Evidence-based use of anti-TNFα therapy in Crohn's disease; where are we in 2011?
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ABSTRACT:
SUBMITTER: Everett SM
PROVIDER: S-EPMC5517221 | biostudies-other | 2011 Jul
REPOSITORIES: biostudies-other
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Project description:The lack of reliable biomarkers of 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 towards specific immune cell sub-populations using single-cell RNA-sequencing.
2024-06-19 | GSE269631 | GEO
Project description:Experimental and clinical investigations have revealed that statins can downregulate both acute and chronic inflammatory processes. Whether statins express anti-inflammatory activities in the treatment of Crohn's disease is unknown.Ten patients were given 80 mg atorvastatin once daily for 13 weeks and then followed up for 8 weeks after the treatment. The anti-inflammatory effects of statin were assessed by measuring levels of plasma C-reactive protein (CRP), soluble (s) CD14, tumour necrosis factor (TNF)-alpha, sTNFRI and II, CCL2 and 8 and the mucosal inflammation by faecal calprotectin. Circulating monocytes were subgrouped and their chemokine receptor expression of CCR2 and CX(3)CR1 were analysed.In 8 of 10 patients, atorvastatin treatment reduced CRP (P=0.008) and sTNFRII (P=0.064). A slight decrease in plasma levels of sCD14, TNF-alpha and sTNFRI was observed in 7/10 patients and faecal calprotectin was reduced in 8/10 patients. We also observed that the treatment diminished expression of CCR2 and CX(3)CR1 on monocyte populations (P=0.014). At the follow-up visit, 8 weeks after the atorvastatin treatment was terminated, CRP levels had returned to those seen before the treatment.Our findings imply that atorvastatin therapy reduces inflammation in patients with Crohn's disease and, therefore, encourage further investigations of statin-mediated protective effects in inflammatory bowel diseases.
| S-EPMC2597264 | biostudies-literature
Project description:Crohn's disease is increasing in incidence and prevalence in younger people and is of a particularly aggressive nature. One emerging treatment targets Mycobacterium avium paratuberculosis (MAP), an organism implicated in the causation of Crohn's disease. This study reviewed a cohort of paediatric patients with active Crohn's disease treated with Anti-Mycobacterial Antibiotic Therapy (AMAT). Sixteen paediatric patients, the majority of whom had failed conventional immunosuppressive therapy, were treated with AMAT. Endoscopic remission was scored using the Simple Endoscopic Score for Crohn's Disease and clinical remission was assessed using the Weighted Paediatric Crohn's Disease Activity Index (wPCDAI). Inflammatory blood markers were also routinely recorded. Patients were followed up clinically and endoscopically during treatment after an average of two months (range 1-6) and 17 months (range 2-49), respectively. A significant reduction in both scores assessing clinical improvement (p < 0.001) and mucosal healing (p < 0.0078) was observed at these timepoints; 47% of patients had achieved clinical remission and 63% endoscopic remission. Haemoglobin and serum inflammatory markers normalised for more than 50% of the cohort by six months of treatment. No adverse effects were reported throughout treatment. This is the first report of Anti-Mycobacterial Antibiotic Therapy offering a safe and efficacious therapy for paediatric patients with Crohn's disease. Further larger randomised studies are required in order to validate these findings.
| S-EPMC7464505 | biostudies-literature
Project description:Crohn's disease (CD) is an inflammatory bowel disease (IBD) with uncertain etiology. Biologic agents have revolutionized the treatment of CD but nonresponders remain a challenge. Ustekinumab is an interleukin 12/23p40 inhibitor that was recently found effective in treating CD. We reviewed the current literature regarding the efficacy of ustekinumab in treating CD and concluded that ustekinumab is a novel, promising and relatively safe agent for the treatment of moderate to severe CD. Additional data from randomized controlled studies and real-life cohorts are pending.
| S-EPMC4935835 | biostudies-literature
Project description:Background/aimsThe optimal timing for initiation of anti-tumor necrosis factor (TNF) therapy in Crohn's disease (CD) is still debated. Little is known about the clinical outcomes of early versus late administration of anti-TNF agents, especially in Asian CD patients. We aimed to evaluate the impact of early anti-TNF therapy on clinical outcomes in Korean CD patients.MethodsUsing the Korean National Health Insurance Claims database, we collected data on patients diagnosed with CD who received anti-TNF therapy for more than 6 months between 2010 and 2016. Early initiation of anti-TNF therapy was defined as those starting infliximab or adalimumab therapy within 1 year of diagnosis. The following outcomes were assessed using a Cox proportional hazard model: abdominal surgery, CD-related emergency room (ER) visit, CD-related hospitalization, and new corticosteroid use.ResultsAmong 1,207 patients, 609 were early initiators of anti-TNF. Late anti-TNF initiation (> 1 year after diagnosis) was associated with increased risk of surgery (adjusted hazard ratio [aHR], 1.64; 95% confidence interval [CI], 1.05 to 2.55) and tended to be associated with increased risk of ER visit (aHR, 1.38; 95% CI, 0.99 to 1.94). However, there were no significant differences in the risk of hospitalization and corticosteroid use between early and late initiators.ConclusionEarly anti-TNF therapy among Korean CD patients within 1 year of diagnosis was associated with better clinical outcomes than late therapy, such as lower surgery and ER visit rates. Our results suggest that aggressive medical intervention in the early stages of CD may potentially change the course of this disease.
| S-EPMC7487310 | biostudies-literature
Project description:BACKGROUND:Ileocolonic expression of IL13RA2 has been identified as a predictive marker for nonresponsiveness to infliximab (IFX) in patients with Crohn's disease (CD). AIM:To validate the IL13RA2 biomarker, study its anti-TNF specificity and get a better understanding of the underlying biology driving its expression. METHODS:IL13RA2 mucosal expression was studied in a cohort of adalimumab and vedolizumab treated patients. To identify the upstream regulators of anti-TNF nonresponsiveness, weighted gene co-expression network analysis was applied on publicly available microarray data of IFX-treated patients. Selected serum proteins, including TNF, were measured prior to first IFX exposure and compared between healers and nonhealers. RESULTS:Increased mucosal IL13RA2 expression prior to start of biological therapy was predictive for anti-TNF nonresponsiveness specifically (AUROC, area under the curve = 0.90, P < 0.001 in anti-TNF vs AUROC = 0.63, P = 0.30 in vedolizumab treated patients). In baseline biopsies, TNF-driven pathways were significantly enriched in future anti-TNF nonhealers (P = 5.0 × 10-34 ). We found an increased baseline mucosal TNF burden in nonhealers (P = 0.02), and TNF mRNA correlated significantly with IL13RA2 expression (? = 0.55, P = 0.02). Baseline serum TNF levels were significantly lower in nonhealers (P = 0.04), and correlated inversely with IFX serum induction levels (r = -0.45, P = 0.002 at week 6). CONCLUSIONS:Increased mucosal IL13RA2 expression is associated with an increased mucosal TNF burden in CD patients. In view of its specificity for prediction of anti-TNF therapy resistance, mucosal IL13RA2 expression is a potential biomarker for therapy selection and/or for the need of increased anti-TNF drug dosing.
| S-EPMC6849553 | biostudies-literature
Project description:Crohn's disease (CD) is a chronic immune-mediated disorder for which there is not a fully effective treatment. Moreover, biological therapy with anti-tumor necrosis factor-α (anti-TNF-α) monoclonal antibodies leads to an effective response in only 60-70% of patients. Our previous data suggested that specific loci polymorphism of the TNFRSF1B, FCGR3A, IL1R, IL1B, and FAS genes could be a predictor of the primary non-response to anti-TNF therapy in CD patients. In this work, we propose to explain this hypothesis by functional analysis in colon biopsies and in a cell culture model. Using the RT-qPCR analysis, we estimated the FCGR3A, IL1R, TNFRSF1B, IL1B, FAS, and ADAM17 genes mRNA level in colon biopsies material from inflamed and non-inflamed tissue from 21 CD patients (14 responders and 7 non-responders to anti-TNF therapy) and 6 controls, as well as in vitro in a peripheral blood mononuclear cells (PBMCs) from 14 CD patients (seven responders and seven non-responders to anti-TNF therapy) and eight controls cultured for 72 h with 10 μg/ml of anti-TNF antibody. Our findings demonstrated a significant down-regulation of TNFRSF1B gene expression in non-responders both in inflamed and in non-inflamed colon tissue, while the expression of the FCGR3A and IL1B genes was significantly up-regulated in non-responders in the inflamed colon region. In vitro research results indicate that the anti-TNF drug induced a significant decrease in TNFRSF1B, FCGR3A, and FAS gene expression in non-responders. These results show that altered TNFRSF1B, FCGR3A, and IL1B genes expression can be a predictor of the primary non-response to anti-TNF therapy in CD patients.
| S-EPMC7985326 | biostudies-literature
Project description:The benefit of continuing immunomodulators when "stepping up" to anti-tumor necrosis factor (anti-TNF) therapy for Crohn's disease (CD) is uncertain. This study assessed the effectiveness and safety of immunomodulators with anti-TNF therapy in CD.We conducted a retrospective cohort study of new users of anti-TNF therapy for CD in Medicare. Users of anti-TNF combination therapy with immunomodulators were matched to up to 3 users of anti-TNF monotherapy via propensity score and compared by using 3 metrics of effectiveness-surgery, hospitalization, and discontinuation of anti-TNF therapy or surgery-and 2 metrics of safety-serious infection and non-Candida opportunistic infection. Cox regression was used for all analyses.Among new users of infliximab, we matched 381 users of combination therapy to 912 users of monotherapy; among new users of adalimumab, we matched 196 users of combination therapy to 505 users of monotherapy. Combination therapy occurred predominantly as "step up" after thiopurine therapy. The rates of surgery (hazard ratio [HR], 1.20; 95% confidence interval, 0.73-1.96), hospitalization (HR, 0.82; 0.57-1.19), discontinuation of anti-TNF therapy or surgery (HR, 1.09; 0.88-1.34), and serious infection (HR, 0.93; 0.88-1.34) did not differ between users of anti-TNF combination therapy and monotherapy. However, the risks of opportunistic infection (HR, 2.64; 1.21-5.73) and herpes zoster (HR, 3.16; 1.25-7.97) were increased with combination therapy.We found that continuation of immunomodulators after "stepping up" to anti-TNF therapy did not improve outcomes but was associated with an increased risk of opportunistic infection.
| S-EPMC4475667 | biostudies-literature
Project description:Background:The effect of low-frequency functional variation on anti-tumor necrosis factor alpha (TNF) response in Crohn's disease (CD) patients remains unexplored. The objective of this study was to investigate the impact of functional rare variants in clinical response to anti-TNF therapy in CD. Methods:CD anti-TNF naïve patients starting anti-TNF treatment due to active disease [Crohn's Disease Activity Index (CDAI > 150)] were included. The whole genome was sequenced using the Illumina Hiseq4000 platform. Clinical response was defined as a CDAI score <150 at week 14 of anti-TNF treatment. Low-frequency variants were annotated and classified according to their damaging potential. The whole genome of CD patients was screened to identify homozygous loss-of-function (LoF) variants. The TNF signaling pathway was tested for overabundance of damaging variants using the SKAT-O method. Functional implication of the associated rare variation was evaluated using cell-type epigenetic enrichment analyses. Results:A total of 41 consecutive CD patients were included; 3250 functional rare variants were identified (2682 damaging and 568 LoF variants). Two homozygous LoF mutations were found in HLA-B and HLA-DRB1 genes associated with lack of response and remission, respectively. Genome-wide LoF variants were enriched in epigenetic marks specific for the gastrointestinal tissue (colon, p = 4.11e-4; duodenum, p = 0.011). The burden of damaging variation in the TNF signaling pathway was associated with response to anti-TNF therapy (p = 0.016); damaging variants were enriched in epigenetic marks from CD8+ (p = 6.01e-4) and CD4+ (p = 0.032) T cells. Conclusions:Functional rare variants are involved in the response to anti-TNF therapy in CD. Cell-type enrichment analysis suggests that the gut mucosa and CD8+ T cells are the main mediators of this response.
| S-EPMC6764039 | biostudies-literature
Project description:Whole blood samples were collected from patients at baseline, 6 weeks and 8 weeks after induction (Ustekinumab or placebo) therapies for RNA extraction and microarray analysis from patients with moderate-to-severe CD who participated in stelara CD phase 3 studies (UNITI-2). These patients failed conventional therapies previously and largely naive to anti-TNF therapy. We used microarrays to detail the transcriptional programme underlying placebo and stelara treatment in the periphery at WK0, WK6, WK8.
2022-11-08 | GSE207465 | GEO