Infliximab In Colitis Research Articles

PGI2 Quantitative Evaluation to Efficacy and Safety of Biosimilar of Infliximab in Inflammatory Bowel Diseases: A Bayesian Network Meta-Analysis of Randomized Controlled Trials

Because there are no clinical trials conducted to compare the safety and efficacy of the biosimilar of infliximab to the previous standard of care, we performed a Bayesian Network Meta-Analysis of randomized controlled trials (RCTs) to evaluate the efficacy and safety of Biosimilar of infliximab in patients with IBD. Electronic searches of PubMed (Medline), EMBASE (Ovid), Scopus, CENTRAL, as well as online material were performed until July 2019 to identify all RCTs evaluating the efficacy or safety of biosimilar versus infliximab and originator infliximab versus placebo in patients with IBD. The outcomes were the pooled rates of clinical response and adverse events. A Bayesian Network Meta-Analysis approach was performed. Five RCTs reporting outcomes in 1,745 patients treated with either biosimilar or originator infliximab were identified. The pooled rates of clinical response among IBD using infliximab and originator infliximab in respect to placebo were 4.19 (95% confidence interval (CI) = 2.49–7.04) and 3.97 (95% CI = 2.374–6.64), respectively. Adverse events did not differ significantly among infliximab and originator infliximab in respect to placebo. No significant difference was found between biosimilar and originator Infliximab in respect to the placebo in terms of efficacy and safety, supporting its use in the treatment of IBD.

Bayes‐based dosing of infliximab in inflammatory bowel diseases: Short‐term efficacy

Therapeutic drug monitoring of infliximab can guide clinical decisions in patients with loss of response and in those who can benefit from a de-intensification. The aim of this study was to determine the impact of therapeutic drug monitoring combined with Bayesian forecasting methodology on clinical response in a real-world dataset of patients suffering from inflammatory bowel disease. We performed a single-centre prospective study with one-group pre-test/post-test design in 108 adult inflammatory bowel disease patients treated with model-based dosing of infliximab maintenance treatment. We recorded clinical activity scores (Harvey-Bradshaw index and partial Mayo) and inflammatory biomarkers per patient. The initial infliximab regimen was maintained in 49 (45.4%) patients and was adjusted in 59 (54.6%) patients (34 treatment intensifications, 9 de-intensifications and 16 treatment discontinuations or therapy replacements). The median time from intervention to index measurement was 126 (103-160) days. The overall proportion of patients in clinical remission increased from 65.7% to 80.4% (P < .0001) and the median infliximab trough concentrations increased from 3.21 (0.99-5.45) to 5.13 mg/L (3.57-6.53) (P < .0001). In the intensified group, the remission rate increased from 35.3% to 61.8% (P = .001) and the percentage of patients in clinical remission or with mild symptoms increased from 76.5% to 94.1%. In the de-intensification cohort, no patients experienced an increase in the Harvey-Bradshaw index or partial Mayo scores, and all patients maintained an infliximab trough concentration of >5 mg/L. In our cohort of inflammatory bowel disease patients, Bayes-based optimized dosing improved the short-term efficacy of infliximab treatment.

P349 Infliximab in inflammatory bowel disease: Is premedication necessary?

Abstract Background The use of infliximab (IFX) in inflammatory bowel disease (IBD) has been associated with a 1–6% risk of infusion reactions. The usefulness of premedication with corticosteroids, paracetamol and/or antihistamines is controversial. The aim of this study is to assess, in IBD patients on IFX, whether there are differences in secondary reactions to the infusion between those who use premedication or not. Methods A retrospective cohort study was performed identifying patients with a diagnosis of IBD who received IFX at a tertiary centre in Santiago-Chile, since 2009. Acute reactions were defined as those that occurred in the first 24 h post-infusion and late reactions for more than 24 h. Infusion reactions were classified as mild, moderate and severe. Descriptive and association statistics were used (χ 2; p &amp;lt; 0.05). Results Sixty-four patients were included with 1,263 infusions in total, 52% men (characteristics in Table 1). Median infusions per patient were 22 (2–66). All induction infusions were administered with premedication and in maintenance, 57% of them. Premedication was given with hydrocortisone, chlorphenamine and paracetamol. Flow chart according to premedication use or not is shown in Figure 1. In the maintenance group, there were 10/718 (1.4%) infusion reactions with premedication and 3/358 (0.8%) without it, non-significant differences (p = 0.432). In the induction group, there were 8/187 (4%) infusion reactions, significantly higher when compared with both maintenance groups (Figure 2). Conclusion In this cohort, premedication use in maintenance phase was not effective at reducing the rate of infusion reactions due to IFX. These results suggest that premedication would not be necessary during maintenance.

718 The Experience of and Access to Rapid Infliximab Infusions at an Academic Tertiary Medical Center

INTRODUCTION: Infliximab (IFX) induces and maintains remission in patients with inflammatory bowel disease (IBD) and rheumatologic disease (RD). It is time-intensive, which places great burden on patients and health systems. Rapid infusions (RI) reduce infusion time from 2 hours to 1 hour, theoretically can alleviate this burden and enhance access to care defined by effectiveness (safety), availability (capacity) and utilization (patient characteristics). We aimed to describe the RI experience at our center, with the hypothesis that RI enhance access to care for all patients regardless of indication for IFX. METHODS: All patients treated with IFX for IBD or RD at our outpatient infusion center from February 2016 to August 2017 were included. Demographic and clinical information including IFX indication, history of infusion reaction, use of pre-medication, number of standard and RI were collected. RESULTS: There were 348 patients, 212 (60.92%) were female, 193 (55.5%) had IBD and 143 (41.1%) had RD. In terms of safety, 21 (6%) had a history of infusion reaction, 7.8% with IBD and 3.5% with RD (P = 0.1127). 33.6% were premedicated for infusions. For only RD, a lower number receiving RI received pre-medications (P = 0.0002). The history of infusion reaction was 5.7% in the RI group and 6.3% in the standard infusion group (P = 1.000). Only 2 patients required switch back to standard infusion after reaction with RI. In terms of capacity, 40% of patients were converted to RI during the study period. This resulted in a 16.1% decrease in average daily infusion time and 9.8% increase in average daily available scheduled chair time or an additional 261.2 (±19.7) minutes per day (P = 0.72). In terms of patient characteristics, a larger number of RD patients received RI versus IBD patients (P = 0.0261). Only for the RD group a lower number of patients receiving RI were female (P = 0.0491). For patients with RD and IBD, a lower number of patients receiving RI versus standard infusions were on public insurance (P = 0.011 and P = 0.0151) and patients receiving RI had been on IFX for a longer period of time (P = 0.0002, P &lt; 0.0001). CONCLUSION: RI were safe and increased available chair time. There were differences in patient characteristics: females with RD and public insurance patients were less likely to receive RI. Future directions include creation of a prospective registry and patient quality of life surveys to understand if implicit bias against disease, gender, socioeconomic status, or other factors impact access to RI.

776 Accelerated Infliximab Infusion Protocol for Inflammatory Bowel Disease: A Safety and Cost-Effectiveness Study in an Asian Tertiary Center

INTRODUCTION: The recommended infusion time for infliximab for inflammatory bowel disease (IBD) is 2 hours or more. Time spent on receiving infliximab infusions in the hospital disrupts school and work activities. Significant nursing time is also spent which increases healthcare costs. Shortening infliximab infusion to over 1 hour has been shown to be safe and has the potential to decrease time spent in hospital. This study aims to determine the safety and effectiveness of this accelerated infliximab infusion protocol in patients with IBD in Southeast Asia. METHODS: We conducted a retrospective study on patients with Crohn's disease (CD) and ulcerative colitis (UC), who received infliximab from September 2018 to May 2019 at Singapore General Hospital. Patients on stable maintenance infliximab were offered the accelerated protocol if they had tolerated ≥4 infliximab infusions without reactions. The need for pre-medications was determined by the prescribing physician. Primary endpoint was infusion-related reaction rate and secondary endpoints were cost and time saved per infusion. RESULTS: A total of 187 infusions were administered to 57 patients (53 CD, 4 UC). The mean age was 52.0 ± 17.0 years and 61.4% of the subjects were male. Out of the 57 patients, 22 of them received the accelerated infusion protocol with a total of 86 1-h infusions. Three reactions (1 immediate, 2 delayed) were observed during the 1-h infusions and were reverted back to the standard 2-h infusion subsequently. However, this was not found to be statistically significant after adjustment for age, sex, administration of pre-medications or types of disease. The median time spent per infusion in the hospital for the accelerated infusion protocol was significantly reduced compared to for the standard infusion (138 ± 26 minutes vs. 216 ± 26 minutes; P &lt; 0.05). This improvement amounts to an estimate of 65 minutes returned to the patient for normal activities outside of the hospital per infusion. There was also a reduction in nursing time and cost (S$ 42.9 per infusion and 46.4% relative cost reduction) to the hospital. CONCLUSION: The accelerated infliximab infusion protocol is safe in our cohort of IBD patients. It also results in a decrease in in-hospital time for patients and improves the efficiency of healthcare delivery.

Infliximab in inflammatory bowel disease.

Anti-tumor necrosis factor (TNF) therapy has revolutionized the medical treatment of the inflammatory bowel diseases (IBD), Crohn’s disease (CD), and ulcerative colitis. Twenty years ago, infliximab became the first anti-TNF agent approved for IBD. Data from randomized controlled trials, large observational cohort studies, postmarketing registries, and meta-analyses show that infliximab is a very effective treatment for moderate to severe IBD with a good safety profile. Infliximab has been also used to treat pouchitis following an ileal pouch–anal anastomosis (IPAA) after restorative proctocolectomy and to prevent postoperative recurrence following an ileocolonic resection for CD with good results. Nevertheless, up to 30% of patients show no clinical benefit following induction and up to 50% lose response over time. Both these unwanted outcomes can be largely explained by inadequate drug concentrations and frequently by the development of antibodies to infliximab. Loss of response can be managed efficiently and often prevented by applying therapeutic drug monitoring. Recently, the first biosimilars of infliximab have been approved and are utilized in clinical practice with comparable efficacy and safety with the originator. This review will mainly focus on the efficacy of infliximab in IBD.

Safety and Tolerability of Accelerated Infliximab Infusions in Patients With Inflammatory Bowel Disease.

Infliximab for inflammatory bowel disease (IBD) is FDA-approved to be administered 2 h or more. We adopted a new protocol to infuse infliximab over 1 h and in this study, we aimed to determine the safety of a 1-h infusion. This retrospective cohort included adult IBD patients who received infliximab between June and December 2017 and compared reaction rates of 1-h maintenance infusions to that of 2-h maintenance infusions. A total of 551 infusions were administered to 179 patients. The infusion groups demonstrated no significant differences in reaction rates. Infliximab infusion over 1 h is well-tolerated.

Infusion administration billing for vedolizumab and infliximab in inflammatory bowel disease

Aims: Increasing use of biologics has led to interest in treatment components with potential for cost savings. This study was aimed at comparing administration times and associated costs of infliximab and vedolizumab infusions for inflammatory bowel disease (IBD).Materials and methods: This study used claims data from the Symphony Health Integrated Dataverse to identify IBD patients using infliximab or vedolizumab between 20 May 2014 and 29 February 2016. Use of Current Procedural Terminology administration codes was evaluated and costs calculated using the 2016 Center for Medicare and Medicaid Services Physician Fee Schedule. Assessments included infusion times, associated costs, productivity loss using average wage estimates from the United States Bureau of Labor Statistics, and home infusion adoption.Results: A total of 10,051 infliximab and 3114 vedolizumab patients with first-hour claims were identified; 52.0% were female and 64.5% had Crohn’s disease. There were 48,377 infliximab first-hour claims (mean 4.8 infusions per patient); 46,462 (96.0%) had a second-hour claim. In comparison, there were 14,717 vedolizumab claims (mean 4.7 infusions per patient), with only 411 (2.8%) second-hour claims, resulting in vedolizumab cost savings of approximately $1.27 million. The difference in second-hour infusions resulted in 46,051 additional hours of productivity loss with infliximab, and lost wages averaging $1.18 million (range $0.68–$1.77 million).Limitations: Administration costs were inferred as charge costs and not directly assessed. Productivity loss assessed time spent on infusion only, and included a small proportion of patients beyond working age.Conclusions: Second-hour infusion billing was significantly lower with vedolizumab than with infliximab, corresponding to cost savings and reduced productivity loss.

Therapeutic Drug Monitoring is More Cost-Effective than a Clinically Based Approach in the Management of Loss of Response to Infliximab in Inflammatory Bowel Disease: An Observational Multicentre Study.

Empirical dose intensification and therapeutic drug monitoring [TDM] of infliximab [IFX] trough levels [ITLs] and antibody to infliximab [ATI] assays are recognized approaches for managing loss of response [LoR] in patients with inflammatory bowel disease [IBD]. The aim of the study was to compare these two interventions in a clinical setting, in terms of effectiveness and cost savings. Consecutive IBD patients experiencing LoR were clinically managed according to a TDM algorithm. A historical group of empirically treated patients, for whom sera for ITLs and ATI assays had been collected, served as the control group. Clinical outcomes 12 weeks after the therapeutic interventions were compared between the two groups. A cost-minimization analysis was performed to compare the economic impact of these two approaches. Ninety-six patients were enrolled prospectively and compared with 52 controls. The two cohorts were similar in characteristics and in the distribution of TDM results. In the prospective cohort, however, we observed less IFX dose escalations compared with in the controls [45% versus 71%, p = 0.003]. Also, more patients were switched to a different anti-TNFα in the prospective cohort than in the control cohort [25% versus 4%, p = 0.001]. The percentages of patients achieving a clinical response at 12 weeks were 52% and 54% for the prospective and control groups, respectively. By cost analysis, we estimated a savings of 15% if the TDM algorithm was applied. In our population, applying a TDM algorithm for LoR to IFX resulted in less dose escalations, without loss of efficacy, compared with empirical adjustment. In addition, the TDM approach was cost-effective.

Impact of Obesity on Short- and Intermediate-Term Outcomes in Inflammatory Bowel Diseases: Pooled Analysis of Placebo Arms of Infliximab Clinical Trials.

To assess whether obesity may affect natural history of inflammatory bowel diseases (IBD), we conducted an individual participant data (IPD) pooled analysis of placebo arms, using data from clinical trials of infliximab in IBD and using the Yale Open Data Access (YODA) Project. We obtained IPD from 4 placebo-controlled trials of infliximab in adults with IBD (ACCENT-I and ACCENT-II; ACT-1 and ACT-2). Patients were categorized into quartiles based on body mass index (BMI) or weight at time of trial entry. Primary outcome was clinical remission (Crohn's disease activity index [CDAI]<150, Mayo Clinic Score <3); secondary outcomes were clinical response and mucosal healing. Using multivariable logistic regression analysis, we compared association between quartiles of BMI (or weight) and achieving remission, after adjusting for sex, smoking, disease activity, and concomitant prednisone or immunomodulators. We included 575 placebo-treated patients (mean age 38 years, 51.6% males, 16% obese). Obesity was not associated with odds of achieving clinical remission (Q4 vs Q1: adjusted OR, 1.36; 95% CI, 0.65-2.89; P-value for trend = 0.57), clinical response (Q4 vs Q1: adjusted OR, 1.31; 95% CI, 0.61-2.81; P = 0.45), or mucosal healing remission (Q4 vs Q1: adjusted OR, 0.55; 95% CI, 0.12-2.34; P = 0.31). These results were consistent across strata based on disease type (CD and ulcerative colitis) and trial design (induction and maintenance therapy). Based on IPD pooled analysis of placebo arms, obesity does not significantly impact short- and intermediate-term clinical outcomes in patients with IBD. The impact of obesity on long-term patient-important outcomes like surgery and hospitalization merits evaluation.

The Experience with Biosimilars of Infliximab in Inflammatory Bowel Disease.

biosimilars are similar versions of existing innovator biologic agents but with distinct manufacturing processes. They were approved in inflammatory bowel disease (IBD) by extrapolation of indication from rheumatic diseases. As regulatory requirements for biosimilar approval focus on pre-clinical evidence of similarity rather than clinical data on efficacy, safety and immunogenicity, it is critical to review clinical evidence supporting their use in IBD in order to overcome reluctance from patients and clinicians alike. to review clinical studies using infliximab (IFX) biosimilars in IBD. we reviewed PubMed for original articles published up to July 1st 2017, reporting data on efficacy and/or safety of IFX biosimilars in IBD. 23 observational studies were found, 12 of them assessing switch from IFX originator to biosimilar and 17 assessing induction therapy with IFX biosimilar. Efficacy, safety and immunogenicity were compared, generally yielding similar results for originator and biosimilar IFX. So far only one randomized controlled trial assessed switching from originator to biosimilar IFX and it was not powered to show similarity in IBD. Ongoing trials are comparing IFX biosimilar and originator head to head in patients in remission, as well as switch versus reverse-switch. Current IBD clinical guidelines are discussed as well as future perspectives for biosimilars in IBD. observational studies seem to confirm biosimilarity in a real-world clinical setting. Current trials are expected to elucidate the remaining doubts about clinical biosimilarity.

Policy Options for Infliximab Biosimilars in Inflammatory Bowel Disease Given Emerging Evidence for Switching.

Biosimilars are becoming increasingly available internationally as patents expire on the originator biologic drugs they are intended to copy. Although substitution policies seen with generic drugs are being considered as a means to reduce expenditures on biologics, some biosimilars pose particular challenges in that the act of substitution may eventually lead to increased rates of therapeutic failure. As evidence requirements from regulators do not directly address this challenge, switch trials of biosimilars have emerged that may provide further answers. Using infliximab in inflammatory bowel disease as an example, we critically examine emerging evidence from two key switch trials (NOR-SWITCH and NCT020968610) and discuss the clinical and economic implications of these and what policy options may be most reasonable for payers. Options include reimbursing biosimilars for only newly diagnosed patients, using product-listing agreements to manage uncertainty, or using tiered co-payments or other incentives to promote biosimilar use.

Prediction of Individual Serum Infliximab Concentrations in Inflammatory Bowel Disease by a Bayesian Dashboard System.

Despite a robust exposure-response relationship of infliximab in inflammatory bowel disease (IBD), attempts to adjust dosing to individually predicted serum concentrations of infliximab (SICs) are lacking. Compared with labor-intensive conventional software for pharmacokinetic (PK) modeling (eg, NONMEM) dashboards are easy-to-use programs incorporating complex Bayesian statistics to determine individual pharmacokinetics. We evaluated various infliximab detection assays and the number of samples needed to precisely forecast individual SICs using a Bayesian dashboard. We assessed long-term infliximab retention in patients being dosed concordantly versus discordantly with Bayesian dashboard recommendations. Three hundred eighty-two serum samples from 117 adult IBD patients on infliximab maintenance therapy were analyzed by 3 commercially available assays. Data from each assay was modeled using NONMEM and a Bayesian dashboard. PK parameter precision and residual variability were assessed. Forecast concentrations from both systems were compared with observed concentrations. Infliximab retention was assessed by prediction for dose intensification via Bayesian dashboard versus real-life practice. Forecast precision of SICs varied between detection assays. At least 3 SICs from a reliable assay are needed for an accurate forecast. The Bayesian dashboard performed similarly to NONMEM to predict SICs. Patients dosed concordantly with Bayesian dashboard recommendations had a significantly longer median drug survival than those dosed discordantly (51.5 versus 4.6 months, P < .0001). The Bayesian dashboard helps to assess the diagnostic performance of infliximab detection assays. Three, not single, SICs provide sufficient information for individualized dose adjustment when incorporated into the Bayesian dashboard. Treatment adjusted to forecasted SICs is associated with longer drug retention of infliximab.

P186 OBESITY AND RESPONSE TO INFLIXIMAB IN PATIENTS WITH INFLAMMATORY BOWEL DISEASES: POOLED ANALYSIS OF INDIVIDUAL PARTICIPANT DATA FROM CLINICAL TRIALS

To assess whether obesity may affect response to infliximab, we conducted an individual participant data (IPD) pooled analysis using data from clinical trials of infliximab in inflammatory bowel diseases (IBD), using the Yale Open Data Access (YODA) Project. We analyzed IPD from 6 clinical trials of infliximab in adults or children with IBD (ACCENT-I and -II, SONIC, ACT-1 and -2, REACH). Patients were categorized into quartiles based on body mass index (BMI) or weight at time of trial entry. Primary outcome was clinical remission (Crohn’s disease activity index [CDAI]<150 or pediatric CDAI<10, Mayo Clinic Score <3); secondary outcomes were clinical response and mucosal healing. Using multivariable logistic regression analysis, association between quartiles of BMI (or weight) and achieving remission were analyzed, after adjusting for sex, smoking, disease activity, and concomitant prednisone and/or immunomodulators. We included 1399 infliximab-treated patients (mean age 36y, 52.1% males, 14% obese). Obesity was not associated with odds of achieving clinical remission (Q4 vs. Q1: adjusted OR, 0.94 [95% CI, 0.61–1.47], p-value for trend=0.97), clinical response (Q4 vs. Q1: adjusted OR, 0.84 [0.52–1.35], p=0.45) or mucosal healing remission (Q4 vs. Q1: adjusted OR, 1.13 [0.55–2.34], p=0.95) (Figure 1). These results were consistent across strata based on disease type (CD and ulcerative colitis), trial design (induction and maintenance therapy), and in adults and pediatric studies (Table 1). Based on IPD pooled analysis, obesity is not associated with inferior response to infliximab in patients with IBD. Future studies examining the association between obesity and fixed-dose therapies are warranted.

P183 IMPACT OF OBESITY ON SHORT- AND INTERMEDIATE-TERM OUTCOMES IN INFLAMMATORY BOWEL DISEASES: POOLED ANALYSIS OF PLACEBO ARMS OF INFLIXIMAB CLINICAL TRIALS

Background and aims To assess whether obesity may affect natural history of inflammatory bowel diseases (IBD), we conducted an individual participant data (IPD) pooled analysis of placebo arms, using data from clinical trials of infliximab in IBD and using the Yale Open Data Access (YODA) Project. Methods We obtained IPD from 4 placebo-controlled trials of infliximab in adults with IBD (ACCENT-I and ACCENT-II; ACT-1 and ACT-2). Patients were categorized into quartiles based on body mass index (BMI) or weight at time of trial entry. Primary outcome was clinical remission (Crohn's disease activity index [CDAI]<150, Mayo Clinic Score <3); secondary outcomes were clinical response and mucosal healing. Using multivariable logistic regression analysis, we compared association between quartiles of BMI (or weight) and achieving remission, after adjusting for sex, smoking, disease activity, and concomitant prednisone or immunomodulators. Results We included 575 placebo-treated patients (mean age 38 years, 51.6% males, 16% obese). Obesity was not associated with odds of achieving clinical remission (Q4 vs Q1: adjusted OR, 1.36; 95% CI, 0.65-2.89; P-value for trend = 0.57), clinical response (Q4 vs Q1: adjusted OR, 1.31; 95% CI, 0.61-2.81; P = 0.45), or mucosal healing remission (Q4 vs Q1: adjusted OR, 0.55; 95% CI, 0.12-2.34; P = 0.31). These results were consistent across strata based on disease type (CD and ulcerative colitis) and trial design (induction and maintenance therapy). Conclusions Based on IPD pooled analysis of placebo arms, obesity does not significantly impact short- and intermediate-term clinical outcomes in patients with IBD. The impact of obesity on long-term patient-important outcomes like surgery and hospitalization merits evaluation.

P186 OBESITY AND RESPONSE TO INFLIXIMAB IN PATIENTS WITH INFLAMMATORY BOWEL DISEASES: POOLED ANALYSIS OF INDIVIDUAL PARTICIPANT DATA FROM CLINICAL TRIALS

To assess whether obesity may affect response to infliximab, we conducted an individual participant data (IPD) pooled analysis using data from clinical trials of infliximab in inflammatory bowel diseases (IBD), using the Yale Open Data Access (YODA) Project. We analyzed IPD from 6 clinical trials of infliximab in adults or children with IBD (ACCENT-I and -II, SONIC, ACT-1 and -2, REACH). Patients were categorized into quartiles based on body mass index (BMI) or weight at time of trial entry. Primary outcome was clinical remission (Crohn’s disease activity index [CDAI]<150 or pediatric CDAI<10, Mayo Clinic Score <3); secondary outcomes were clinical response and mucosal healing. Using multivariable logistic regression analysis, association between quartiles of BMI (or weight) and achieving remission were analyzed, after adjusting for sex, smoking, disease activity, and concomitant prednisone and/or immunomodulators. We included 1399 infliximab-treated patients (mean age 36y, 52.1% males, 14% obese). Obesity was not associated with odds of achieving clinical remission (Q4 vs. Q1: adjusted OR, 0.94 [95% CI, 0.61-1.47], p-value for trend=0.97), clinical response (Q4 vs. Q1: adjusted OR, 0.84 [0.52-1.35], p=0.45) or mucosal healing remission (Q4 vs. Q1: adjusted OR, 1.13 [0.55-2.34], p=0.95) (Figure 1). These results were consistent across strata based on disease type (CD and ulcerative colitis), trial design (induction and maintenance therapy), and in adults and pediatric studies (Table 1). Based on IPD pooled analysis, obesity is not associated with inferior response to infliximab in patients with IBD. Future studies examining the association between obesity and fixed-dose therapies are warranted.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

A Role for Thiopurine Metabolites in the Synergism Between Thiopurines and Infliximab in Inflammatory Bowel Disease.

Interactions between principal cytotoxic thiopurine metabolites, that is 6-thioguanine nucleotides [6-TGN], and infliximab [IFX] and anti-IFX antibodies [Abs] may contribute to higher effectiveness of IFX-thiopurine combination therapy than monotherapies in inflammatory bowel disease. To examine if thiopurine metabolites influenced trough IFX and anti-IFX Abs, 89 patients previously assessed for anti-IFX Abs were included. To assess if IFX influenced thiopurine metabolites, eight patients who had responded to 12 weeks of intensified IFX at a constant thiopurine dosing were included. In the first cohort, IFX-thiopurine combination therapy reduced anti-IFX Ab detection [8/40; 20%] as compared with IFX monotherapy [22/49; 45%], odds ratio [OR] 0.31 [0.12-0.80], p < 0.05. 6-TGN was significantly lower in anti-IFX Ab-positive patients (50 pmol/8 × 108 red blood cells [RBC] vs 105, p < 0.01). All anti-IFX Ab-positive patients had 6-TGN < 117 pmol/8 × 108 RBC (sensitivity 100% [63-100], specificity 47% [29-65], area under the curveROC = 0.82, p < 0.01). Trough IFX was similar between anti-IFX Ab-negative patients in IFX monotherapy and IFX-thiopurine combination therapy [5.1 μg/mL vs 4.9, p = 0.76]. 6-TGN and IFX did not correlate [rP = 0.04, p = 0.83; rS = 0.02, p = 0.89, respectively]. In the second cohort, trough IFX increased during IFX intensification [ΔIFX median 6.5 μg/mL, p = 0.02], but 6-TGN was stable [6-TGN at Weeks 0, 4, 8, 12: 90 pmol/8 × 108 RBC, 93, 101, 90; p > 0.05]. Methylated mercaptopurine metabolite associations were consistently negative. Superior effect of IFX-thiopurine combination therapy over monotherapies partly relates to decrease in anti-IFX Abs, which associates with 6-TGN levels and has a lower therapeutic threshold than during thiopurine monotherapy. Additional benefit likely ascribes to synergy between different anti-inflammatory modes of action rather than direct drug interactions.

Rapid Infliximab Infusion in Children: A Multicenter Retrospective Cohort Study.

Pediatric data on rapid infliximab infusion are scarce. We report our experience with a 1-hour rapid infusion protocol, prescribed in 3 pediatric inflammatory bowel disease units during 18 to 26 months. Children treated with infliximab for inflammatory bowel disease using a standard 2- to 3-hour infusion protocol were switched to a 1-hour protocol if they had received at least 4 standard duration infusions with no infusion reactions, there was no recent dose increase and no more than 10 weeks had elapsed since the previous infusion. A total of 102 children received infliximab infusions during the study period (85 Crohn disease; mean age 14.6 ± 2.6 years) of whom 63 were switched to the rapid infusions. Seven patients on the rapid protocol (11%) and 6 patients on the standard protocol (15%) had infusion reactions (P = 0.55). Consistent with adult data, our study indicates that a 1-hour infliximab protocol in selected patients offers a safe alternative to the traditional 2- to 3-hour infusions.

Erratum: Transmembrane TNF-α Density, But Not Soluble TNF-α Level, is Associated with Primary Response to Infliximab in Inflammatory Bowel Disease.

This corrects the article DOI: 10.1038/ctg.2017.44.

Transmembrane TNF-α Density, but not Soluble TNF-α Level, is Associated with Primary Response to Infliximab in Inflammatory Bowel Disease.

Objectives:Anti-tumor necrosis factor (TNF)-α agents like Infliximab (IFX) are effective in the treatment of inflammatory bowel diseases (IBDs) and are widely used. However, a considerable number of patients do not respond or lose response to this therapy. Preliminary evidence suggests that transmembrane TNF-α (tmTNF-α) might be linked to response to IFX by promoting reverse signaling-induced apoptosis in inflammatory cells. The main aim of this study was the evaluation of this hypothesis in primary IFX non-responders.Methods:A total of 47 IFX naive IBD patients were included in the study. Blood samples were taken before the start of IFX therapy (at week 0) and after induction therapy (at week 14). Endoscopic disease activity and markers of inflammation at baseline and at week 14 were used to evaluate response. Baseline soluble TNF-α (sTNF-α), percentage of circulating TNF-α positive cells, mean fluorescence intensity (MFI) of tmTNF-α, and apoptosis rate at week 14 in the peripheral blood mononuclear cells (PBMCs) were evaluated in IFX responders and non-responders.Results:Mean sTNF-α was not significantly different in responders compared to non-responders (P=0.13). Mean percentage of tmTNF-α bearing lymphocytes and monocytes was higher in the PBMCs of responders (P=0.05 and P=0.014, respectively). Mean MFI of tmTNF-α in circulating lymphocytes and monocytes was greater in responders (P=0.002 and P<0.001, respectively). Moreover, the mean percentage of apoptosis in PBMCs was significantly greater in responders compared to non-responders (P=0.002).Conclusions:The percentage of tmTNF-α bearing lymphocytes and monocytes and the intensity of tmTNF-α in the circulating leukocyte population of IBD patients was directly related to primary response to IFX. This was likely due—as assessed by the apoptosis rate—to promotion of inflammatory cell death. Thus, our data suggest that peripheral leukocytes could in principle be used for predicting primary response to IFX in IBD patients.