Infliximab Dose Intensification Research Articles

Treatment Targets Should Influence Choice of Infliximab Dose Intensification Strategy in Inflammatory Bowel Disease: A Pharmacokinetic Simulation Study.

The optimal infliximabdose intensification strategy to address loss of response associated with subtherapeutic infliximabtrough levels remains uncertain, as does whether post-intensification trough and treatment targets should influence this decision. This pharmacokineticsimulation study aimed to identify infliximab dose intensification strategies capable of achieving post-intensification infliximab trough thresholds associated with clinical and objective treatment targets in Crohn's disease and ulcerative colitis. A validated pharmacokinetic infliximab model, applied to 200 simulated patients, identified those with subtherapeutic (<3.00mg/L) trough levels after 30weeks of standard (5mg/kg 8-weekly) dosing, and subsequently applied 10 dose intensification strategies over a further 32weeks. The proportion of simulations achieving 32-week post-intensification infliximab trough levels associated with endoscopic remission (ulcerative colitis >7.50 mg/L, Crohn's disease >9.70 mg/L) was the primary outcome, with perianal fistula healing (Crohn's disease >10.10 mg/L) and clinical improvement (ulcerative colitis >3.70 mg/L, Crohn's disease >7.00mg/L) evaluated as secondary outcomes. All outcomes were stratified by intensity of dose intensification, with standard (≤10mg/kg 8-weekly or 5mg/kg 4-weekly; n=5) and intensive (>10mg/kg 8-weekly or 5mg/kg 4-weekly; n=5) dosing strategies defined, respectively. The median pre-intensification infliximab trough level was 0.91mg/L (interquartile range 1.37). Intensive dosing strategies were more likely to achieve infliximab trough concentrations associated with endoscopic remission (ulcerative colitis 36.48% vs. 10.80%, Crohn's disease 25.98 vs. 4.68%), perianal fistula healing (24.52% vs. 4.36%) and clinical improvement (ulcerative colitis 61.90% vs. 34.86%, Crohn's disease 40.32 vs. 12.08%) than standard intensification strategies (all p<0.01). When controlling for cumulative (mg/kg) infliximab dose over 32weeks, strategies that concurrently dose increased and interval shortened achieved the highestinfliximab trough levels (all p<0.01). This simulation-based analysis highlights the potential of using post-intensification infliximab trough thresholds associated with aspirational treatment targets in Crohn's disease and ulcerative colitis to guide choice of infliximab dose intensification strategy. Intensive dose intensification strategies, particularly those that concurrently dose increase and interval shorten, appear to achieve higher infliximab levels than standard dose intensification strategies. This may be particularly important in the pursuit of stringent endpoints, such as endoscopic remission and fistula healing, which have been consistently associated with higher infliximab trough levels. These findings require validation across real-world cohorts.

Dose intensification strategy influences infliximab pharmacokinetics but not clinical response after the same number of doses.

The optimal infliximab dose intensification strategy to address secondary loss of response (LOR) remains unclear. This study aimed to compare clinical and pharmacokinetic outcomes following (i) upfront infliximab re-induction with (ii) ongoing 6-weekly dose interval shortening (DIS), after the same number of doses. A prospective parallel cohort study of inflammatory bowel disease patients who required infliximab dose intensification for secondary LOR using (i) re-induction (i.e., repeat 5mg/kg 0, 2, 6-week dosing) followed by 8-weekly maintenance or (ii) 6-weekly 5mg/kg DIS was undertaken. Week 32 clinical response was the primary outcome, with secondary evaluation of infliximab pharmacokinetics and predictors of response. Of 104 patients, 54 underwent re-induction, and 50 underwent 6-weekly DIS; 43 per cohort had clinically active disease, with comparable baseline infliximab levels (2.03 vs 2.02ug/mL, P=0.83). Clinical response was similar across re-induction and DIS cohorts at weeks 12 (69.8 vs 65.1%) and 32 (53.5 vs 62.8%, each P>0.50); however, both strategies demonstrated distinct pharmacokinetic profiles at weeks 6 (18.45 vs 5.36ug/mL, P<0.01), 12 (8.94 vs 5.96ug/mL, P=0.02) and 30 (3.89 vs 6.35ug/mL, P=.0.02). In multivariable analyses, objectively verified active disease at baseline (OR 12.92, 95% CI [1.84-90.84], P=0.01), subtherapeutic week 6 infliximab levels (OR 0.12, 95% CI [0.01, 0.99], P=0.049) and week 12 clinical response (OR 5.44, 95% CI [1.20-19.97], P=0.04) were associated with week 32 response, as were week 2 infliximab levels (OR 1.34, 95% CI [1.02-1.47], P=0.04) following re-induction. Following re-induction, week 2 infliximab levels <15.6ug/mL (AUROC 0.76, 95% CI [0.54-0.99], P<0.05) predicted nonresponse at week 32. Dose intensification strategy impacted immediate and sustained infliximab levels but not clinical response. Upfront intensification was associated with short-term pharmacokinetic advantages, including predictors of response, that diminished with time. Hence, when applying upfront dose intensification, clinicians should consider continuing intensified dosing to sustain early pharmacokinetic advantages based on predictors of (non)response.

Free antibodies-to-infliximab are biomarker for predicting the effect of dose intensification in pediatric Crohn's disease patients with secondary loss of response.

Immunogenicity to antitumor necrosis factor alpha agents, such as infliximab (IFX), may lead to therapeutic failure. This study evaluated the relationship between free and total antibodies-to-infliximab (ATIs), trough levels (TLs) of IFX, and the response to dose intensification. We performed a prospective, observational study including pediatric patients with Crohn's disease (CD) receiving IFX maintenance therapy without dose intensification. We compared clinical and laboratory outcomes according to the presence of free and total ATIs. Factors associated with response to IFX dose intensification were investigated by analyzing IFX TLs and free and total ATIs. Of the 98 patients, 9 patients had detectable free ATIs and 38 patients had total ATIs. Patients with free ATIs had significantly lower TLs (0.7 versus 5.1 µg/mL, p < 0.001) than patients without free ATIs. However, there was no difference in the IFX TLs according to the presence of total ATIs (p = 0.2523). Analysis of the 38 samples with total ATIs showed that response to dose intensification was significantly lower in patients with free ATIs than those without free ATIs (22.2% versus 65.5%, p < 0.001). In addition, free ATIs were the only factor with poor response to dose intensification [odds ratio (OR): 14.15, 95% confidence interval (CI): 1.31-151.97, p = 0.0140]. According to the receiver operating characteristic analysis, the optimal cutoff level indicating non-response to IFX dose intensification was 30.0 AU/mL for free ATIs concentration (area under curve, 0.792; 95% CI: 0.590-0.942; sensitivity, 60.0%; specificity, 96.7%; p = 0.0241). Free ATIs, but not total ATIs, have a negative impact on the course of CD. Free ATIs are potential reliable biomarker for predicting the effect of dose intensification in patients with loss of response to IFX. Future studies based on serial and proactive therapeutic drug monitoring are required in the future.

S824 Cost-Effectiveness of Precision-Guided Dosing in Adult Crohn’s Disease Patients Initiating Infliximab Maintenance Therapy

Introduction: Crohn’s disease (CD) patients that lose response to biologics experience reduced quality of life (QoL) and costly hospitalizations. Precision-guided dosing provides clinicians with a comprehensive pharmacokinetic (PK) profile that allows for the next biologic dose to be personalized. We analyzed the cost-effectiveness of infliximab (IFX) Precision-guided dosing relative to two IFX dose intensification strategies (DIS). Methods: We developed a hybrid (Markov and decision tree) model of CD patients who had a clinical response to IFX induction and entered IFX maintenance in “remission” or “mild symptoms” health states. The analysis took a US payer perspective, a time horizon of 2 years in the base case, and a cycle length of 4 weeks. There were 3 comparators for IFX dosing: Precision-guided dosing, dose intensification based on symptoms, inflammatory markers, and trough IFX concentration (DIS1), and IFX dose intensification based on symptoms alone (DIS2). Patients that failed IFX initiated ustekinumab (UST), followed by vedolizumab, and conventional therapy. Transition probabilities for IFX were estimated from real-world clinical PK data and interventional clinical trial (PMID: 34978325; 29317275) patient-level data. All other transition probabilities were derived from published randomized clinical trials and cost-effectiveness analyses. Utility values were sourced from previous health technology assessments. Direct costs included biologic acquisition and infusion, surgeries and procedures, conventional therapy, and lab testing. The primary outcomes were total discounted costs, total quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs). The robustness of results was assessed via one-way sensitivity and scenario analyses. Results: Total costs and QALYs at 2 years are presented in Table. The ICERs of Precision-guided dosing relative to DIS1 and DIS2 were 171,810 and 127,990, respectively. One-way sensitivity analyses (Figure) demonstrated that the cost-effectiveness of Precision-guided dosing was most sensitive to the time between IFX doses. Precision-guided dosing had the lowest proportion of patients requiring a new biologic through 2 years (0.5% vs 2.4% and 27.7% for DIS1 and DIS2, respectively). Conclusion: Precision-guided dosing provides substantial clinical and QoL benefits for adult CD patients by maintaining clinical remission and avoiding IFX failure; it is cost-effective relative to other DISs at a WTP of $175,000/QALY.Figure 1.: Precision-guided Dosing ICER Relative to DIS2 † Varied by ±10% * Varied by ±5% CD: Crohn's disease, DIS: dose intensification strategy, ICER: incremental cost-effectiveness ratio, IFX: infliximab, M-S: moderate-severe, PMPM: per member per month, Rem: remission Table 1. - Base Case Results (2-year Horizon Discounted) DIS Total QALYs Total Costs ICER Relative to Precision-guided Dosing ICER Relative to DIS1 ICER Relative to DIS2 Incremental NMB vs DIS1 (WTP $150,000/QALY) Incremental NMB vs DIS1 (WTP $50,000/QALY) Incremental NMB vs DIS2 (WTP $150,000/QALY) Incremental NMB vs DIS2 (WTP $50,000/QALY) Precision-guided Dosing* 1.572 $50,753 - 171,810 127,990 -$765 -$4,274 $1,816 -$6,436 DIS1† 1.537 $44,725 171,810 - 95,581 - - $2,581 -$2,162 DIS2 ‡ 1.489 $40,191 127,990 95,581 - -$2,581 $2,162 - - DIS: dose intensification strategy, ICER: incremental cost-effectiveness ratio, NMB: net monetary benefit, QALY: quality-adjusted life year, WTP: willingness to pay.*Model informed precision dosing with homogenous mobility shift assay (Prometheus Laboratories).†Dose intensification based on a combination of symptoms, inflammatory markers and proactive therapeutic drug monitoring. Corresponds to cohorts 1 and 2 of the TAILORIX clinical trial.‡Dose intensification reactive on symptoms only. Corresponds to cohort 3 of the TAILORIX clinical trial.

P462 Upfront infliximab dose intensification for secondary loss of response in IBD: similar efficacy to dose interval shortening with the added advantage of early clinical and pharmacokinetic predictors of response

Abstract Background The efficacy and pharmacokinetic profile of upfront dose intensification strategies such as re-induction (RI) have not been well described, nor directly compared with more prevalent intensification strategies to address secondary loss of response (LOR) in inflammatory bowel disease (IBD). Hence this study aimed to prospectively compare infliximab RI and 6-weekly dose interval shortening (DIS) with reference to clinical and pharmacokinetic effectiveness, and to identify early predictors of response. Methods A prospective multicentre parallel cohort study of consecutive patients with IBD who underwent dose intensification to address secondary LOR using (1) infliximab RI (i.e. repeat week 0,2,6 dosing) followed by 8-weekly maintenance, or (2) 6-weekly DIS, over 30 weeks (6 doses) was undertaken. Primary outcomes were: (1) Clinical response, defined as a decrease in Harvey Bradshaw Index ≥3 or partial Mayo score ≥2 from pre-intensification baseline, assessed at weeks 12 and 32, and (2) Clinical and pharmacokinetic predictors of week 32 response, with serum infliximab samples collected at predefined timepoints (Figure 1). Patients who were dose intensified in the absence of clinical symptoms, were excluded from the primary analysis. Results Of 104 patients, 54 underwent RI and 50 underwent 6-weekly DIS (Table 1), including 43 patients from each cohort who were dose intensified to address clinically active disease. Baseline infliximab trough levels prior to RI and DIS (2.03 v 2.02ug/ml, p=0.83) were comparable. Clinical response was similar across both RI and DIS cohorts at weeks 12 (70 v 65%, p=0.89) and 32 (53 v 63%, p=0.51). Multivariate logistic analyses demonstrated that objectively verified active disease at baseline (OR 20.43[2.53–64.94]; p=0.005) and clinical response at week 12 (OR 15.44[1.20–19.97]; p=0.036) were associated with week 32 response, as were week 2 infliximab levels within the RI cohort only (OR 1.34[1.02–1.47]; p=0.036). Following RI, week 2 infliximab levels below 15.6ug/ml (sensitivity 100.0%; specificity 42.9%; AUROC 0.76; p&amp;lt;0.05) were predictive of not achieving clinical response at week 32; potentially indicating that amongst this patient subset, week 12 clinical response may be useful in differentiating between early clinical responders who may benefit from sequential DIS following RI to prevent subsequent non-response, and early clinical non-responders who may benefit from early biologic switching. Conclusion Despite similar clinical outcomes across both dose intensification strategies, only upfront dose intensification using infliximab RI was associated with early clinical and pharmacokinetic predictors of response capable of facilitating early dose optimisation and biologic switching.

Comparison of three commercially available ELISA assays for anti-infliximab antibodies

Three commercially available assays for the measurement of antibodies to infliximab (ATI) are approved for clinical use in Australia: Promonitor anti-infliximab (Grifols), Lisa Tracker anti-infliximab (Theradiag) and Ridascreen anti-IFX (R-Biopharm). All are bridging ELISA assays. Measurement of ATI has been incorporated into treatment algorithms for assessing loss of response to infliximab in patients with inflammatory bowel disease, but results obtained by the three ATI assays have not been systematically compared. We performed a series of experiments to allow comparison of results between the assays. Forty-two patient samples known to be positive for ATI by the Lisa Tracker assay were run on the Promonitor assay in singlicate, of which 26 were run on the Ridascreen assay in duplicate, according to the manufacturers' instructions. The Spearman correlation coefficient for all three pairwise assay comparisons was 0.95. Results were not numerically comparable between the assays. The coefficient of variation (CV) was 2.3% for the Lisa Tracker assay, 7.6% for the Promonitor assay and 7.4% for the Ridascreen assay. The presence of infliximab interfered with all three assays in a dose dependent manner. The cut-point for loss of response to infliximab dose intensification, previously demonstrated to be 200 ng/mL on the Lisa Tracker assay, is equivalent to approximately 60 ng/mL on the Ridascreen assay and between 22.9 and 41 AU/mL on the Promonitor assay. All three assays are suitable for clinical use.

P549 A virtual clinic enhances the quality use of anti-TNF dose intensification and rates of treatment success using a treat-to-target approach compared with standard outpatient care in Crohn’s disease

Abstract Background Virtual clinics (VC) represent a novel model-of-care which promote quality use of biologics and facilitate a treat-to-target (T2T) approach. We aimed to evaluate the clinical and process-driven outcomes of intensified anti-TNF therapy for secondary loss of response (SLoR) in a VC compared with standard outpatient care (SoC). Methods A retrospective multicenter, parallel observational cohort study of patients with Crohn’s disease (CD) who underwent anti-TNF dose intensification to address SLoR with up to 2-years of follow-up was undertaken. Objective assessments of disease activity and anti-TNF trough levels at SLoR then during subsequent 6-month semesters were compared longitudinally between VC and SoC groups. ‘Anti-TNF escalation success’ was the primary endpoint, defined as achieved when two consecutive 6-month semesters of objective assessment demonstrated inactive disease. Dose intensification was defined as ‘appropriate’ if there was both objective evidence of disease activity, plus anti-TNF trough levels at or below the lower limit of the therapeutic range prior to intensification. ‘Treatment escalation failure’ was defined by the occurrence of one or more of biologic switching, discontinuation or further intensification; recommencement of corticosteroids, or IBD-related surgery. Results 149 patients (69 VC vs. 80 SoC) underwent infliximab (n = 94) or adalimumab (n = 55) dose intensification with similar baseline patient, disease and treatment characteristics between cohorts. The median duration of follow-up post dose-intensification was 1.9 and 1.5 years for the SoC and VC cohorts respectively (p = 0.37). There were higher rates of appropriate dose intensification (82.6 vs. 40.0%, p &amp;lt; 0.01) across the VC cohort. Higher proportions of anti-TNF escalation success (60.9 v 35.0%, p &amp;lt; 0.01), biomarker remission (i.e., C-Reactive Protein (&amp;lt;5mg/l) and faecal calprotectin (&amp;lt;150 μg/ml) normalisation, log-rank tests, p = 0.06 and p &amp;lt; 0.01 respectively), tight disease monitoring (84.1 vs. 28.8%, p &amp;lt; 0.01) and de-escalation of intensified therapy (21.3 vs. 10.0%, p = 0.03) were also achieved by the VC cohort following dose-intensification. Conclusion This study favoured a VC-led model of care over standard outpatient-based IBD care in facilitating an effective T2T approach to CD management. A VC model of care improved quality use of intensified anti-TNF therapy through processes that promoted appropriate dose intensification and encouraged more frequent anti-TNF dose de-escalation. Moreover, tight semester-based monitoring using a T2T-based strategy facilitated by the VC was associated with improved treatment outcomes.

Predicting response after infliximab salvage in acute severe ulcerative colitis.

Acute severe ulcerative colitis (ASUC) is a medical emergency requiring prompt therapeutic intervention. Although infliximab has been used as salvage therapy for over 15years, clinical predictors of treatment success are lacking. We performed a retrospective analysis to identify factors that predict colectomy and may guide dose intensification. Fifty-four hospitalized patients received infliximab for ASUC at seven Australian centers (April 2014-May 2015). Follow-up was over 12months. The data were primarily analyzed for predictors of colectomy. Accelerated (AI) versus standard (SI) infliximab induction strategies were also compared. Of 54 patients identified, the overall colectomy rate was 15.38% (8/52) at 3months and 26.92% (14/52) at 12months. Two patients were lost to follow-up. There was a numerically higher colectomy rate in those treated with AI compared with SI (P=0.3); however, those treated with AI had more severe biochemical disease. A C-reactive protein (CRP)/albumin ratio cut-off of 0.37 post-commencement of infliximab and before discharge was a significant predictor of colectomy with an area under receiver operating curve of 0.73. Pretreatment CRP and albumin levels were not predictive of colectomy. A Mayo Endoscopic Score of 2 had a 94% PPV for avoidance of colectomy following infliximab salvage. The baseline Mayo Endoscopic Score and the CRP/albumin ratio following infliximab salvage are significant predictors of treatment response for ASUC and identify patients at high risk of colectomy. Whether this risk can be mitigated using infliximab dose intensification requires prospective evaluation before the CRP/albumin ratio can be integrated into ASUC management algorithms.

Review article: dose optimisation of infliximab for acute severe ulcerative colitis.

Although optimal medical management of acute severe ulcerative colitis (UC) is ill-defined, infliximab has become a standard of care. Accumulating evidence suggests an increased rate of infliximab clearance in patients with acute severe UC and a reduced colectomy rate with an intensified infliximab induction regimen. To assess the strength of the current evidence for the relationship between infliximab pharmacokinetics, dosing strategies and disease behaviour in patients with acute severe UC. We systematically searched MEDLINE and conference proceedings from 2000 to 2016 for relevant articles describing the pharmacokinetics of infliximab in acute severe UC and/or infliximab dose intensification strategies in acute severe UC. Eligible articles described randomised controlled trials, and cohort, cross-sectional, and case-controlled studies. Of 400 citations identified, 76 studies were eligible. Increased infliximab clearance occurs in patients with acute severe UC, and is driven by the total inflammatory burden and leakage of drug into the colonic lumen. Several cohort studies suggest that infliximab dose intensification is beneficial to at least 50% of acute severe UC patients and the results of case-controlled studies indicate that an intensified infliximab dosing regimen with 1-2 additional infusions in the first 3 weeks of treatment could reduce the early (3-month) colectomy rate by up to 80%, although these data require prospective validation. Uncontrolled studies suggest a benefit for infliximab dose optimisation in patients with acute severe UC. A randomised controlled trial in acute severe UC patients comparing a personalised infliximab dose-optimisation strategy with conventional dosing is a research priority.

Practical Use of Infliximab Concentration Monitoring in Pediatric Crohn Disease.

Therapeutic drug monitoring (TDM) that guides infliximab (IFX) intensification strategies has been shown to improve IFX efficacy. We conducted a review to evaluate the utility of TDM in the assessment and subsequent management of IFX loss of response in our pediatric population with Crohn disease (CD). Single-center retrospective study of patients with CD receiving IFX that had TDM from December 2009 to September 2013. We defined subtherapeutic trough as a drug level below the detection limit of the Prometheus enzyme-linked immunoabsorbant assay and Anser reference values (1.4 and 1 μg/mL, respectively) or a mid-interval level <12 μg/mL. One hundred ninety-one IFX concentration tests were performed on 72 patients with CD with loss of response to therapy as the primary indication (72%). 34% of all TDM were subtherapeutic. After initial TDM, 25 of the 72 patients received regimen intensification with 72% in clinical remission at 6 months. Including all of the TDM that resulted in IFX dose intensification, we found a significant improvement in 6-month remission rates whether intensification followed mid-interval (88% remission) or trough (56% remission) testing (P = 0.026). Antibody to infliximab was found in 14 patients with 5 occurring in the first year of therapy. Furthermore, 71% of patients with antibody to infliximab that were switched to an alternative anti-tumor necrosis factor achieved clinical remission at six months. In multivariable regression analysis, we found IFX dose (mg/kg), IFX dosing frequency (weeks), and the erythrocyte sedimentation rate at the previous infusion were significantly associated with the IFX concentration. TDM in our pediatric population with CD led to informed clinical decisions and improved rates of clinical remission.

Extent of Early Clinical Response to Infliximab Predicts Long-term Treatment Success in Active Ulcerative Colitis.

The long-term effectiveness of infliximab (IFX) in ulcerative colitis (UC) and predictors of treatment response remain poorly characterized. A retrospective cohort study was conducted in 213 consecutive patients with active steroid-refractory or steroid-dependent UC treated with induction and scheduled maintenance IFX at an inflammatory bowel disease referral center. Outcomes included annual steroid-free remission (SFR), IFX failure with discontinuation, colectomy, and serious adverse events. The 1- and 5-year cumulative probabilities for SFR were 39% and 14%, for IFX failure were 31.7% and 55.6%, and for colectomy were 19.2% and 37.4%, respectively. A sensitivity analysis considering the last clinical observation in patients with incomplete follow-up demonstrated a long-term SFR rate of 36%. Among responders to IFX induction therapy, achieving clinical remission before maintenance IFX therapy predicted SFR at 1 year (adjusted odds ratio = 4.50; 95% CI, 1.75-11.53), whereas the need for IFX dose intensification during the first year of therapy predicted a lower odds of SFR at 1 year (adjusted odds ratio = 0.28; 95% CI, 0.11-0.67) and a greater hazard of IFX failure beyond 1 year (adjusted hazard ratio = 2.57; 95% CI, 1.14-5.81). Older age and shorter UC duration at IFX initiation predicted poorer long-term outcomes. In patients with moderate-to-severe UC treated with scheduled IFX at an inflammatory bowel disease center, close to half of the patients are still on IFX at 5 years, although a smaller proportion of patients achieve long-term SFR. The magnitude and stability of early response to IFX is associated with long-term therapeutic benefit to this agent.

The use of adalimumab, etanercept, golimumab and infliximab in rheumatic pathologies: variation between label dosage and real-world use

Rheumatoid arthritis (AR), psoriatic arthritis (PSA) and ankylosing spondylitis (AS) are autoimmune systemic diseases characterized by inflammation, pain and joint degeneration. The objective of this study is to evaluate, under the actual conditions of use, dosing patterns of adalimumab, etanercept, golimumab and infliximab in these pathologies, and compare them with the label regimens recommended, as well as evaluating the financial implications of these regimen modifications. The study population included all adult patients diagnosed with RA, PSA or AS who had been treated with adalimumab, etanercept, golimumab and infliximab for at least 6 months between 1 January 2011 and 31 December 2013. The main variable of this study was to assess the dose dispensed for drugs administered subcutaneously and the dose prepared/administered for drugs administered intravenously, and the annual costs of the treatment. A total of 5,428 episodes were included. The mean weekly dose was lower than the standard dose in the three pathologies studied in the patients treated with adalimumab and etanercept (84.3% vs 81.2% for RA, 85.0% vs 78.0% for PSA and 87.8% vs 81.6% for AS). The drugs with highest dose optimization in RA are etanercept (46.3%) followed by adalimumab (46%); however, the highest percentage of patients with major dose optimization corresponds to etanercept (11.6%). Both in the PA and the AS group, we also observed that etanercept is the drug more optimized, corresponding to 53.9 and 43% of patients, respectively. By contrast, 48.5% of patients with RA treated with infliximab required dose intensification; however, infliximab dose intensification in PSA and AS is not so pronounced. The practice of optimization of dose regimens in patients with rheumatic diseases under treatment with anti-TNFα is spreading among professionals, resulting in annual cost reduction in the treatment of rheumatic arthropathies. However, long term follow-up will be necessary to assess the influence of this optimization on health outcomes.

The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn's disease

ObjectiveAlthough low infliximab trough concentrations and antibodies to infliximab (ATI) are associated with poor outcomes in patients with Crohn's disease (CD), the clinical relevance of ATI in patients with adequate...

Early infliximab trough levels are associated with persistent remission in pediatric patients with inflammatory bowel disease.

Low infliximab (IFX) trough levels and high anti-infliximab antibodies (ATI) levels are associated with loss of response to IFX. Optimizing IFX levels to maintain target concentrations before loss of response may improve long-term efficacy. We hypothesized that trough levels at week 14 are predictive of IFX durability. A prospective observational cohort of pediatric patients with inflammatory bowel disease initiating IFX had IFX and ATI levels drawn at weeks 14 and 54. Primary outcome was week 54 persistent remission (PR), defined as clinical remission without IFX dose intensification. Univariate analyses tested associations of week 14 IFX (IFX14) and ATI (ATI14) levels, clinical and laboratory data with week 54 outcomes. Receiver operating curve analysis and positive and negative predictive values for IFX14 cut-off points were examined. Of 58 patients enrolled, 8 (13%) stopped IFX before week 14 and 4 discontinued IFX between weeks 14 and 54. IFX14 level (P = 0.03), baseline C-reactive protein (CRP) level (P = 0.01), and week 14 CRP (CRP14) level (P = 0.0001) were associated with PR. A model with IFX14 levels predicting PR had an area under the receiver operating curve of 0.68 and a model with both IFX14 level and CRP14 >1.0 mg/dL had an area under the receiver operating curve of 0.74. IFX14 cut points of >3, >4, and >7 µg/mL had positive predictive values of 64%, 76% and 100%, respectively, for predicting PR. Both IFX levels and CRP at week 14 were significantly associated with week 54 efficacy. A model combining both CRP and IFX at week 14 may help predict remission at week 54.

A 10-year, single tertiary care center experience on the durability of infliximab in pediatric inflammatory bowel disease.

Despite increasing use of infliximab (IFX) in children with Crohn's disease (CD) and ulcerative colitis (UC), long-term durability and safety of IFX beyond 1 year is limited in pediatric inflammatory bowel disease. We performed a 10-year single-center retrospective cohort study of 188 patients initiating IFX at <21 years of age with 1-year minimum follow-up. Data were retrieved from medical records. IFX outcomes were defined as sustained remission in the absence of dose modification (sustained durable remission), recaptured response, and treatment failure. Adverse events, anti-infliximab antibodies (ATI), and role of concomitant low-dose oral methotrexate (<10 mg/wk) on IFX durability were analyzed. Univariate associations and survival analysis were performed. As of the last follow-up, 39% of patients with CD and 29% of patients with UC achieved sustained durable remission and another 60% recaptured and maintained response. For CD, 88% remained on IFX at 1 year, 80% at 2 years, and 82% at 5 years. In UC, 70% avoided colectomy at 1 year. Of IFX failures, 25% with CD and 11% with UC developed ATI. The most common adverse event causing cessation of therapy was infusion reactions. Treatment limiting recurrent infections occurred in <1%, and 1 patient developed lymphoproliferative disease. Low-dose methotrexate did not influence any IFX outcomes. IFX is safe and effective for long-term maintenance therapy in pediatric patients with inflammatory bowel disease. IFX dose intensification can optimize durability and overcome loss of response. Loss of response is likely affected by development of ATI. Higher doses of oral methotrexate may be needed to optimize IFX.

Therapeutic Drug Monitoring of Infliximab and Mucosal Healing in Inflammatory Bowel Disease

Data on the value of therapeutic drug monitoring of infliximab (IFX) to predict mucosal healing (MH) in inflammatory bowel diseases (IBD) are scarce. All consecutive patients with IBD receiving ongoing IFX (5 mg/kg) treatment and developing secondary failure to IFX were enrolled in a prospective study between June 2010 and May 2011. IFX trough levels, antibodies to IFX concentrations, C-reactive protein levels, and fecal calprotectin were measured before IFX optimization and at week 8. A proctosigmoidoscopy was performed on the day of first IFX optimization and at week 8 in all patients with ulcerative colitis (UC). MH was defined by fecal calprotectin <250 μg/g stools in Crohn's disease (CD) and by an endoscopic Mayo score of 0 or 1 in UC. This study included 52 patients with IBD: 34 patients with CD (mean Crohn's Disease Activity Index, 300; mean C-reactive protein, 28 ± 10 mg/L; mean fecal calprotectin, 705 ± 300 μg/g) and 18 patients with UC (mean Simple Clinical Colitis Activity Index, 7; mean Mayo endoscopic score, 3). After IFX dose intensification, half of CD and UC patients achieved MH. Increase in IFX trough levels (called "delta IFX" in micrograms per milliliter) was associated with MH in both CD and UC (P = 0.001). A delta IFX >0.5 μg/mL was associated with MH (sensitivity [se], 0.88; specificity [sp], 0.77; P = 0.0001, area under the receiver operating characteristic curve, 0.89). On multivariate analysis, the only factor associated with MH after IFX optimization was a delta IFX >0.5 µg/mL (likelihood ratio = 2.02; 95% confidence interval, 1.01-4.08; P = 0.048) in patients with IBD. Therapeutic drug monitoring of IFX strongly predicts the likelihood of achieving MH following IFX dose intensification in both CD and UC.

Individualised therapy is more cost-effective than dose intensification in patients with Crohn’s disease who lose response to anti-TNF treatment: a randomised, controlled trial

ObjectiveAlthough the reasons for secondary loss of response to infliximab (IFX) maintenance therapy in Crohn’s disease vary, dose intensification is usually recommended. This study investigated the cost-effectiveness of interventions defined...

SAT0480 High Doses of Infliximab in the Management of Juvenile Idiopathic Arthritis

BackgroundAlthough biologics have revolutionized treatment of juvenile idiopathic arthritis (JIA), many patients have active disease despite therapy [1]. Studies have shown benefit of dose intensification of infliximab in several conditions,...

Sa1902 Short- and Long-Term Outcomes of Infliximab Dose Intensification in Patients With Ulcerative Colitis

Shortand Long-Term Outcomes of Infliximab Dose Intensification in Patients With Ulcerative Colitis Carlos Taxonera, Manuel Barreiro-de Acosta, Marta Calvo, Cristina Saro, Guillermo Bastida, Maria Dolores Martin Arranz, Javier P. Gisbert, Valle Garcia-Sanchez, Ignacio Marin-Jimenez, Fernando Bermejo, Maria Chaparro, Angel Ponferrada Diaz, Ignacio Fernandez-Blanco, Pilar Martinez-Montiel, R. Pajares, Celia de Gracia, David Olivares, Fermin Estremera Arevalo, Juan L. Mendoza

Sa1888 Need for Infliximab Dose Intensification in Patients With Crohns Disease and Ulcerative Colitis

Sa1888 Need for Infliximab Dose Intensification in Patients With Crohns Disease and Ulcerative Colitis