Search

Background: The relationship between subcutaneous infliximab [SC-IFX] concentrations and favourable therapeutic outcomes in patients with Crohn's disease [CD] and ulcerative colitis [UC] remains elusive., Patients and Methods: This cross-sectional study included consecutive adult patients with inflammatory bowel disease [IBD] treated with SC-IFX at a maintenance dose of 120 mg/2 weeks. Investigated therapeutic outcomes included sustained clinical remission; composite clinical and biomarker remission [clinical remission and C-reactive protein <5 mg/L]; biochemical remission [faecal calprotectin <250 µg/g]; and deep remission [clinical, biological, and biochemical remission]., Results: Of 91 patients identified, 71 qualified for inclusion in the study [70% with CD; 27% with concomitant immunomodulators]. At the time of drug concentration measurement [median 13.5 months after switch], 55 [77%] patients had sustained clinical remission; n = 44 [62%] composite clinical and biomarker remission; n = 40 [56%] biochemical remission; and n = 31 [43%] deep remission. The mean SC-IFX concentrations were significantly higher in patients with sustained clinical remission [p = 0.014]; composite clinical and biomarker remission [p = 0.003]; biochemical remission [p < 0.001]; and deep remission [p < 0.001] compared to patients without having these outcomes. In multivariate analysis, SC-IFX concentration was the only factor independently associated with sustained clinical remission (odds ratio [OR]: 4.7, 95% confidence interval [CI]: 3.1-12.2, p = 0.005); clinical and biomarker remission [OR: 9.21, 95% CI: 6.09-18.7, p = 0.006]; biochemical remission [OR: 37, 95% CI: 14-39.3, p < 0.001]; and deep remission [OR: 29, 95% CI: 15.7-37.4, p < 0.001]. The optimal SC-IFX concentration cut-off associated with deep remission based on ROC analysis was 20 µg/mL [sensitivity: 0.91, specificity: 0.80, accuracy: 0.85]. Combination with an immunomodulator failed to improve SC-IFX pharmacokinetics., Conclusion: Higher SC-IFX concentrations are associated with higher rates of favourable therapeutic outcomes in IBD patients. Serum SC-IFX concentrations >20 µg/mL were significantly associated with deep remission., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: While indirect comparison of infliximab (IFX) and vedolizumab (VDZ) in adults with Crohn's disease (CD) or ulcerative colitis (UC) shows that IFX has better effectiveness during induction, and comparable efficacy during maintenance treatment, comparative data specific to subcutaneous (SC) IFX (i.e., CT-P13 SC) versus VDZ are limited., Aim: Pooled analysis of randomised studies to compare efficacy and safety with IFX SC and VDZ in moderate-to-severe inflammatory bowel disease., Methods: Parallel-group, randomised studies evaluating IFX SC and VDZ in patients with moderate-to-severe CD or UC were identified. Eligible studies reported ≥ 1 prespecified outcome of interest at Week 6 (reflecting treatment during the induction phase) and/or at 1 year (Weeks 50-54; reflecting treatment during the maintenance phase). Prespecified efficacy and safety outcomes considered in this pooled analysis included the proportions of patients achieving disease-specific clinical responses, clinical remission, or discontinuing due to lack of efficacy, and the proportions of patients experiencing adverse events (AEs), serious AEs, infections, serious infections, or discontinuing due to AEs. Data from multiple studies or study arms were extracted and pooled using a random-effect model; comparative analyses were performed separately for patients with CD and UC., Results: We identified three eligible CD trials and four eligible UC trials that assigned over 1200 participants per disease cohort to either IFX SC or VDZ. In patients with CD, intravenous induction therapy with IFX demonstrated better efficacy (non-overlapping 95% confidence intervals [CIs]) compared with VDZ; during the maintenance phase, IFX SC showed numerically better efficacy (overlapping 95% CIs) than VDZ. A lower proportion of IFX SC-treated patients discontinued therapy due to lack of efficacy over 1 year. In patients with UC, efficacy profiles were similar with IFX SC and VDZ during the induction and maintenance phases, and a lower proportion of IFX SC-treated patients discontinued therapy due to lack of efficacy over 1 year. In both cohorts, safety profiles for IFX SC and VDZ were generally comparable during 1 year., Conclusion: IFX SC demonstrated better efficacy than VDZ in patients with CD, and similar efficacy to VDZ in patients with UC; 1-year safety was comparable with IFX SC and VDZ., (© 2024. The Author(s).)

Background: Extra-intestinal manifestations (EIM) are common in inflammatory bowel diseases (IBD) and may affect up to 40% of the patients during the course of the disease. Peripheral arthralgia (PA) is by far the most common EIM. To date, TNFα inhibitors are the most established treatment for EIMs in IBD. Infliximab (IFX) trough levels (TL) and anti-IFX antibodies (ATI) are correlated with multiple outcomes in IBD such as clinical response and remission, mucosal healing, fistular healing, and more. So far, a correlation between PA and IFX TL\ATI has not been evaluated., Methods: This retrospective study included IBD patients followed by the gastroenterology department of Sheba Medical Center. Patients with active PA at onset of IFX treatment were included. IFX TL and ATI were evaluated at week 6, 14, and 26 and correlated with PA persistence., Results: Forty patients (37 Crohn's and 3 ulcerative colitis) with IBD-related PA were included. The overall prevalence of PA was 55% (22/40), 42.5% (17/40), and 55% (22/40) after 6, 14, and 26 weeks, respectively. IFX trough drug levels were not associated with reported PA at week 6 [median, 11.8 μg/ml (IQR 6.6-15.5) vs 10.05 μg/ml (IQR 7.35-12.87), p = 0.56], week 14 [median, 4.7 μg/ml (IQR 2.3-7) vs 3.1 μg/ml (IQR 1.35-7.35), p = 0.55], and week 26 [median, 3 μg/ml (IQR 1.15-5.17) vs 3.4 μg/ml (IQR 0.13-6.75), p = 0.94]. Detectable ATI were significantly more prevalent in patients with PA than in patients without PA at week 26 [11/22 (50%) vs 3/18 (16.7%), p = 0.028]., Conclusions: In patients with IBD-related PA, ATI are associated with an increased risk of persistence of PA. No direct correlation was demonstrated between IFX TL and persistence of PA.

Background: Few data exist to help select a second biologic agent in patients with refractory ulcerative colitis (UC)., Aim: To compare the efficacy of infliximab (IFX) and vedolizumab (VDZ) in UC patients who failed a first subcutaneous anti-tumor necrosing factor (TNF) agent., Methods: Consecutive UC patients from 12 French centres starting IFX or VDZ after at least one injection of adalimumab or golimumab have been included in a retrospective study. Outcomes were clinical remission at week 14, survival without treatment discontinuation and survival without UC-related event., Results: Among the 225 patients included, clinical remission at week 14 was achieved in 40/154 (26%) patients treated with IFX and in 35/71 (49%) treated with VDZ (P = 0.001). After a propensity score matching analysis, this difference remained significant (odds ratio: 1.67; 95% confidence interval: 1.08-2.56; P = 0.02). With a median follow-up of 117 weeks, survival rates without treatment discontinuation at years 1 and 3 were 50% and 29% with IFX, and 80% and 55% with VDZ, respectively (P < 0.001). Regarding survival without UC-related event, they were 49% and 27% with IFX, and 74% and 52% with VDZ (P < 0.01)., Conclusion: After failure of a first subcutaneous anti-TNF agent, UC patients were more likely to achieve clinical remission with VDZ than those treated with IFX. Although due to prescription habits patients in the IFX group had a significantly more severe disease, these differences remained after adjustments and subgroup analyses. Such results have to be confirmed prospectively and warrant dedicated head-to-head trials., (© 2020 John Wiley & Sons Ltd.)

Introduction: Loss of response (LOR) to infliximab occurs in ∼30% of IBD patients. At time of LOR, lower infliximab-trough-levels (TL), in the absence of anti-drug-antibodies (ATI), have been associated with the need for therapy escalation. Nevertheless, few studies have examined the outcome of infliximab-therapy intensification, based on different TL., Aim: To evaluate the impact of infliximab-TL on efficacy of therapy intensification (dose-elevation/interval-shortening)., Methods: This was a retrospective observational study performed at two tertiary-centers between 2013-2017. Study population included IBD patients who underwent infliximab therapy escalation (dose elevation/interval shortening) due to clinical LOR. Patients with TL < 3 μg/ml or positive ATI were excluded. TL and clinical scores before intensification and after 6, 12 months were obtained prospectively., Results: Forty-eight IBD patients were included; 23(49%), and 29(60%) reached clinical remission by 6, 12 months before intensification. TL among patients in clinical remission were significantly lower than among those clinically active, both at 6 (p = 0.001, median TL 4.7,8.7 μg/ml, IQR 3.6-8.1, 5.9-16 μg/ml) and 12 months (p = 0.005, median TL 4.6,8.7 μg/ml, IQR 3.6-8, 5.3-16 μg/ml), respectively., Conclusions: In IBD patients experiencing clinical LOR to infliximab in the absence of ATI, success of doubling the dose was inversely associated with baseline TL. Patients with baseline TL above 9 mcg/ml were very unlikely to reach clinical remission., (Copyright © 2019 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Drug de-escalation is considered in Crohn's disease patients in sustained remission on optimized infliximab treatment., Aim: We built a model to evaluate the magnitude of cost savings in patients' disease course with or without drug de-escalation guided by infliximab trough levels., Methods: We designed 4 virtual cohorts (P1-P4) of 10,000 patients in clinical remission on optimized infliximab treatment followed for 2 years. P1: no drug de-escalation - 10 mg/kg/8 weeks; P2: drug de-escalation from 10 mg/kg/8 weeks to 5 mg/kg/8 weeks according to trough levels; P3: no drug de-escalation - 10 mg/kg/6 weeks; and P4: drug de-escalation from 10 mg/kg/6 weeks to 10 mg/kg/8 weeks according to trough levels. For P2 and P4 cohorts, drug de-escalation was decided if trough levels were ≥7 μg/mL and no de-escalation if trough levels were <7 μg/mL. Only costs related to drug administration were considered., Results: The cost differences when comparing P1 versus P2 and P3 versus P4 were 7.6% and 4.6%, respectively, corresponding to costs savings of €30.5 millions and €20.3 million for 10,000 patients., Conclusion: Over a 2-year period, infliximab de-escalation according to trough levels led to cost saving of about 6%, corresponding to around €25.4 million., (Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: SB2, an infliximab (IFX) biosimilar to the reference infliximab (R.I.) product (Remicade), received approval in the European Union for all IFX indications. Many decision algorithms based on the measurement of IFX trough levels and antibodies to infliximab are being increasingly used to optimize IFX treatment. The aim of our study was to evaluate whether the biosimilar SB2 could be efficiently monitored using the LISA-TRACKER IFX and anti-IFX assays developed by Theradiag (Croissy Beaubourg, France)., Methods: Standard curves of R.I. and SB2 were compared, and then accuracy of the LISA-TRACKER IFX assay in detecting the spiked concentration of SB2 was measured. Levels of IFX from SB2 spiked samples and R.I. clinical samples were calculated. Intra-run and inter-run imprecision were also measured with SB2 spiked samples. The ability of polyclonal antibodies directed against R.I. to block the detection of SB2 using the LISA-TRACKER IFX assay and the capacity of SB2 to block the detection of anti-R.I. antibodies using the LISA-TRACKER anti-IFX assay were tested., Results: Twelve patients treated with SB2 including 2 patients with SB2-specific antibodies were measured with the LISA-TRACKER anti-IFX assay. We demonstrated that the LISA-TRACKER assay is suitable for the quantification of SB2 in human serum samples. The percentage of recovery was between 82% and 113%. High intra-run and inter-run imprecisions were obtained with the LISA-TRACKER infliximab assay for the quantification of SB2 (SD ranged from 3.3% to 17.9%). The SB2-blocking capacity of R.I. polyclonal antibodies in spiked samples was demonstrated with inhibition between 80% and 97%. SB2 trough levels and anti-SB2 antibodies have also been confirmed in SB2-treated patients., Conclusions: LISA-TRACKER IFX and anti-IFX assays are suitable for the monitoring of patients treated with SB2.

Objective: The primary objective is to assess whether the POC assays to measure infliximab residual trough level in the serum of IBD patients were non-inferior to the ELISA techniques available on the market, and to determine which of them was the most robust. The second is to compare three different ELISA kits for monitoring anti-infliximab antibodies (ATI)., Methods: The assays were carried out on patients' sera using four ELISA kits from four different suppliers (three with a monoclonal antibody and one polyclonal) and two rapid techniques provided by BÜHLMANN (Quantum Blue ® ) and R-Biopharm (Ridaquick) for monitoring infliximab levels. ATI were measured by three ELISA sets (Grifols, Theradiag, and R-Biopharm) which have different positivity limits and different units., Results: We measured infliximab residual level and ATI in the serum of 90 IBD patients (85 treated with infliximab and five with adalimumab). All of the infliximab assays were very well correlated when analyzed with Spearman nonparametric correlation (0.93 ≤ r ≤ 0.99), and the two POC assays were also excellently correlated (r = 0.98). The ATI monitoring kits revealed a correlation ranging from 0.73 to 0.96 when comparing positive and negative patients. When normalizing the quantitative values between the different ELISA tests (expressed arbitrarily by using multiples of the positivity limits defined by each supplier), the Spearman r coefficient ranged from 0.81 to 0.93., Conclusion: The available evidence allows us to conclude that all of the infliximab monitoring assays correlate well and may be used for IFX monitoring; albeit variations in measured IFX concentration among different assays remain present, these assays could be interchangeable. The ATI monitoring techniques are all capable of detecting ATI-positive patients, but because of the difference in the positivity limits and the measurement units, it is better to follow a patient rate with one definite kit.

Background: Data on combination-biologic treatment in (IBD) are still scant., Aim: To explore outcomes of patients co-exposed to anti-TNF and vedolizumab., Methods: Patients starting vedolizumab having measurable anti-TNF levels after recently stopping adalimumab/infliximab ('VDZ-aTNF' group), were compared with control vedolizumab patients in a retrospective 1:2 matched case-control study., Results: Seventy-five patients were included (25 VDZ-aTNF, 50 VDZ). Adverse events were experienced by 9/25 VDZ-aTNF compared to 13/50 VDZ patients (P = 0.4, follow-up 14 weeks in all). Week 14 clinical remission was attained in 10/25 (40%) of VDZ-aTNF patients versus 23/50 (46%) of VDZ patients (OR = 0.8, 95% CI 0.3-2.1, P = 0.6) and clinical response in 19/25 (76%) versus 39/50 (78%) respectively (OR = 0.9, 95% CI 0.3-2.7, P = 0.8). Corticosteroid-free remission and corticosteroid-free response were experienced by 30% and 54%, respectively, of the entire cohort, and were similar between the two groups. Vedolizumab drug concentrations at week 2, 6 and 14 were similar among VDZ-aTNF and VDZ patients (P > 0.5). Multi-variable analysis showed independent association of some vedolizumab drug-levels time-points with baseline albumin and weight, but not with anti-TNF co-exposure. In a prospective study of a separate cohort of patients starting infliximab (n = 12), the percentage of α4β7+ memory T cells, slightly but nonsignificantly increased throughout weeks 0, 2 to 14 (26 ± 2.3%, 27.8 ± 2.9%, 29.5 ± 2.6% respectively, P = 0.06)., Conclusions: Vedolizumab/anti-TNF co-exposure did not generate new safety signals during 14-weeks induction, nor did it reduce efficacy or alter vedolizumab pharmacokinetics. These observations may aid the design of future co-biologics trials and also suggest that a deliberate waiting-interval between anti-TNF cessation and subsequent vedolizumab initiation may not be warranted., (© 2018 John Wiley & Sons Ltd.)

Objective: Ciclosporin and infliximab have demonstrated short-term similar efficacy as second-line therapies in patients with acute severe UC (ASUC) refractory to intravenous steroids. The aim of this study was to assess long-term outcome of patients included in a randomised trial comparing ciclosporin and infliximab., Design: Between 2007 and 2010, 115 patients with steroid-refractory ASUC were randomised in 29 European centres to receive ciclosporin or infliximab in association with azathioprine. Patients were followed until death or last news up to January 2015. Colectomy-free survival rates at 1 and 5 years and changes in therapy were estimated through Kaplan-Meier method and compared between initial treatment groups through log-rank test., Results: After a median follow-up of 5.4 years, colectomy-free survival rates (95% CI) at 1 and 5 years were, respectively, 70.9% (59.2% to 82.6%) and 61.5% (48.7% to 74.2%) in patients who received ciclosporin and 69.1% (56.9% to 81.3%) and 65.1% (52.4% to 77.8%) in those who received infliximab (p=0.97). Cumulative incidence of first infliximab use at 1 and 5 years in patients initially treated with ciclosporin was, respectively, 45.7% (32.6% to 57.9%) and 57.1% (43.0% to 69.0%). Only four patients from the infliximab group were subsequently switched to ciclosporin. Three patients died during the follow-up, none directly related to UC or its treatment., Conclusions: In this cohort of patients with steroid-refractory ASUC initially treated by ciclosporin or infliximab, long-term colectomy-free survival was independent from initial treatment. These long-term results further confirm a similar efficacy and good safety profiles of both drugs and do not favour one drug over the other., Trial Registration Number: EudraCT: 2006-005299-42; ClinicalTrials.gouv number: NCT00542152; post-results., Competing Interests: Competing interests: DL: consulting and/or lecture fees from Abbvie, Ferring, Janssen, MSD, Pfizer, Takeda. AB: consulting and/or lecture fees from Abbvie, Ferring, MSD, Pfizer, Takeda. MA: consulting and/or lecture fees from Janssen, MSD, Takeda. YB: consulting and/or lecture fees from Abbvie, Ferring, Hospira, Janssen, MSD, Pfizer, Takeda. JF: consulting and/or lecture fees from Abbvie, Ferring, MSD, Takeda. FZ: lecture fees for Abbvie, Takeda. GS: lecture fees from Abbvie, Ferring, MSD, Takeda. LV: lecture fees from Abbvie, Ferring, MSD, Hospira and Takeda and consulting fees from Abbvie. JM: lecture fees from Abbvie, Ferring, MSD, Takeda. AA: consulting and/or lecture fees from Abbvie, Ferring, MSD, Takeda. JC: consulting fees from Abbvie, Vifor. ER: consulting and/or lecture fees from Abbvie, MSD. OD: lecture fees from MSD. AL-S: lecture fees from Abbvie, MSD. MF: lecture fees from Abbvie, MSD, Takeda. GB: lecture fees from Abbvie, MSD, Takeda. BC: lecture fees from Abbvie, MSD. XR: consulting and/or lecture fees from Abbvie, Ferring, Janssen, MSD, Pfizer, Takeda, Theradiag. GvA: consulting and/or lecture fees and research support from MSD, Novartis. ME: consulting and/or lecture fees for MSD, Abbott, Shire Pharmaceuticals. JPG: consulting and/or lecture fees Abbvie, Janssen, Hospira, MSD, Pfizer, Takeda. PM: consulting and/or lecture fees from Abbvie, Ferring, MSD, Pfizer, Takeda. SN: consulting and/or lecture fees from Abbvie, Ferring, MSD, Takeda. MdV: consulting and/or lecture fees from Abbott, Ferring, MSD. EL: research grants from AstraZeneca, Schering-Plough; consulting and/or lecture fees from Abbott, Abbvie, AstraZeneca, Ferring, Schering-Plough, MSD, Chiesi, Menarini, Millenium, Mitsubishi Pharma, Nycomed, Falk, Takeda, UCB., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Background and Aims: One of the reasons for the failure of infliximab (IFX) is immediate hypersensitivity reactions (IHR). We aimed to report the efficacy and safety of a tolerance induction protocol in inflammatory bowel diseases (IBD) patients who had previously experienced IHR during IFX infusions., Patients and Methods: We reported all cases of IBD patients who had previously experienced IHR due to IFX and who were submitted to a standardized protocol of tolerance induction to IFX from 2010 to 2015., Results: IHR occurred in a majority of patients (69%) during the first 3 infusions and for half of them after a period of IFX withdrawn. Skin prick tests were negative and only 2 intradermal tests were positive. Basophil activation tests and antidrug antibody measurements were performed in 8 out of 16 patients and were positive in 3 and 4 patients respectively. Induction of tolerance was successful in 69% of patients and IFX was pursued with clinical efficacy > 1 year in 7 patients (44%). Allergologic investigations were not predictive of tolerance induction success., Conclusion: A majority of IHR to IFX infusions occurred during the beginning or restarting of treatment and was related to a nonallergic hypersensitivity. Induction of tolerance to IFX is feasible and effective and may safely allow retreatment of IFX in almost 70% of IBD patients., (© 2018 S. Karger AG, Basel.)

Background: Several studies have reported a strong correlation between infliximab (IFX) trough levels (trough levels of infliximab [TLI]) and clinical remission (CR). We aimed to determine threshold values of TLI associated with the occurrence of CR, with or without normal inflammatory biomarkers, including serum C-reactive protein (CRP) and fecal calprotectin (fCal)., Methods: We included prospectively all consecutive patients with inflammatory bowel disease under IFX therapy (5 mg/kg every 8 wk) for at least 6 months. Disease activity (using the Crohn's Disease Activity Index or Mayo score) was recorded, and TLI, CRP, and fCal were measured before IFX infusion., Results: Two hundred thirteen patients (131 Crohn's disease) were included. The median TLIs were higher in patients who achieved CR compared with those in patients who did not (2.6 versus 1.2 μg/mL, P < 0.01). The median TLI were higher in patients achieving CR with CRP normalization or CR with fCal <250 μg/g in comparison with patients with persistent elevated CRP or fCal (3.5 versus 1.6 μg/mL, P < 0.01 and 4.9 versus 1.8 μg/mL, P < 0.001, respectively). Finally, the median TLIs were higher in patients achieving CR with normal CRP and fCal <50 μg/g in comparison with patients without strictly normal biomarkers (5.9 versus 2.1 μg/mL, P < 0.001). The more the expected level of response to IFX was stringent, the more the median TLI and optimal thresholds were high., Conclusions: Threshold values of TLI differ according to therapeutic outcomes expected in patients with inflammatory bowel disease under maintenance therapy with IFX.

Background: Endoscopic recurrence is associated with a risk of clinical recurrence in patients with Crohn's disease after ileocecal or small bowel resection. Drug levels and presence of antidrug antibodies are associated with important clinical and endoscopic outcomes in patients with Crohn's disease treated with tumor necrosis factor inhibitors, such association was not evaluated for endoscopic postsurgical recurrence., Methods: Consecutive patients with Crohn's disease treated with anti-tumor necrosis factors after surgery were identified in the databases of the participating centers. Anti-tumor necrosis factor levels and antidrug antibodies were correlated with Rutgeerts score on colonoscopy performed ≥6 months postoperatively. Significant endoscopic recurrence (SER) was defined as Rutgeerts score >2., Results: Seventy-three consecutive patients (32-infliximab, 41-adalimumab) were included in the study. The colonoscopies were performed after a median of 15 (7-43) months after surgery and 8 (6-15) months from treatment onset. SER was demonstrated in 26/73 (35.6%) of the patients. The need for dose optimization, as well as trough infliximab levels (2.4 μg/mL [0.45-4.1] versus 1.1 (0-0.6), P = 0.008) and presence of antidrug antibodies (1/18 [5.6%] versus 10/14 [71.4%], P = 0.0001) were significantly associated with a risk of SER. The optimal cutoff infliximab level for prediction of SER was 1.8 μg/mL. No association between adalimumab levels and antiadalimumab antibodies was demonstrated.

Objective: To assess adherence to infliximab (IFX) therapy in inflammatory bowel disease patients, to investigate reasons for non-adherence and to identify predictors for non-adherence., Methods: This observational study was conducted in two French referral university hospitals between 1 September and 31 October, 2011. Patients were systematically asked if they had already delayed or missed an IFX perfusion since the beginning of the treatment and about the reasons for their non-adherence., Results: Of the 162 included patients (121 Crohn's disease [CD], 41 ulcerative colitis), 87 (53.7%) reported a delay of at least one IFX injection and 14 (8.6%) missed at least one IFX perfusion since the beginning of the treatment. The overall non-adherence rate was 54.3%. Pooling all misses, the main reasons for non-adherence were pregnancy (33.3%), intentional non-adherence (20%) and forgetfulness (13.3%). Pooling all delays, the main reasons for non-adherence were professional constraints (46.9%), infections (17.3%) and travels (14.3%). Perineal disease was associated with IFX delays (P = 0.0007, odds ratio 4.0), whereas active CD/UC was associated with IFX misses (P = 0.0258, OR = 5.4)., Conclusions: The overall non-adherence rate for IFX use was 54.3%. Professional constraints and intentional non-adherence were the leading causes of non-adherence. Perineal disease and active CD were negatively related to adherence., (© 2017 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Background: Cytomegalovirus (CMV) is frequently detected in patients with ulcerative colitis (UC). The impact of CMV infection on the outcome of UC exacerbation remains unclear. The benefit of combining antiviral with anti-inflammatory treatment has not been evaluated yet. The aim of this study was to compare the outcome of CMV-positive hospitalized patients with UC treated with antiviral therapy either alone or combined with salvage anti-inflammatory therapy (infliximab [IFX] or cyclosporine A [CsA])., Methods: This was a multicenter retrospective study of hospitalized CMV-positive patients with UC. The patients were classified into 2 groups: antiviral-if treated with antivirals alone; combined-if treated with both antiviral and anti-inflammatory therapy. The outcomes included the rate of colectomy in both arms during the course of hospitalization and after 3/12 months., Results: A total of 110 patients were included; 47 (42.7%) patients did not receive IFX nor CsA; 36 (32.7%) received IFX during hospitalization or within 1 month before hospitalization; 20 (18.1%) patients received CsA during hospitalization; 7 (6.4%) were exposed to both IFX and CsA. The rate of colectomy was 14.5% at 30 days, 20.0% at 3 months, and 34.8% at 12 months. Colectomy rates were similar across treatment groups. No clinical and demographic variables were independently associated with the risk of colectomy., Conclusions: IFX or cyclosporine therapy is not associated with additional risk for colectomy over antiviral therapy alone in hospitalized CMV-positive patients with UC.

Background: Infliximab (IFX) combined with azathioprine (AZA) is more effective than IFX monotherapy in inflammatory bowel disease (IBD)., Aim: To identify the AZA optimal dose that is required for efficacy when receiving combination therapy., Methods: Patients with IBD in durable remission on combination therapy were enrolled in a 1-year, open-label, prospective trial after randomisation into three groups: AZA steady (2-2.5 mg/kg/day, n=28) vs AZA down (dose was halved 1-1.25 mg/kg/day, n=27) vs AZA stopped (n=26). Primary endpoint was failure defined as occurrence of a clinical relapse and/or any change in IBD therapy., Results: Eighty-one patients were included. Five (17.9%), 3 (11.1%), and 8 (30.8%) patients experienced failure at 1 year in groups AZA steady, AZA down and AZA stopped, respectively (P=.1 across the groups). The median trough levels of IFX at inclusion were close to those measured at the end of follow-up in group AZA steady (3.65 vs 3.45 μg/mL, P=.9) and in group AZA down (3.95 vs 3.60 μg/mL, P=.5), whereas these levels dropped from 4.25 to 2.15 μg/mL (P=.02) in group AZA stopped. Four (14.3%), four (14.8%) and 11 (42.3%) patients experienced an unfavourable evolution of IFX pharmacokinetics in groups AZA steady, AZA down and AZA stopped, respectively. A threshold of 6-TGN <105 pmoles/8.10 8 RBC was associated with an unfavourable evolution of IFX pharmacokinetics., Conclusions: Under combination therapy, AZA dose reduction, but not withdrawal, appears to be as effective as continuation of AZA at full dose., (© 2017 John Wiley & Sons Ltd.)

Background: The best noninvasive method predicting clinical relapse remains undetermined in infliximab (IFX)-treated patients with Crohn's disease., Methods: All patients with CD on IFX maintenance treatment and in clinical remission for at least 16 weeks, between 2011 and 2014, were enrolled in a prospective single-center study. The Crohn's Disease Activity Index (CDAI), fecal calprotectin, C-reactive protein levels, antibodies (ATI), and trough level (TLI) of IFX were measured at every IFX infusion. The best thresholds of TLI (2 versus 3 μg/mL) and calprotectin (50 versus 250 μg/g stools) were identified across four logistic regression models., Results: One hundred nineteen patients (mean age: 34 ± 12 yrs, mean disease duration: 7.8 yrs) were included. Mean follow-up was 20.4 months, and 17% of the patients were on IFX and azathioprine at inclusion. During follow-up, 37 patients (31.1%) relapsed, 78% within the first 6 months. The clinical characteristics of the relapsed and nonrelapsed patients were similar. After logistic regression, fecal calprotectin >250 μg/g stools (OR: 4.09; 95% CI, 1.01-16.21; P = 0.049) and TLI <2 μg/mL (OR: 14.85; 95% CI, 3.67-60; P < 0.0001) were associated with loss of response. A training cohort of 55 patients was isolated randomly to implement prediction rules for loss of response. The best predictive rules were the combination of a TLI <2 μg/mL and a fecal calprotectin level >250 μg/g stools (78.3%). These rules were validated on a test cohort of 64 patients with an accuracy of 87%, (sensitivity = 0.94, specificity = 0.84, positive predictive value = 0.73, and negative predictive value = 0.97)., Conclusions: In IFX-treated patients with CD in clinical remission, a combination of TLI (<2 μg/mL) and fecal calprotectin (>250 μg/g of stools) is a good model for predicting loss of response. In contrast with previous data, low TLIs ranging from 2 to 3 μg/mL should neither systematically lead to the optimization of IFX use nor a switch in the treatment.

6-thioguanine nucleotides levels are associated with clinical remission in patients with inflammatory bowel disease (IBD) on thiopurine monotherapy. Recently, few studies investigated the interaction between thiopurine metabolism and anti-tumor necrosis factor therapy among patients with IBD on combotherapy. Two studies demonstrated that infliximab therapy increases 6-thioguanine nucleotides level, while such effect could not be observed with adalimumab. Three studies showed that a Delta mean corpuscular volume >7 and high 6-thioguanine nucleotides levels are associated with favorable outcomes, i.e., greater mucosal healing rates, and have a positive impact on the pharmacokinetics of infliximab. These results suggest a synergistic effect between thiopurine metabolism and anti-tumor necrosis factor therapy, especially with infliximab. We propose here some algorithms for clinical practice integrating thiopurine metabolism in patients with IBD on combotherapy. Further randomized controlled trials are needed to further investigate the relationships between thiopurine metabolism and anti-tumor necrosis factor therapy and to establish the clinical utility of measuring thiopurines' metabolites in these patients in clinical practice. Whether measuring thiopurine metabolism can be used to guide decision-making in patients with IBD on combotherapy when considering drug de-escalation or discontinuation will require further investigation.

Background: Anti-tumour necrosis factor [TNF] therapy in combination with thiopurine is the most effective strategy for Crohn's disease, but raises safety concerns., Methods: In a retrospective multicentre study, we investigated long-term outcome of patients starting anti-TNF monotherapy for Crohn's disease and investigated whether introducing an immunomodulator in patients losing response to anti-TNF monotherapy is effective for resetting immunogenicity., Results: A total of 350 adult patients with Crohn's disease received either infliximab [n = 178, 51%] or adalimumab [n = 172, 49%] monotherapy. Mean duration of follow-up was 42 months. An immunomodulator was initiated in 53 patients [15%]. At last follow-up, 73.1% [n = 38] were in clinical remission [one patient with missing data]. Multivariate analysis identified anti-TNF type [higher need for starting immunomodulator for infliximab than for adalimumab; p = 0.0058] and first- vs second-/third-/fourth-line anti-TNF therapy [p = 0.014] as predictors of immunomodulator initiation. Among the 18 patients with available data, introduction of an immunomodulator was able to restore infliximab trough level within the therapeutic range and to induce clinical remission in 10 patients [55%]. Cumulative probability of remaining on anti-TNF therapy was 57.9% at 5 years among the 297 patients not starting an immunomodulator during follow-up., Conclusion: An immunomodulator was initiated in 15% of patients with Crohn's disease starting anti-TNF monotherapy. Independent predictors of immunomodulator initiation were infliximab use and second-/third-/fourth-line anti-TNF therapy. Resetting immunogenicity with an immunomodulator was effective in half of patients in a sub-study. Persistence of anti-TNF treatment at 5 years was observed in half of the 297 patients not starting an immumodulator in a real-life setting., (Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Local or national policy, patients' preferences, safety and/or economic concerns, or reimbursement issues may dictate stopping drug in inflammatory bowel diseases (IBD) patients. Sustained deep remission is an important predictor of a better outcome after anti-tumor necrosis (TNF) factor therapy discontinuation, including infliximab (IFX) in IBD patients, but this is not sufficient to prevent future relapse in these patients. In IBD patients under combotherapy, trough level of infliximab (TRI) could be helpful to choose stopping one of the two drugs. In patients on IFX monotherapy, TRI could help to decide reduction of drug dosing, particularly in IBD patients with supratherapeutic trough levels. Incidental findings of undetectable TRI in patients with deep remission may identify a subset of patients who may be considered for IFX cessation. Controlled trials further assessing this issue are eagerly awaited. Pending these trials, clear international recommendations for discontinuing anti-TNF therapy are needed.

Background: Immunosuppressive therapies used for treating ulcerative colitis are known to favor chronic and latent viral diseases. This study aimed at evaluating prospectively the association between colonic cytomegalovirus (CMV) reactivation and anti-tumor necrosis factor (TNF) monoclonal antibodies (mabs) by comparison to azathioprine (AZA) in a series of flare-ups occurring in consecutive ulcerative colitis patients., Methods: A total of 109 flare-ups were recorded in 73 patients receiving a maintenance therapy by anti-TNF mabs (n = 69) or AZA (n = 40). The CMV DNA load in colonic tissue was determined by reverse transcription polymerase chain reaction on a pair of biopsies., Results: The number of CMV reactivation was of 35% and 38% in patients receiving anti-TNF mabs and AZA, respectively. The median of CMV DNA load was 378 [10-29,800] and 8300 [10-3,25,000] copies/mg of tissue in patients treated by anti-TNF mabs and AZA, respectively (P = 0.11 by Mann-Whitney U test). In a subgroup of 45 patients under anti-TNF mabs requiring an optimized treatment by infliximab, clinical remission (partial Mayo score <3) was not significantly impacted by the presence of CMV reactivation at the time of flare-up (P = 0.52). Twenty of these patients underwent a second colonic biopsy 8 weeks after the initiation of flare-up therapy; except for 3 patients, the colonic CMV DNA load was stable or decreased., Conclusions: Patients under anti-TNF maintenance therapy are not at higher risk of CMV reactivation in case of flare-up. No reciprocal adverse influence was observed between anti-TNF mabs and CMV infection, suggesting that these drugs must be considered for treating flare-ups associated to CMV reactivation.

Background: Antibodies to infliximab [ATI] and trough levels to infliximab [TRI] are associated with loss of response in inflammatory bowel diseases [IBD]. The best way to predict loss of response [LOR] to infliximab [IFX] is unknown., Methods: We conducted a prospective observational cohort study enrolling all IBD patients who were in clinical remission at Week 14 after IFX treatment initiation. TRI, ATI and C-reactive protein [CRP] level were measured at Week 22 [T1] and thereafter at every other IFX infusion. Loss of clinical response was defined by a flare requiring therapeutic change [IFX dose intensification, initiation of another drug class, and/or surgery]., Results: A total of 93 patients [59 Crohn's disease, mean duration of follow-up 17.2 months] were included; 32 patients [34.4%] lost clinical response during follow-up. Cumulative probability of LOR was 50% at 20 months. Mean TRI at T1 was significantly lower in IBD patients with stable ATI as compared with those with transient ATI or without ATI [0.052, 3.34 ,and 4.29 µg/ml, respectively; p = 0.001 between no ATI vs stable ATI, and p = 0.005 between stable and transient ATI] [p = 0.0001]. Three independent factors were predictive of LOR after Cox proportional hazards modelling: TRI > 5.5 µg/ml (hazard ratio [HR]: 0.21; 95% confidence interval [CI]: 0.05-0.89;p = 0.034) at T1, CRP > 5mg/l [HR: 2.5; 95% CI: 1.16-5.26; p = 0.019] at T1, and stable ATI defined by two consecutive ATI > 20ng/ml [HR: 3.77; 95% CI: 1.45-10.0; p = 0.007]. Transient ATI did not influence LOR., Conclusions: LOR can be predicted based on a combination of CRP, TRI and stable ATI with a high degree of accuracy., (Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background and Aims: Long-term benefits of combination therapy (combotherapy) with infliximab (IFX) and azathioprine (AZA) have been less studied in ulcerative colitis (UC) than in Crohn's disease. The aim of the present study was to determine UC disease activity in patients who received at least 6 months of combotherapy, and whether cotreatment for more than 6 months was useful in these patients., Methods: A retrospective multicenter study was conducted in seven French academic centers from January 2010 to September 2012, including all UC patients having received at least 6 months of combotherapy in prolonged remission off steroids. During the follow-up period, which was divided into trimesters, scheduled IFX was continued as maintenance and AZA could be withdrawn. Assessment of UC activity by trimester was based on the following events: disease relapse defined by clinical relapse requiring a change of treatment, IFX failure, and colectomy., Results: Eighty-two patients were included (mean age 38 years; male:female ratio 1:1) and followed up for a median of 22.3±14.0 months. Comparing 393 trimesters of combotherapy with 282 trimesters of IFX alone, fewer clinical relapses were observed with combotherapy (p = 0.049). Similar results were observed for IFX failure (p = 0.048). No difference was observed for colectomy. Duration of combotherapy longer than 9 months was inversely associated with clinical relapse (hazard ratio = 0.32 [95% confidence interval 0.15-0.70])., Conclusions: UC patients treated with combotherapy should maintain IFX and AZA for at least 9 months. Further studies are required to determine the optimal duration of combotherapy before stopping AZA in this situation., (Copyright © 2015 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background Low drug levels are associated with emerging loss of response to anti-TNF. However, this may not be the case in patients with long-term remission. Aim To investigate the outcome of anti-TNF discontinuation in patients with long-term remission and incidental undetectable drug levels. Methods A retrospective cohort study examining the duration of relapse-free survival in IBD patients in remission who discontinued infliximab or adalimumab having undetectable drug levels. Results Forty eight patients who discontinued anti-TNF while in remission and had available drug levels were identified in two centres in France and Israel (infliximab-treated 35, adalimumab-13, Crohn's disease 30, ulcerative colitis 18, mean treatment duration of 22.7 ± 12.4 months). Endoscopy/MRE before stopping showed absence of active inflammation in 40/42 (95%) of evaluated patients, while inflammatory biomarkers (CRP and/or Calprotectin) were completely normal in only 31/ 48 (65%) of patients. During 12 months median follow-up, relapse occurred in 16/ 20 (80%) of patients who stopped anti-TNF while having measurable drug levels compared with 9/28 (32%) of patients who had undetectable drug levels (OR: 8.4, 95% CI: 2.2-32, P = 0.002). Relapse-free survival after anti-TNF cessation was significantly longer in patients with absent drug compared to those with detectable drug (P < 0.001, log rank test). On multivariate analysis, a patient's decision to stop therapy was weakly associated and abnormal inflammatory biomarkers and detectable drug levels were both strongly and independently associated with a higher risk of relapse after drug discontinuation. Conclusion Incidental finding of undetectable anti-TNF drug levels in patients with stable long-term deep remission may identify a subset of patients whose clinical remission is no longer dependent on anti-TNF treatment. [ABSTRACT FROM AUTHOR]

Background Mucosal healing can be achieved with infliximab ( IFX). Aim To assess the impact of mucosal healing on long-term outcomes in patients with ulcerative colitis (UC) when treated with infliximab ( IFX) beyond 1 year. Methods All consecutive adult patients with refractory UC receiving maintenance treatment with IFX in five French referral centres were analysed retrospectively. Only patients who had endoscopic evaluation between 6 and 52 weeks following IFX initiation were included. According to their Mayo endoscopic sub-score, patients were categorised into mucosal healing (sub-score: 0-1) and no mucosal healing (2-3). Outcome measures were colectomy and IFX failure defined by drug withdrawal due to secondary failure among primary responders. Results Of the 63 patients (30 women; median age: 38 years), 30 (48%) achieved mucosal healing. The median follow-up duration was 27 (3-79) months. Colectomy-free survival rates at 12, 24 and 36 months were, respectively, 100%, 96% and 96% in patients with mucosal healing. The corresponding figures were, respectively, 80%, 65% and 65% in patients without mucosal healing ( P = 0.004). By multivariate analysis, mucosal healing was the only factor associated with colectomy-free survival, with an odds ratio of 18.01 (95% CI: 1.58-204.92). IFX failure-free survival rates at 12, 24 and 36 months were, respectively, 76%, 69% and 64% in patients with mucosal healing, and 44%, 25% and 21% in those without mucosal healing ( P = 0.003). Conclusion Patients with refractory UC who achieved mucosal healing after IFX initiation had better long-term outcomes, with significantly less colectomy and less IFX failure. [ABSTRACT FROM AUTHOR]

Aliment Pharmacol Ther 31, 1178–1185 Background Efficacy of infliximab in treating ulcerative proctitis remains unknown. Aim To evaluate the clinical, biological and endoscopic efficacy of infliximab therapy in refractory proctitis. Methods The charts of 420 patients treated with infliximab for ulcerative colitis were reviewed. Thirteen patients were treated with infliximab for refractory ulcerative proctitis in six referral centres between 2005 and 2009. Results Following infliximab therapy induction, 9/13 patients (69%) had a complete response (defined as absence of diarrhoea and blood), 2/13 (15%) had a partial response and 2/13 (15%) were primary nonresponders. The median follow-up was 17 months (range, 3–48). Among the 11 patients with clinical response after infliximab induction therapy, 9 (82%) patients maintained response at last follow-up. Disappearance of rectal disorders was observed in all nine patients who maintained clinical response at last follow-up. Following infliximab induction therapy, the mean CRP level fell from 12.8 mg/L to 4.7 mg/L. Endoscopic evaluation was performed before and after infliximab in seven patients, showing an improvement in mucosal lesions in four patients, persistent mild endoscopic activity in two patients and no improvement in one patient. One patient underwent proctocolectomy. Conclusion Infliximab therapy seems to be effective in inducing and maintaining a clinical response in refractory ulcerative proctitis. [ABSTRACT FROM AUTHOR]

Background Although the use of tumour necrosis factor (TNF) antagonists is increasingly codified, several unresolved issues remain. Aim To conduct a French national survey on TNF antagonists use in inflammatory bowel disease (IBD). Methods A postal questionnaire was sent to all French gastroenterologists among whom 450 prescribe TNF antagonists for IBD. Only anti-TNF prescribers were invited to respond. Results A total of 333 questionnaires could be analysed, which represented a rate of survey completeness of 74%. Scheduled maintenance infliximab treatment was prescribed by 92% of gastroenterologists. In Crohn’s disease in remission after 1 year of TNF antagonists, 77.4% of physicians continued treatment. In luminal Crohn’s disease, 97% of hospital practitioners introduced infliximab as first-line anti-TNF therapy vs. 78% of physicians with nonhospital activity ( P = 0.002); only 22.5% of gastroenterologists opted for adalimumab as first-line therapy. In Crohn’s disease in remission after 6 months of azathioprine in combination with infliximab, 63.8% of practitioners discontinued azathioprine. In case of pregnancy during anti-TNF treatment, 35.1% of physicians discontinued therapy at the time of conception and did not administer anti-TNF therapy during pregnancy. Conclusions The attitudes of French gastroenterologists generally reflect the recommendations regarding the use of anti-TNF and concomitant immunosuppressive therapy in IBD. [ABSTRACT FROM AUTHOR]

Background Adalimumab may be effective in inducing remission in patients with mild-to-moderate ulcerative colitis who had secondary failure to infliximab. Aim To evaluate long-term efficacy and safety of adalimumab in patients with ulcerative colitis who previously responded to infliximab, and then lost response or became intolerant. Methods We report our single-centre experience in 13 patients. The patients received a loading dose of 160 mg of adalimumab subcutaneously in week 0, followed by 80 mg at week 2 and then 40 mg every other week starting at week 4. The primary efficacy measure was the proportion of patients on adalimumab therapy during the study. Results Median duration of follow-up was 42 weeks (range, 10–100). The mean number of adalimumab infusions was 21 (range, 5–50). The probability of maintaining adalimumab was 92.3%, 84.6%, 60.6% and 32.5% at 1, 3, 6 and 23 months respectively. Six of 13 patients (46.2%) underwent colectomy during the study. No serious toxicities occurred in the study. Conclusion Adalimumab is well-tolerated and may be effective in maintaining clinical remission in a subgroup of patients with ulcerative colitis and lost response or intolerance to infliximab, potentially avoiding colectomy in about half of the patients. [ABSTRACT FROM AUTHOR]

: A drug interaction has been observed between infliximab and methotrexate in rheumatoid arthritis. : To look for an interaction between infliximab and azathioprine in Crohn's disease patients using the active metabolites of azathioprine: 6-tioguanine nucleotides. : Patients receiving azathioprine who required infliximab for ileo-colonic or ano-perineal Crohn's disease were recruited prospectively. 6-tioguanine nucleotide levels were evaluated before infusion, within 1–3 weeks after the first infusion and 3 months after the first infusion. The clinical outcome was evaluated by the Harvey–Bradshaw index or the closure of ano-perineal fistulas. : Thirty-two patients were included (17 received one infusion and 15 received three infusions). The mean 6-tioguanine nucleotide level was comparable before and 3 months after the first infusion, but a significant increase was observed within 1–3 weeks after the first infusion ( P < 0.001). In parallel, a significant decrease in leucocyte count and increase in mean corpuscular volume were observed; these modifications were normalized 3 months after infusion. An increase in 6-tioguanine nucleotide level of greater than 400 pmol/8 × 108 erythrocytes was strongly related to good tolerance and a favourable response to infliximab, with a predictive value of 100%. : This prospective study provides evidence for a drug interaction between azathioprine and infliximab . [ABSTRACT FROM AUTHOR]