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Practical strategy for optimizing the timing of anti-tumor necrosis factor-? therapy in Crohn disease: A nationwide population-based study.

ABSTRACT: There is little consensus on the optimal timing of anti-tumor necrosis factor (anti-TNF) therapy to decrease the rates of hospitalization and surgery in Crohn disease (CD). We aimed to assess the real-world outcomes of anti-TNF therapy and estimate the optimal timing of anti-TNF therapy in Korean patients with CD.Claims data were extracted from the Korean Health Insurance Review and Assessment Service database. Incident patients diagnosed with CD between 2009 and 2016, with at least 1 anti-TNF drug prescription, and with follow-up duration >?6 months were stratified according to the number of relapses prior to initiation of anti-TNF therapy: groups A (?1 relapse), B (2 relapses), C (3 relapses), and D (?4 relapses). The cumulative survival curves free from emergency hospitalization (EH) and surgery were compared across groups.Among the 2173 patients analyzed, the best and worst prognoses were noted in groups A and D, respectively. The incidences of EH and surgery decreased significantly as the use of anti-TNF agents increased. The 5-year rate of hospitalization was significantly lower in group A than in groups C and D (P?=?.004 and .020, respectively), but similar between groups A and B. The 5-year rate of surgery was lower in group A than in group C (P?=?.024), but similar among groups A, B, and D.In Asian patients with CD, anti-TNF therapy reduces the risk of EH and surgery and should be considered before three relapses, regardless of disease duration.

SUBMITTER: Kwak MS

PROVIDER: S-EPMC7478703 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Practical strategy for optimizing the timing of anti-tumor necrosis factor-α therapy in Crohn disease: A nationwide population-based study.

Kwak Min Seob MS Cha Jae Myung JM Ahn Ji Hyun JH Chae Min Kyu MK Jeong Sara S Lee Hun Hee HH

Medicine 20200301 10

There is little consensus on the optimal timing of anti-tumor necrosis factor (anti-TNF) therapy to decrease the rates of hospitalization and surgery in Crohn disease (CD). We aimed to assess the real-world outcomes of anti-TNF therapy and estimate the optimal timing of anti-TNF therapy in Korean patients with CD.Claims data were extracted from the Korean Health Insurance Review and Assessment Service database. Incident patients diagnosed with CD between 2009 and 2016, with at least 1 anti-TNF d ...[more]

PMID: 32150045

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Project description:Purpose:A significant feature of pediatric inflammatory bowel diseases (IBD), which include Crohn disease (CD), and ulcerative colitis (UC), is failure to suppress inflammation. The inability to regulate inflammation renders a major challenge toward establishing effective treatments in IBD. Nuclear factor kappa-light-chain-enhancer of activated B-cells-induced inflammation is inhibited by A20 through interactions with TAX1BP1 (Tax1-binding protein 1) and A20-binding inhibitor of NF-?? activation (ABIN)-1 (A20 binding and inhibitor of NF-??) and upon phosphorylation by inhibitor of nuclear factor kappa-? kinase subunit beta (IKK?), which stabilizes it. We hypothesized that dysregulation of A20 is an important factor in uncontrolled inflammation in pediatric IBD. Patients and methods:Gene expression of A20, IKK?, ABIN-1, TAX1BP1, A20 protein, cytokine levels, and A20 phosphorylation was analyzed in the terminal ileum (TI) of 39 patients (14 non-IBD, 15 CD, and 10 UC). A20 expression and protein in T-84 cells and ex vivo biopsies of patients were measured after treatment with Escherichia coli strains or tumor necrosis factor (TNF)-?. Results:TNF-? levels and A20 expression were increased in the TI of CD patients. A20 protein levels and ABIN-1 expression were low, TAX1BP1 expression was high, and IKK? was unchanged. A20 expression positively correlated with biopsy TNF-? levels and inflammatory markers in CD patients. A20 phosphorylation appeared lower in CD patients. A20 expression in TI biopsies from CD patients and T84 cells was triggered with E. coli, strain LF82, while A20 protein levels remained unchanged. Conclusion:We describe a potential mechanism related to failure of A20 to suppress inflammation in CD, characterized by high A20 expression and low A20 protein levels. The dysregulation of A20 is potentially due to alterations in ABIN-1, and infection with E. coli strain LF82 could affect the function and stability of A20. Our study signifies an important finding in A20 regulation in IBD, which prevents it from suppressing inflammation.

Project description:This study aims to investigate the prevalence of short-term and long-term adverse events associated with tumor necrosis factor-α (TNF-α) blocker treatment in Chinese Han patients suffering from ankylosing spondylitis (AS).The study included 402 Chinese Han AS patients treated with TNF-α blockers. Baseline data was collected. All patients were monitored for adverse events 2 hours following administration. Long-term treatment was evaluated at 8, 12, 52 and 104 weeks follow-up for 172 patients treated with TNF-α blockers.Short-term adverse events occurred in 20.15% (81/402), including rash (3.5%; 14/402), pruritus (1.2%; 5/402), nausea (2.2%; 9/402), headache (0.7%; 3/402), skin allergies (4.0%; 16/402), fever (0.5%; 2/402), palpitations (3.0%; 12/402), dyspnea (0.5%; 2/402), chest pain (0.2%; 1/402), [corrected] abdominal pain (1.0%; 4/402), hypertension (2.2%; 9/402), papilledema (0.5%; 2/402), laryngeal edema (0.2%; 1/402) and premature ventricular contraction (0.2%; 1/402). Long-term adverse events occurred in 59 (34.3%; 59/172) patients, including pneumonia (7.6%; 13/172), urinary tract infections (9.9%; 17/172), otitis media (4.7%; 8/172), tuberculosis are (3.5%; 6/172) [corrected], abscess (1.2%; 2/172), oral candidiasis (0.6%; 1/172), elevation of transaminase (1.7%; 3/172), anemia (1.2%; 2/172), hematuresis (0.6%; 1/172), constipation (2.3%; 4/172), weight loss (0.6%; 1/172), exfoliative dermatitis (0.6%; 1/172). CRP, ESR and disease duration were found to be associated with an increased risk of immediate and long-term adverse events (P<0.05). Long-term treatment with Infliximab was associated with more adverse events than rhTNFR-Fc (P<0.01).This study reports on the prevalence of adverse events in short-term and long-term treatment with TNF-α blocker monotherapy in Chinese Han AS patients. Duration of disease, erythrocyte sedimentation rate, and c-reactive protein serum levels were found to be associated with increased adverse events with anti-TNF-α therapy. Long-term treatment with Infliximab was associated with more adverse events than rhTNFR-Fc.

Project description:Background and aimAnti-tumor necrosis factor-α (anti-TNF-α) agents have been used for inflammatory bowel disease; however, it has up to 30% nonresponse rate. Identifying molecular pathways and finding reliable diagnostic biomarkers for patient response to anti-TNF-α treatment are needed.MethodsPublicly available transcriptomic data from inflammatory bowel disease patients receiving anti-TNF-α therapy were systemically collected and integrated. In silico flow cytometry approaches and Metascape were applied to evaluate immune cell populations and to perform gene enrichment analysis, respectively. Genes identified within enrichment pathways validated in neutrophils were tracked in an anti-TNF-α-treated animal model (with lipopolysaccharide-induced inflammation). The receiver operating characteristic curve was applied to all genes to identify the best prediction biomarkers.ResultsA total of 449 samples were retrieved from control, baseline, and after primary anti-TNF-α therapy or placebo. No statistically significant differences were observed between anti-TNF-α treatment responders and nonresponders at baseline in immune microenvironment scores. Neutrophil, endothelial cell, and B-cell populations were higher in baseline nonresponders, and chemotaxis pathways may contribute to the treatment resistance. Genes related to chemotaxis pathways were significantly upregulated in lipopolysaccharide-induced neutrophils, but no statistically significant changes were observed in neutrophils treated with anti-TNF-α. Interleukin 13 receptor subunit alpha 2 (IL13RA2) is the best predictor (receiver operating characteristic curve: 80.7%, 95% confidence interval: 73.8-87.5%), with a sensitivity of 68.13% and specificity of 84.93%, and significantly higher in nonresponders compared with responders (P < 0.0001).ConclusionsHyperactive neutrophil chemotaxis influences responses to anti-TNF-α treatment, and IL13RA2 is a potential biomarker to predict anti-TNF-α treatment response.

Dataset Information

Practical strategy for optimizing the timing of anti-tumor necrosis factor-? therapy in Crohn disease: A nationwide population-based study.

Publications

Practical strategy for optimizing the timing of anti-tumor necrosis factor-α therapy in Crohn disease: A nationwide population-based study.

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