Pooled analysis of the comparative efficacy between tacrolimus and infliximab for ulcerative colitis.
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ABSTRACT: Background
Acute moderate-to-severe steroid-refractory ulcerative colitis (UC) has a poor prognosis and requires optimal rescue therapy. A pooled analysis was conducted to assess tacrolimus and infliximab (IFX) as rescue agents in patients with moderate-to-severe and steroid-refractory UC.Methods
A literature search identified studies that investigated tacrolimus and IFX in moderate-to-severe steroid-refractory patients with UC. The primary outcome was short-term clinical response to treatment, including the remission and response rates. Secondary outcomes included the rates of colectomy at 3 months and adverse events rate.Results
A total of 6 studies comprising 438 cases were eligible for inclusion. The pooled analysis showed that the short-term clinical response rate, clinical remission rate, and 3-month colectomy rate were 72.1%, 52.4%, and 10.1%, respectively, for those receiving tacrolimus, and 76.9%, 48.8%, and 12.4%, respectively, for those receiving IFX. No significant difference was, however, seen for tacrolimus compared with IFX with regard to clinical remission rate (odds ratio [OR] =1.08, 95% confidence interval [CI] = 0.77-1.49, P?=?.67), clinical response rate (OR?=?0.92, 95% CI?=?0.63-1.34, P?=?.66), and 3-month colectomy rate (OR?=?0.86, 95% CI?=?0.39-1.93, P?=?.72). More adverse events were, however, observed in the Tac group (OR?=?2.16, 95% CI?=?1.25-3.76, P?=?.006).Conclusions
Our meta-analysis suggested that both tacrolimus and IFX appeared to be effective and safe for the rescue therapy of moderate-to-severe active UC and steroid-refractory UC. Therefore, tacrolimus is another choice for these patients.
SUBMITTER: Liu YJ
PROVIDER: S-EPMC6133612 | biostudies-literature | 2018 Aug
REPOSITORIES: biostudies-literature
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Project description:BackgroundPositioning infliximab (IFX), cyclosporine and tacrolimus (TAC) for treating ulcerative colitis (UC) is in great debate.MethodsA literature search identified studies that investigated IFX vs. cyclosporine or IFX vs TAC in UC patients. Short-term remission, short-term, 1-year and 3-year colectomy rate were employed as primary end-points to assess efficacy. Odds ratios (ORs) with 95% confidence intervals (CIs) were analyzed.ResultsOverall, 15 studies comprised 596 patients in IFX group and 866 in calcineurin inhibitors group (644 received cyclosporine and 222 received TAC). No significant difference was seen between IFX and calcineurin inhibitors with regard to short-term remission. IFX led to a lower short-term (OR: 0.59, 95% CI: 0.43-0.82, P:.001), 1-year (OR: 0.53, 95% CI: 0.38-0.73, P < .001), 3-year colectomy (OR: 0.41, 95% CI: 0.20-0.84, P:.02) than calcineurin inhibitors. IFX led to a lower short-term (OR: 0.51, 95% CI: 0.36-0.71, P < .001), 1-year (OR: 0.53, 95% CI: 0.37-0.74, P:.003) colectomy and a trend of lower 3-year colectomy (OR: 0.49, 95% CI: 0.22-1.06, P:.07) than cyclosporine while no significant difference was seen between IFX and TAC. Results of network meta-analysis showed that the order was cyclosporine, TAC and IFX from high rate to low with regard to short-term and 1-year colectomy.ConclusionIFX treatment leads to a lower short-term, 1-year colectomy rate and a trend of lower 3-year colectomy rate in UC patients than cyclosporine while no significant difference is seen between IFX and TAC. TAC may be superior than cyclosporine with regard to efficacy based on indirect comparisons. Randomized trials with fixed protocol are warranted to identify the optimal medical strategy in patients with UC.
| S-EPMC7598782 | biostudies-literature
Project description:Background & aimsWith several options available for patients with moderate-severe ulcerative colitis (UC), rapidity of symptom resolution could be an important differentiator. We compared the efficacy and speed of onset of action of infliximab vs golimumab induction therapy using patient-level data from phase 3 trials (ACT-1, ACT-2, and PURSUIT-SC).MethodsWe compared differences in proportions of patients who achieved the composite outcome of a rectal bleeding score=0 and stool frequency score ?1 (patient-reported outcome 2 remission) at weeks 2 and 6 of treatment with standard-dose infliximab vs golimumab using logistic generalized estimating equation. Overall efficacy for inducing clinical remission (Mayo clinic score <3) was compared using logistic regression. Analyses were adjusted for sex, disease extent, baseline clinical and endoscopic severity, C-reactive protein, albumin, body weight and concomitant medications (immunomosuppressives, corticosteroids, and 5-aminsalicylates).ResultsTrial populations were similar and no differences were observed among the placebo groups in the studies. A significantly higher proportion patients treated with infliximab than golimumab achieved patient-reported outcome 2 remission at week 2 (35% vs 30%; adjusted odds ratio [OR], 1.71; 95% CI, 1.15-2.55) and at week 6 (50.0% vs 38.9%; adjusted OR, 2.0; 95% CI, 1.40-2.94). Infliximab-treated patients were also significantly more likely to achieve clinical remission than golimumab-treated patients (adjusted OR, 3.01; 95% CI, 1.95-4.70), with consistent findings in patients with moderate or severe UC.ConclusionsBased on a patient-level analysis of data from phase 3 trials, infliximab resolves symptoms more rapidly and has greater efficacy for inducing remission than golimumab in patients with moderate-to-severe UC.
| S-EPMC6858937 | biostudies-literature
Project description:PURPOSE: Infliximab, a monoclonal antibody, is approved for the treatment of inflammatory diseases at doses that depend on the patient disease population. It was the aim of this study to evaluate its population pharmacokinetics in patients with moderately to severely active ulcerative colitis and characterize patient covariates that affect its disposition in this population. METHODS: Information collected from 482 patients in two randomized, double-blind, placebo-controlled international studies were analyzed using NONMEM. RESULTS: A two-compartment, population pharmacokinetic model described the serum infliximab concentration-time data. Population pharmacokinetic estimates (typical value +/- standard error), based on the final covariate model, were clearance (CL: 0.407 +/- 0.0103 L/day), apparent volumes of distribution in the central (V(1): 3.29 +/- 0.0679 L) and peripheral (V(2): 4.13 +/- 0.16 L) compartments, and intercompartment clearance (Q: 7.14 +/- 0.489 L/day). Infliximab exhibited interindividual variability for CL and V(1) of 37.7% and 22.1%, respectively. Infliximab t(1/2) is approximately 14 days. Covariate analysis showed that V(1) increased as body weight increased, and CL was higher in patients who developed antibodies to infliximab. An additional novel covariate, serum albumin concentration, was found to be inversely and strongly related to infliximab clearance in this population. CONCLUSIONS: The disposition of infliximab in patients with moderately to severely active ulcerative colitis, unlike in rheumatoid arthritis, was not affected by coadministration of immunomodulators and corticosteroids but was related to formation of antibodies to infliximab and, notably, to serum albumin levels.
| S-EPMC2778780 | biostudies-other
Project description:BackgroundReal-world comparative benefits and risks of infliximab (IFX) and adalimumab (ADA) in patients with ulcerative colitis (UC) are unclear.AimTo evaluate the comparative effectiveness and safety of IFX and ADA in patients with UC who were new users of anti-TNF agents.MethodsUsing an administrative claims database (Optum Labs Data Warehouse), we identified patients who received first anti-TNF (IFX, ADA) prescription after a 12-month period without any anti-TNF treatment (baseline), and with a minimum 6-month follow-up after anti-TNF initiation. Primary outcome measures were: all-cause and UC-related hospitalisation, abdominal surgery, corticosteroid use >60 days after starting anti-TNF, and serious infections. We performed 2:1 propensity-score matched Cox proportional hazard analysis, and inverse probability-of-treatment weight (IPTW) analysis, accounting for healthcare utilisation, comorbidities and use of UC-related medication.ResultsWe included 1400 new users of anti-TNF agents (age, 43 ± 15 years; 52% males), from 2006 to 2014. On propensity-score matched analysis, there was no significant difference in the risk of UC-related hospitalisation [IFX vs. ADA; adjusted hazard ratio (aHR), 1.04; 95% confidence interval (CI) 0.71-1.51], corticosteroid use (aHR, 0.85; 95% CI, 0.68-1.06) and serious infections (aHR, 0.62; 95% CI, 0.29-1.34) between IFX- and ADA-treated patients; the number of surgical events was very small. On IPTW analysis, risk of corticosteroid use was significantly lower in IFX - as compared to ADA - treated patients (aHR, 0.82; 95% CI, 0.68-0.99). Results were stable on multiple sensitivity analyses.ConclusionsIn a large retrospective cohort of patients with UC who were new users of anti-TNF agents, IFX-treated patients may have lower corticosteroid use than ADA-treated patients, but risk of hospitalisation and serious infections were comparable.
| S-EPMC4917292 | biostudies-literature
Project description:Background: Data on serum infliximab concentrations during induction in pediatric ulcerative colitis are limited. The study aim is to evaluate the relationship between serum infliximab concentrations during induction and short-term clinical remission in children with ulcerative colitis. Methods: We carried out a prospective, multi-center cohort study in pediatric patients with ulcerative colitis. Serum infliximab concentrations were collected at peak dose #1, week 1, trough pre-dose #2, and trough pre-dose #3. Infliximab dosing was left to investigator discretion. Clinical remission was defined by pediatric ulcerative colitis activity index <10 at week 8. Results: Twenty-four of thirty-four subjects (71%) achieved clinical remission at week 8. The median infliximab concentrations were 33.0 μg/mL (interquartile range: 26.5-52.1 μg/mL) pre-dose #2 and 22.5 μg/mL (interquartile range:15.9-32.3 μg/mL) pre-dose #3. Trough pre-dose #2 infliximab concentration yielded area under receiver operator characteristic curve 0.7, 95% CI: 0.5-0.9 in predicting week 8 clinical remission; a cut-off of 33.0 μg/mL yielded 62.5% sensitivity, 66.7% specificity. Trough pre-dose #3 infliximab concentrations were lower for subjects <10 years compared to ≥ 10 years [median 15.9 μg/mL, interquartile range (IQR) 8.5-21.8 μg/mL vs. 27.7 μg/mL, IQR 17.2-46.7 μg/mL, p = 0.01] and correlated with baseline weight (Spearman's rank correlation coefficient 0.45, p = 0.01). The median half-life following first IFX dose was 6.04 days (IQR 5.3-7.9 days). Conclusions: Infliximab concentrations ≥33 μg/mL prior to the second dose were associated with week 8 clinical remission. As young age and low body weight impact infliximab concentration, prospective studies with proactive adjustment in pediatric patients with ulcerative colitis should be carried out. Clinicians caring for children with UC should diligently adjust and monitor infliximab to optimize response.
| S-EPMC8358797 | biostudies-literature
Project description:AimsThe therapeutic failure of infliximab therapy in patients with ulcerative colitis remains a challenge even 2 decades after its approval. Therapeutic drug monitoring (TDM) has shown value during maintenance therapy, but induction therapy has still not been explored. Patients may be primary nonresponders or underexposed with the standard dosing regimen. We aimed to: (i) develop a population pharmacokinetic-pharmacodynamic model; (ii) identify the best exposure metric that predicts mucosal healing; and (iii) build an exposure-response (ER) model to demonstrate model-based dose finding during induction therapy with infliximab.MethodsData were retrospectively collected from a clinical database. A total of 583 samples, from 204 patients, was used to develop a population pharmacokinetic model to generate exposure metrics for subsequent ER modelling. A subset of 159 patients was used to develop a logistic regression ER model, describing the relationship between infliximab exposure and ordered transitions between Mayo endoscopic subscore (MES) 3, 2 and ≤1 (baseline to post-induction).ResultsA 1-compartment population pharmacokinetic model with interindividual and interoccasion variability was found to fit the data best. Covariates influencing exposure were C-reactive protein, albumin, baseline MES, fat-free mass, concomitant corticosteroid use and pancolitis. The cumulative area under the infliximab concentration-time curve until endoscopy (CAUCendoscopy ) was found to be the best exposure metric for predicting mucosal healing (baseline MES >1 and post-induction MES ≤1). The model predicted that 70% of patients will attain mucosal healing with infliximab administered at days 0, 14 and 42 and a target CAUCendoscopy of 3752 mg/L*day at day 84.ConclusionsTDM-based dose individualisation targeting CAUCendoscopy has the potential to improve the effectiveness of infliximab during induction therapy.
| S-EPMC6422726 | biostudies-literature
Project description:Ulcerative Colitis (UC) is an inflammatory bowel disease typically affecting the colon. Patients with active UC have elevated tumor necrosis factor (TNF) concentrations in serum and colonic tissue. Infliximab is a monoclonal antibody directed against TNF and binds with high affinity. Target-mediated drug disposition (TMDD) is reported for monoclonal antibodies meaning that their pharmacokinetics are affected by high target affinity. Here, a TMDD model is proposed to describe the interaction between infliximab and TNF in UC patients. Data from 20 patients with moderate to severe UC was used. Patients received standard infliximab induction therapy (5 mg kg-1) at week 0, followed by infusions at week 2 and 6. IFX, anti-drug antibodies and TNF serum concentrations were measured at day 0 (1 h after infusion), 1, 4, 7, 11, 14, 18, 21, 28 and 42. A binding model, TMDD model, and a quasi-steady state (QSS) approximation were evaluated using nonlinear mixed effects modeling (NONMEM). A two-compartment model best described the concentration-time profiles of infliximab. Typical clearance of infliximab was 0.404 L day-1 and increased with the presence of anti-drug antibodies and with lower albumin concentrations. The TMDD-QSS model best described the pharmacokinetic and pharmacodynamics data. Estimate for TNF baseline (Bmax was 19.8 pg mL-1 and the dissociation constant (Kss) was 13.6 nM. This model could eventually be used to investigate the relationship between suppression of TNF and the response to IFX therapy.
| S-EPMC6868113 | biostudies-literature
Project description:Background: Infliximab (IFX) is a potent therapeutic agent used for the treatment of conventional refractory ulcerative colitis (UC). However, the high non-response rate of IFX brings difficulties to clinical applications. In the context of proteomics research, our study of differentially expressed proteins (DEPs) is essential for non-response to IFX in UC patients and provides powerful insights into underlying drug resistance mechanisms. Methods: A total of 12 UC patients were divided into responders to IFX (UCinfG), non-responders to IFX (UCinfL), severe UC (UCsevere) without an IFX treatment history, and mild UC (UCmild) without an IFX treatment history. Subsequently, DEPs were identified from intestinal biopsy tissue between responders and non-responders to IFX by a label-free proteomic quantitative approach, and the general principle of functional protein screening was followed to deduce the potential drug targets and predictors for non-response to IFX in UC patients. Meanwhile, these targets excluded DEPs caused by the severity of inflammation for the first time. The differential expressions of candidate protein targets were validated at the gene sequence level using GEO2R analysis of the GEO database and qRT-PCR in some independent cohorts. Results: A total of 257 DEPs were screened out by mass spectrometry between UCinfG and UCinfL groups, excluding 22 DEPs caused by the severity of inflammation, and compared and verified at the gene sequence level in the Gene Expression Omnibus (GEO) database. Finally, five DEPs, including ACTBL2 (Q562R1), MBL2 (P11226), BPI (P17213), EIF3D (O15371), and CR1 (P17927), were identified as novel drug targets and predictive biomarkers for non-response to IFX. The drug targets were confirmed in the GEO database of the microarray results from three independent cohorts of 70 human intestinal biopsies and validated in qPCR data from 17 colonic mucosal biopsies. Among them, CR1 might affect the activation of the lectin pathway via complement-coated bacteria to play an opsonizing role in inflammation-related pathways closely associated with non-responders to IFX. Conclusion: This is the first report of proteomics analysis for the identification of novel drug targets based on intestinal biopsy tissue, which is significant for hypotheses for mechanistic investigation that are responsible for non-response to IFX and the development of clinical new pharmaceutical drugs.
| S-EPMC9234463 | biostudies-literature
Project description:Infliximab, an anti-TNFa monoclonal antibody, is an effective treatment for ulcerative colitis (UC) inducing over 60% of patients to respond to treatment. Consequently, about 40% of patients do not respond. This study analyzed mucosal gene expression from patients enrolled in ACT1 to provide a predictive response signature for infliximab treatment. Keywords: predictive response signature
2009-08-25 | GSE12251 | GEO
Project description:Background/aimsTacrolimus is effective for refractory ulcerative colitis in adults, while data for children is sparse. We aimed to evaluate the effectiveness and safety of tacrolimus for induction and maintenance therapy in Japanese children with ulcerative colitis.MethodsWe retrospectively reviewed the multicenter survey data of 67 patients with ulcerative colitis aged < 17 years treated with tacrolimus between 2000 and 2012. Patients' characteristics, disease activity, Pediatric Ulcerative Colitis Activity Index (PUCAI) score, initial oral tacrolimus dose, short-term (2-week) and long-term (1-year) outcomes, steroid-sparing effects, and adverse events were evaluated. Clinical remission was defined as a PUCAI score < 10; treatment response was defined as a PUCAI score reduction of ≥ 20 points compared with baseline.ResultsPatients included 35 boys and 32 girls (median [interquartile range] at admission: 13 [11-15] years). Thirty-nine patients were steroid-dependent and 26 were steroidrefractory; 20 had severe colitis and 43 had moderate colitis. The initial tacrolimus dose was 0.09 mg/kg/day (range, 0.05-0.12 mg/kg/day). The short-term clinical remission rate was 47.8%, and the clinical response rate was 37.3%. The mean prednisolone dose was reduced from 19.2 mg/day at tacrolimus initiation to 5.7 mg/day at week 8 (P< 0.001). The adverse event rate was 53.7%; 6 patients required discontinuation of tacrolimus therapy.ConclusionsTacrolimus was a safe and effective second-line induction therapy for steroid-dependent and steroid-refractory ulcerative colitis in Japanese children.
| S-EPMC6821948 | biostudies-literature