Adalimumab Therapy Improves Intestinal Dysbiosis in Crohn's Disease.
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ABSTRACT:
SUBMITTER: Ribaldone DG
PROVIDER: S-EPMC6832711 | biostudies-literature | 2019 Oct
REPOSITORIES: biostudies-literature
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Project description: Not available
| S-EPMC6953260 | biostudies-literature
Project description:Background & aimsAntibodies against tumor necrosis factor-? are widely used to treat patients with Crohn's disease (CD). This study compared the effectiveness of infliximab and adalimumab, the 2 most commonly used anti-tumor necrosis factor agents, in patients with CD.MethodsWe conducted a retrospective cohort study by using U.S. Medicare data from 2006 through 2010. Patients with CD who were new users of infliximab (n = 1459) or adalimumab (n = 871) after January 31, 2007, were included. Patients older than age 85 and those with rheumatoid arthritis, psoriasis, psoriatic arthritis, or ankylosing spondylitis were excluded. The primary outcome measures were disease persistence on therapy at week 26, surgery (including bowel resection, creation of an ostomy, or surgical treatment of a perforation or abscess), and hospitalization for CD. Propensity score-adjusted logistic and Cox regression were used to compute adjusted odds ratios or hazard ratios and 95% confidence intervals (CIs).ResultsAfter 26 weeks of treatment, 49% of patients receiving infliximab remained on drug, compared with 47% of those receiving adalimumab (odds ratio, 0.98; 95% CI, 0.81-1.19). Fewer patients treated with infliximab underwent surgery than those treated with adalimumab, but this difference was not statistically significant (5.5 vs 6.9 surgeries per 100 person-years; hazard ratio, 0.79; 95% CI, 0.60-1.05). Rates of hospitalization did not differ between groups (hazard ratio, 0.88; 95% CI, 0.72-1.07).ConclusionsWe observed similar effectiveness of infliximab and adalimumab for CD on the basis of 3 clinically important outcome measures.
| S-EPMC3883891 | biostudies-literature
Project description:BACKGROUND/AIMS:This was a Phase 2 study (NCT02015793) to evaluate the pharmacokinetics, safety, and efficacy of adalimumab in Chinese patients with Crohn's disease (CD). METHODS:Thirty, adult Chinese patients with CD (CD Activity Index [CDAI] 220-450; high-sensitivity [hs]-C-reactive protein [CRP] ?3 mg/L) received double-blind adalimumab 160/80 mg or 80/40 mg at weeks 0/2, followed by 40 mg at weeks 4 and 6. An open-label extension period occurred from weeks 8-26; patients received 40 mg adalimumab every other week. Serum adalimumab concentration and change from baseline in fecal calprotectin (FC) were measured during the double-blind period. Clinical remission (CDAI <150), response (decrease in CDAI ?70 points from baseline), and change from baseline in hs-CRP were assessed through week 26. Nonresponder imputation was used for missing categorical data and last observation carried forward for missing hs-CRP/FC values. No formal hypothesis was tested. Adverse events were monitored. RESULTS:Mean adalimumab serum concentrations during the induction phase were 13.9-18.1 µg/mL (160/80 mg group) and 7.5-9.5 µg/mL (80/40 mg group). During the double-blind period, higher remission/response rates and greater reductions from baseline in hs-CRP and FC were observed with adalimumab 160/80 mg compared to that with 80/40 mg. Adverse event rates were similar among all treatment groups. CONCLUSIONS:Adalimumab serum concentrations in Chinese patients with CD were comparable to those observed previously in Western and Japanese patients. Clinically meaningful remission rates and improvement in inflammatory markers were achieved with both dosing regimens; changes occurred rapidly with adalimumab 160/80 mg induction therapy. No new safety signals were reported.
| S-EPMC4863049 | biostudies-literature
Project description:Although genetic polymorphisms in NOD2 (nucleotide-binding oligomerization domain-containing 2) have been associated with the pathogenesis of Crohn's disease (CD), little is known regarding the role of wild-type (WT) NOD2 in the gut. To date, most murine studies addressing the role of WT Nod2 have been conducted using healthy (ileitis/colitis-free) mouse strains. Here, we evaluated the effects of Nod2 deletion in a murine model of spontaneous ileitis, i.e., the SAMP1Yit/Fc (SAMP) strain, which closely resembles CD. Remarkably, Nod2 deletion improved both chronic cobblestone ileitis (by 50% assessed, as the % of abnormal mucosa at 24 wks of age), as well as acute dextran sodium sulfate (DSS) colitis. Mechanistically, Th2 cytokine production and Th2-transcription factor activation (i.e., STAT6 phosphorylation) were reduced. Microbiologically, the effects of Nod2 deletion appeared independent of fecal microbiota composition and function, assessed by 16S rRNA and metatranscriptomics. Our findings indicate that pharmacological blockade of NOD2 signaling in humans could improve health in Th2-driven chronic intestinal inflammation.
| S-EPMC5433921 | biostudies-literature
Project description:Microbial dysbiosis has been suggested to be involved in the pathogenesis of Crohn's disease (CD); however, many studies of gut microbial communities have been confounded by environmental and patient-related factors. In this study, the microbial flora of fecal samples from 19 children newly diagnosed with CD and 21 age-matched controls were analyzed using high-throughput sequencing to determine differences in the microbial composition between CD patients and controls. Analysis of the microbial composition of specific bacterial groups revealed that Firmicutes percentages were significantly lower in CD patients than in controls and that this was due largely to changes in the class Clostridia. Bacteroidetes and Proteobacteria percentages were higher and significantly higher in CD patients than in controls, respectively. Both the detection frequencies of Bacteroidetes and Firmicutes correlated (positively and negatively, respectively) with the calculated pediatric Crohn's disease activity index scores of patients. Upon further analysis, differences in the microbial compositions of patients with mild disease and moderate to severe disease were identified. Our findings indicate that a combination of different bacterial species or a dynamic interplay between individual species is important for disease and is consistent with the dysbiosis hypothesis of CD.
| S-EPMC3457451 | biostudies-literature
Project description:The efficacy of adalimumab in inducing and maintaining remission in children with moderately to severely active Crohn's disease was shown in the IMAgINE 1 trial (NCT00409682). As per protocol, nonresponders or patients experiencing flare(s) on every other week (EOW) maintenance dosing could escalate to weekly dosing; we aimed to determine the therapeutic benefits of weekly dose escalation in this subpopulation.Week 52 remission and response rates were assessed in patients who escalated to weekly dosing from their previous EOW schedule, which was according to randomized treatment dose (higher dose [HD] adalimumab [?40 kg, 40 mg EOW; <40 kg, 20 mg EOW] or lower dose [LD; ?40 kg, 20 mg EOW; <40 kg, 10 mg EOW]). Adverse events were reported for patients remaining on EOW dosing and patients receiving weekly dosing.Escalation to weekly dosing occurred in 48/95 (50.5%) patients randomized to LD and 35/93 (37.6%) patients randomized to HD adalimumab (P = 0.076). Week 52 remission and response rates were 18.8% and 47.9% for patients receiving LD adalimumab weekly and 31.4% and 57.1% for patients receiving HD adalimumab weekly, respectively (LD versus HD, P = 0.19 for remission; P = 0.41 for response). Adverse event rates were similar for patients receiving EOW and weekly adalimumab.Weekly adalimumab dosing was clinically beneficial for children with Crohn's disease who experienced nonresponse or flare on EOW dosing. No increased safety risks were observed with weekly dosing.
| S-EPMC4794130 | biostudies-literature
Project description:Antimicrobial peptides, including defensins, are essential effectors in host defence and in the maintenance of immune homeostasis. Clinical studies have linked the defective expression of both ?- and ?-defensin to the reduced killing of certain microorganisms by the intestinal mucosa of patients suffering from ileal and colonic Crohn's disease (CD), respectively. Only recently have the events leading to defective expression of defensins in CD been further elucidated, and are discussed herein. These events may account for CD-associated alterations in the microbiome and may subsequently precipitate the development of granulomatous inflammatory lesions in genetically-predisposed patients. We also address how these discoveries may pave the way for the development of a molecular medicine aimed at restoring gut barrier function in CD.
| S-EPMC3040328 | biostudies-literature
Project description:BACKGROUND:Paneth cell dysfunction has been implicated in a subset of Crohn's disease (CD) patients. We previously stratified clinical outcomes of CD patients by using Paneth cell phenotypes, which we defined by the intracellular distribution of antimicrobial proteins. Animal studies suggest that Paneth cells shape the intestinal microbiome. However, it is unclear whether Paneth cell phenotypes alter the microbiome complexity in CD subjects. Therefore, we analyzed the correlation of Paneth cell phenotypes with mucosal microbiome composition and ileal RNA expression in pediatric CD and noninflammatory bowel disease (non-IBD) patients. METHODS:Pediatric CD (n = 44) and non-IBD (n = 62) patients aged 4 to 18 were recruited prior to routine endoscopic biopsy. Ileal mucosal samples were analyzed for Paneth cell phenotypes, mucosal microbiome composition, and RNA transcriptome. RESULTS:The prevalence of abnormal Paneth cells was higher in pediatric versus adult CD cohorts. For pediatric CD patients, those with abnormal Paneth cells showed significant changes in their ileal mucosal microbiome, highlighted by reduced protective microbes and enriched proinflammatory microbes. Ileal transcriptome profiles showed reduced transcripts for genes that control oxidative phosphorylation in CD patients with abnormal Paneth cells. These transcriptional changes in turn were correlated with specific microbiome alterations. In non-IBD patients, a subset contained abnormal Paneth cells. However, this subset was not associated with alterations in the microbiome or host transcriptome. CONCLUSION:Paneth cell abnormalities in human subjects are associated with mucosal dysbiosis in the context of CD, and these changes are associated with alterations in oxidative phosphorylation, potentially in a feedback loop. FUNDING:The research was funded by Helmsley Charitable Trust (to T.S. Stappenbeck, R.J. Xavier, and D.P.B. McGovern), Crohn's and Colitis Foundation of America (to N.H. Salzman, T.S. Stappenbeck, R.J. Xavier, and C. Huttenhower), and Doris Duke Charitable Foundation grant 2014103 (to T.C. Liu).
| S-EPMC5033844 | biostudies-literature
Project description:ObjectiveTo evaluate the efficacy of adalimumab in the healing of draining fistulas in patients with active Crohn's disease (CD).DesignA phase III, multicentre, randomised, double-blind, placebo controlled study with an open-label extension was conducted in 92 sites.PatientsA subgroup of adults with moderate to severely active CD (CD activity index 220-450) for >or=4 months who had draining fistulas at baseline.InterventionsAll patients received initial open-label adalimumab induction therapy (80 mg/40 mg at weeks 0/2). At week 4, all patients were randomly assigned to receive double-blind placebo or adalimumab 40 mg every other week or weekly to week 56 (irrespective of fistula status). Patients completing week 56 of therapy were then eligible to enroll in an open-label extension.Main outcome measuresComplete fistula healing/closure (assessed at every visit) was defined as no drainage, either spontaneous or with gentle compression.ResultsOf 854 patients enrolled, 117 had draining fistulas at both screening and baseline (70 randomly assigned to adalimumab and 47 to placebo). The mean number of draining fistulas per day was significantly decreased in adalimumab-treated patients compared with placebo-treated patients during the double-blind treatment period. Of all patients with healed fistulas at week 56 (both adalimumab and placebo groups), 90% (28/31) maintained healing following 1 year of open-label adalimumab therapy (observed analysis).ConclusionsIn patients with active CD, adalimumab therapy was more effective than placebo for inducing fistula healing. Complete fistula healing was sustained for up to 2 years by most patients in an open-label extension trial.
| S-EPMC2689393 | biostudies-literature
Project description:BackgroundPYRAMID was an international multicenter, noninterventional, postmarketing registry assessing long-term safety and effectiveness of adalimumab (Humira), as used in routine clinical practice.MethodsAdult patients with moderately to severely active Crohn's disease with or without prior adalimumab experience were enrolled in the registry and followed for up to 6 years. Effectiveness measurements included the Physician's Global Assessment (PGA, a composite of Harvey Bradshaw Index [HBI] and rectal bleeding score), clinical remission (HBI < 5), Short Inflammatory Bowel Disease Questionnaire (SIBDQ), and Work Productivity and Activity Impairment (WPAI) questionnaire. Data were reported for adalimumab-naïve patients and analyzed by baseline immunomodulator use and disease duration.ResultsThis study evaluated 2057 adalimumab-naïve patients. Mean PGA improved from 7.5 (baseline) to 3.9 (year 1) and 3.3 (year 6). The proportion of patients in HBI remission increased from 29% (573 of 1969; baseline) to 68% (900 of 1331; year 1) and 75% (625 of 831; year 6). Patients stratified by baseline immunomodulator use had similar HBI remission rates; patients with disease duration <2 years achieved numerically higher HBI remission rates than patients with longer disease duration. Patient-reported SIBDQ and WPAI scores improved at year 1; all WPAI subscore improvements were clinically meaningful (?7% point change) at year 1 and maintained through year 6. Serious infections were reported in 11.1% of patients; incidence rates of malignancies, lymphoma, and demyelinating disorders were low.ConclusionAdalimumab therapy, as used in routine clinical practice, improved physician-reported and patient-reported disease outcomes and remission rates for up to 6 years. No new safety signals were observed.
| S-EPMC6701510 | biostudies-literature