptoms of disease activity (CDAI > 220) and a therapeutic intervention with CD medication(s), or a hospitalization with complications related to active CD. Genetic analyses were performed on samples from 14 patients (n = 6 who had a sustained long term remission after stopping infliximab, n = 8 who rapidly relapsed after stopping infliximab). Nucleotide-binding oligomerization domain 2 (NOD2)/caspase activation recruitment domain 15 (CARD15) polymorphisms (R702W, G908R and L1007fs) and the inflammatory bowel disease 5 (IBD5) polymorphisms (IGR2060a1 and IGR3081a1) were analyzed in each group.

RESULTS: Five single nucleotide polymorphisms of IBD5 and NOD2/CARD15 genes were successfully analyzed for all 14 subjects. There was no significant increase in frequency of the NOD2/CARD15 polymorphisms (R702W, G908R and L1007fs) and the IBD5 polymorphisms (IGR2060a1 and IGR3081a1) in either group of patients; those whose disease relapsed rapidly or those who remained in sustained long term remission following the discontinuation of infliximab. Nearly a third of patients in full clinical remission who stopped infliximab for reasons other than loss of response remained in sustained clinical remission, while two-thirds relapsed rapidly. There was a marked difference in the duration of clinical remission following discontinuance of infliximab between the two groups. The patients who lost remission did so after 1.0 years ± 0.6 years, while those still in remission were at the time of this study, 8.1 years ± 2.6 years post-discontinuation of infliximab, P < 0.001. The 8 patients who had lost remission after discontinuing infliximab had a mean number of 5 infusions (range 3-7), with a mean treatment time of 7.2 mo (range 1.5 mo-15 mo). The mean duration of time from the last infusion of infliximab to the time of loss of remission was 382 d (range 20 d-701 d). The 6 patients who remained in remission after discontinuing infliximab had a mean number of 6 infusions (range 3-12), with a mean treatment duration of 12 mo (range 3.6 mo-32 mo) (P = 0.45 relative to those who lost remission).

CONCLUSION: There are no IBD5 or NOD2/CARD15 mutations that predict which patients might have sustained remission and which will relapse rapidly after stopping infliximab.

• Infliximab
• Anti-tumor necrosis factor alpha
• Crohn’s disease
• Inflammatory bowel disease
• Genotype