Higher Infliximab Trough Levels Research Articles

Infliximab Trough Levels Are Associated With Endoscopic Remission in Small Bowel Crohn's Disease.

To identify the association between infliximab trough levels (ITL) and treatment outcomes in small bowel Crohn's disease (SB-CD). Higher ITL are associated with favorable treatment outcomes in CD. However, the association between ITL and SB-CD treatment outcomes are rarely studied. This was a retrospective cross-sectional study. Patients with SB-CD who received maintenance infliximab therapy were recruited, and treatment efficacy was evaluated through double balloon endoscopy. Serum samples were collected to test ITL. The primary outcome was endoscopic remission (ER), which is defined as a Simple Endoscopic Score of Crohn's disease (SES-CD) of <3. The secondary outcome was mucosal healing (MH) (SES-CD: 0) and endoscopic response (SES-CD decreased by 50% from baseline). The factors associated with ER were also explored through logistic regression analysis. In total, 111 patients with SB-CD were enrolled. Forty-seven patients (42.3%) achieved ER. Median ITL was significantly higher in patients with ER than patients without ER (2.74 vs. 1.12µg/mL, P<0.01). In a multivariate model, an elevated ITL was the only independent factor associated with an increased probability of ER [odds ratio (OR): 1.24, 95% CI: 1.08-1.43, P=0.003]. The cutoff level of ITL used to predict ER with a specificity of >80% was 3.45µg/mL, and the area under the curve (AUC) was 0.790. Meanwhile, the AUC cutoff to predict MH and endoscopic responses was 0.767 and 0.759, respectively. There was a significant association between higher ITL and favorable SB-CD treatment outcomes.

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.

Infliximab trough levels among patients with inflammatory bowel disease in correlation with infliximab treatment escalation: a cross-sectional study from a Greek tertiary center.

Infliximab monitoring correlates with improved outcomes in inflammatory bowel disease (IBD). We aimed to evaluate the association between serum infliximab trough levels (TLs) and therapeutic outcomes in Greek patients with Crohn's disease (CD) or ulcerative colitis (UC). This cross-sectional study included consecutive adult patients with IBD receiving intravenous infliximab maintenance therapy at a Greek tertiary center. Therapeutic outcomes assessed were clinical remission (CR), steroid-free clinical remission (SFCR), biochemical remission (BR: C-reactive protein <5 mg/L), and combined (steroid-free and biochemical) remission (SFCBR). Seventy-seven patients participated (62.3% with CD, 16.8% on concomitant immunomodulators), with a mean infliximab infusion duration of 5.1±4.6 years. Forty-seven (61%) patients underwent treatment escalation. Infliximab mean TLs were 7.2±4.9 μg/mL, correlating only with treatment escalation (9.7 vs. 3.6 μg/mL, P<0.001). CR was achieved in 88.3% of patients, SFCR in 80.5%, BR in 62.3%, and SFCBR in 55.8%. In a subgroup analysis, for patients without treatment escalation, higher mean TLs were significantly associated with BR (4.2 vs. 0.8 μg/mL, P=0.020) and SFCBR (4.3 vs. 1.5 μg/mL, P=0.035). In receiver operating characteristic analysis, TLs predicted SFCBR (P=0.016) with good accuracy (area under the curve [AUC] 0.768, 95% confidence interval [CI] 0.584-0.952), with an optimal TL cutoff at 3.4 μg/mL. For patients with treatment escalation, TLs predicted SFCBR (P=0.018) with fair accuracy (AUC 0.653, 95%CI 0.527-0.755), with an optimal TL cutoff at 11 μg/mL. Infliximab TLs correlate with treatment escalation. Higher infliximab TLs may predict combined remission among patients with treatment escalation.

Infliximab Trough Levels Are Associated With Transmural Sonographic Healing in Inflammatory Bowel Disease.

Mucosal healing improves clinical outcomes in patients with inflammatory bowel disease (IBD) and is associated with higher infliximab trough levels (ITLs). Transmural healing, assessed by intestinal ultrasound (IUS), is emerging as an objective target in Crohn's disease (CD) and ulcerative colitis (UC). This study explores the correlation between maintenance ITLs and sonographic transmural healing. Patients on maintenance infliximab therapy were prospectively enrolled to undergo paired IUS examination and serum ITL. Infliximab trough levels were compared between patients with and without sonographic markers of inflammation using the Mann-Whitney U test. A prospective cohort of 103 patients (51% male; 79 CD; 24 UC; median duration of disease 8 years) underwent IUS and serum ITL testing. Forty-one percent of CD and 66% of UC patients demonstrated sonographic healing (bowel wall thickening ≤3 mm with no increase in color Doppler signal). Crohn's disease patients with sonographic healing had higher median ITL compared with those with sonographic inflammation (4.8 μg/mL vs 3.1 μg/mL; P = .049). Additionally, the presence of hyperemia on Doppler was independently associated with lower ITL compared with those without hyperemia (2.1 μg/mL vs 4.2 μg/mL, respectively; P = .003). There was no significant association between ITL and other sonographic markers of inflammation. In UC, lower ITL was associated with hyperemia on Doppler imaging (P = .04). There was no association between ITL and sonographic healing or any other individual sonographic parameter of inflammation. Lower maintenance infliximab levels are associated with sonographic parameters of inflammation in UC and CD. Further studies are needed to determine whether targeting higher infliximab levels can increase sonographic healing.

P499 Accessing ultrasonographic transmural healing in patients with Crohn’s disease after induction therapy with infliximab: should we aim for higher infliximab trough levels?

Abstract Background Higher infliximab trough levels (ITL) have been shown to be associated with better rates of clinical remission and mucosal healing. Transmural healing (TMH) assessed by cross-sectional imaging [such as intestinal ultrasound (IUS)] is emerging as a potential target in Crohn′s disease (CD) treatment, but whether there is any relation with ITL remains unclear. Our goal was to investigate the association between ITL and bowel wall thickness (BWT) in patients with CD after induction therapy with IFX. Methods Prospective multicentric cohort study of CD patients who started IFX in mono or combination therapy. Patients performed IUS and ITL at weeks 0 and 14. TMH was defined as BWT ≤3 mm in the most affected segment. A ROC curve was plotted to determine the best cut-off point of ITL to predict TMH. Chi-square test, Mann-Whitney test and Spearman correlation were performed to assess the ITL relation with BWT. Results We included 57 patients, 30 (53%) of whom were men with mean age of 36±15 years. Disease extension according to Montreal classification was L1 in 19 (33%), L2 in 8 (14%) and L3 in 30 (53%) patients; 6 (11%) patients also had L4 extension and 19 (33%) patients had perianal disease. Disease behavior was B1 in 36 (63%), B2 in 13 (23%) and B3 in 8 (14%) of patients. Most patients (61%) were under immunomodulators and 15 (26%) were under corticosteroids when infliximab was started; most (88%) were naïve for infliximab. At week 0, all patients had endoscopic activity and 97% had increased BWT at the most affected segment. The most affected segment on IUS at week 0 was the terminal ileum in 38 (67%) patients and the ascending, transverse, descending and sigmoid colon in 5 (9%), 2 (3%), 7 (12%) and 5 (9%) patients, respectively. There was a very good agreement between IUS and colonoscopy for evaluation of the most affected segment at baseline (kappa 0.81, p&amp;lt;0.001). Median ITL at week 14 was 4.30 μg/ml (IQR 0.01–21). TMH at week 14 was achieved in 13 (23%) patients. ITL and BWT at week 14 were negatively correlated, with a fair correlation (r=-0.3, p=0.03). The AUC of ITL for BWT was 0.661 (best cut-off value 7.65, sensitivity 54%, specificity 89%). ITL ≥7.65 μg/ml was associated with higher rates of TMH (44% vs 15%, OR 4.47 [95%CI 1.2–16.4], p=0.04). Conclusion In our cohort of CD patients completing induction therapy with infliximab, higher ITL were associated with higher ultrasonographic transmural healing rates. The best cut-off for predicting TMH was ITL above 7.65μg/ml.

Delaying an infliximab infusion by more than 3 days is associated with a significant reduction in trough levels but not with clinical worsening

Background:Higher infliximab trough levels (TLs) correlate with better clinical, inflammatory, and endoscopic outcomes among inflammatory bowel disease (IBD) patients. Although standard scheduled infliximab therapy regimen consists of infusions at pre-defined time-points (weeks 0, 2, 6, and every 8 weeks), short-period deviations from therapeutic schedule are common in ‘real life’, but the pharmacokinetic impact of these deviations has not been explored. In this study, we aim to determine whether short-period deviations from infusion schedule affect infliximab-TL.Methods:A retrospective analysis of all IBD patients receiving infliximab maintenance therapy every 8 weeks was conducted in a tertiary medical center. Patients with anti-drug antibodies, deliberate interval shortening and <3 sequential maintenance sera available were excluded. Associations between time since last infusion and TL were studied. Statistical analysis was performed using generalized estimating equations.Results:Out of over 10,000 sera, 2088 sera of 302 maintenance period stable infliximab-therapy-patients met inclusion criteria (median TL 4.1 μg/mL, interquartile range (IQR) 2.3–6.5 μg/mL). A delay beyond 3 days in infusion schedule (n > 59 days since last infusion) was found to significantly affect TL (mean difference in TL 0.9 μg/mL, 95% confidence interval (CI): 0.03–1.9 μg/mL, p < 0.04). Furthermore, among patients with delayed infusions, 80% had TL below 5 μg/mL, in comparison to 55% of patients who were not late (odds ratio (OR): 2.81, CI: 2.02–3.92, p < 0.0001).Conclusion:Real-life delays of ⩽3 days from infusion protocol can probably be allowed. Delays >3 days culminate in measurable decrease of TL, although effect on clinical outcome is unclear. This needs to be taken into account when interpreting drug-level test results.Summary:A total of 2088 sera of 302 maintenance period inflammatory bowel disease (IBD) patients treated with infliximab were analyzed, to assess effect of small deviations from infusion schedule on TLs. A significant decline in patients’ trough level (TL) was noted as early as 3 days after scheduled infusion.

Supratherapeutic Infliximab Levels Do Not Predict Risk of Short-term Complications in Adults With Crohn's Disease.

It is uncertain if higher infliximab trough levels (TLs) confer a greater risk of infectious/noninfectious complications (IC/NIC). We aimed to assess the risk of IC and NIC in patients with different TLs. We retrospectively evaluated a cohort of Crohn's disease (CD) patients treated with infliximab who underwent therapeutic drug monitoring (TDM), at a tertiary inflammatory bowel disease center, between January 1, 2010, and December 1, 2019. TDM was defined as checking of infliximab trough and antibody levels within a 48-hour period before administration. Patients with a minimum of 3-month assessment pre-TDM and post-TDM were included. In the case of multiple TDMs, the highest TL was considered, and patients were distributed across 4 predefined TL groups (A: <5 µg/mL, B: 5 to 10 µg/mL, C: 10 to 15 µg/mL, and D: ≥15 µg/mL). Rates of IC and NIC during the 3-month prior and following TDM were compared across the groups. In addition, duration of exposure, in terms of months up to TDM, was collected to analyze differences in rates of IC and NIC. Our study included 341 CD patients (median age: 35 y, 58% men). IC and NIC occurred in 52 (15%) and 30 (9%) patients, respectively. Rates of IC and NIC were similar across the 4 TL groups ( P =0.9 and 0.7, respectively for IC and NIC). On multivariable analysis, exposure to infliximab >40 months (as determined by receiver operating characteristic curve analysis) was associated with decreased odds for IC (adjusted odds ratio=0.51, P =0.04), but not NIC (adjusted odds ratio=0.72, P =0.46). In this large CD cohort, there was no association between infliximab TL and risk of short-term IC or NIC. Interestingly, a shorter duration of exposure predicted higher rates of IC. This supports the safety of targeting higher infliximab TLs when necessary and greater vigilance during the early stages of treatment.

P373 Psoriasis and psoriasiform skin lesions in patients with Inflammatory Bowel Disease treated with infliximab: a pharmacokinetic analysis

Abstract Background Anti-TNF agents are used to treat a variety of autoimmune conditions, including psoriasis. Paradoxically, new onset of psoriasis or psoriasiform skin lesions (PPSL) can occur in patients treated with these agents. We report a case series of patients featuring PPSL induced by infliximab (IFX) with pharmacokinetic and fecal calprotectin (Fc) correlation. Methods One hundred and thirty-five consecutive patients with Inflammatory Bowel Disease under proactive therapeutic drug monitoring (TDM) with IFX were evaluated for PPSL. Results Fifteen patients (11.1%) developed PPSL, 12 females (80%), with median age at diagnosis of 52.0 years (38-63). At the onset of PPSL, 6 patients were on 10 mg/kg every 6 weeks, 5 patients on 5 mg/kg every 8 weeks, 2 patients on 10 mg/kg every 4 weeks, 1 patient on 10 mg/kg every 8 weeks, and 1 patent on 5 mg/kg every 6 weeks. In patients with PPSL, IFX trough levels (IFXTL) significantly increased before and after the advent of PPSL: 6.18 µg/mL (3.28-9.91) vs 9.20 µg/mL (5.89-13.91), P= 0.001. At the time of PPSL, all but 2 patients were in Fc remission (&amp;lt; 250 µg/g), median 41 µg/g (30-103). Seven patients improved with topic therapy and 8 patients (53.3%) discontinued IFX (3 switched to ustekinumab) all of which improved. Compared with the overall cohort, IFXTL were higher in patients with PPSL: 7.27 µg/mL (4.02-10.86) vs 6.26 µg/mL (3.37-9.14), P= 0.023. In multivariate regression analysis, female gender [OR 4.84 95%CI (1.23-19.00), P= 0.024], and any IFXTL≥ 10 µg/mL [OR 5.66 95%CI (1.40-22.87), P= 0.015] were independent predictors of developing PPSL. Conclusion Most patients with PPSL presented high IFXTL and low Fc. We hypothesize that high concentrations of IFX in the setting of deep remission may signal aberrant pro-inflammatory pathways potentially responsible for PPSL.

Infliximab Exposure Associates With Radiologic Evidence of Healing in Patients With Crohn’s Disease

Higher infliximab trough levels are associated with clinical and endoscopic remission in patients with Crohn's disease (CD). We investigated pharmacodynamic features of infliximab and radiological healing. We performed a substudy of the TAILORIX trial (patients with active luminal CD in Europe, treated with infliximab), analyzing baseline and week 54 magnetic resonance enterography (MRE) data. MREs were scored using the MaRIA score by blinded central readers. Radiologic response and remission were defined, based on MaRIA criteria in all segments, as scores below 11 and 7, respectively. We collected data on infliximab trough levels, biomarkers, and endoscopic findings. Our primary aim was to evaluate pharmacodynamic features associated with radiologic response and remission, based on MRE assessments at baseline and at 54 weeks after initiation of infliximab therapy. We analyzed data from 36 patients (50% female; median age 35.7 years; interquartile age range, 25.6-48.6 years; median disease duration, 1.5 months; interquartile duration range, 0.6-22.4 months). At week 54 of treatment, 36.4% of patients had a radiologic response, 30.3% of patients were in remission, and 71% had endoscopic features of remission. At baseline, there was a correlation between the CD endoscopic index of severity and MaRIA scores (κ = 0.46; P = .008), but we found no correlation at week 54 (κ = 0.06; P = .75). Radiologic remission correlated with infliximab trough level at week 14 (P = .049) when the infliximab trough level cut-off value was set at 7.8 μg/mL (area under the curve, 0.74; 75% sensitivity; 86% specificity; 90% negative predictive value; 57% positive predictive value). Radiologic response correlated with infliximab trough levels at week 14 (P = .048) when the infliximab trough level cut-off value was set at 7.8 μg/mL (area under the curve, 0.73; 70% sensitivity; 90% specificity; 86% negative predictive value; 78% positive predictive value) and with continuous pharmacologic evidence of response (infliximab trough levels above 5.0 μg/mL at all time points) (P = .034). In a substudy of data from the TAILORIX trial of patients with active luminal CD, we identified a relationship between exposure to infliximab and radiologic evidence of outcomes.

P384 Lower infliximab trough levels are associated with higher bowel wall thickness in Crohn’s disease

Abstract Background Therapeutic drug monitoring (TDM) is currently used to optimise anti-TNFα therapy in Crohn’s disease, as higher infliximab trough levels (ITL) are associated with better rates of clinical remission and mucosal healing. Transmural healing is emerging as a potential target in Crohn′s disease, but whether there is any relation with ITL remains unclear. Here, we investigated the relation between ITL with bowel wall thickness (BWT) in patients with CD in maintenance therapy with IFX. Methods A retrospective cohort study of CD patients treated with IFX in mono or combination therapy. Patients were included if they had an available ITL during maintenance therapy and available entero-magnetic resonance or computerised tomography performed ±4 months. Transmural inflammation was defined as BWT ≥ 4 mm. Median BWT was measured in the most affected segment. An ROC curve was plotted to determine the best cut-off point of ITL to predict transmural inflammation. Mann–Whitney U-test, logistic regression and Spearman correlation were performed to assess the ITL relation with BWT. Results Twenty-nine patients were included (males 55.2%; mean age 39.6 ± 18 years; combo therapy 48.2%). According to the Montreal Classification, most patients were A2 (75.2%), with ileal (L1: 34.5%) or ileocolic disease (L3: 51.7%), and behaviour was: B1 41.4%, B2 24.1%, and B3 34.5%, with concomitant perianal disease in 37.9%. 82.2% were in clinical remission. The median IFX TL was 3.2 μg/ml (IQR 1.15–5.15) and median bowel wall thickness was 7 mm (IQR 4–9). 75.9% of patients had BWT &amp;gt; 4 mm. A BWT &amp;gt; 4 mm was associated with lower clinical remission rates (75% vs. 100%, p = 0.27) and higher C-reactive protein (0.31 vs. 0.14, p = 0.09), albeit not significantly. The area under the curve of ITL for bowel wall thickness was 0.70 (best cut-off value 1.8). Having ITL &amp;lt; 1.8 μg/ml was associated with higher median BWT (8.7 vs. 5.9 mm, p = 0.02) and was a predictive factor for transmural inflammation (OR 1.57, 95% CI [1.08–2.30], p = 0.02). BWT showed a fair correlation with ITL (r = −0.43, p = 0.02). Conclusion In our cohort of CD patients treated with infliximab (mono or combo therapy), lower infliximab trough levels were associated with higher bowel wall thickness, reflecting worse transmural inflammation. Proactive TDM could offer a possibility to improve BWT and reduce transmural inflammation.

Usefulness of therapeutic drug monitoring of infliximab during the induction period in patients with inflammatory bowel disease.

previous studies have shown that higher infliximab trough levels are associated with favorable short-term and long-term therapeutic outcomes in inflammatory bowel disease. There is a need to determine which patients could benefit from proactive therapeutic drug monitoring in the induction phase. The aim of this study was to evaluate the pharmacokinetic variability of infliximab, determine the factors associated with achieving target infliximab trough levels in the induction phase and analyze the clinical and biochemical response at week 26 of treatment. a retrospective observational study was performed of patients with inflammatory bowel disease and data available on serum levels of infliximab during the induction period. The percentage of patients that achieved target infliximab trough levels at week 6 was determined. Clinical remission and response and biochemical remission were evaluated at week 26. thirty patients were included and only 13 (43.3 %) had infliximab trough levels > 15 µg/mL at week 6. A clinical response was observed during the maintenance period in 71.4 % of patients, their infliximab levels were significantly higher than in non-responders (6.3 µg/mL [IQR: 6.7] vs 1.0 µg/mL [IQR: 5.0], respectively; p = 0.016). Likewise, 53.6 % of patients achieved biochemical remission (responders 6.2 µg/mL [IQR: 5.2] vs non-responders 3.2 µg/mL [IQR: 5.0]; p = 0.031). less than half of patients had target infliximab levels during the induction period. Therapeutic drug monitoring during this period is related to the achievement of therapeutic levels of infliximab and may lead to a better clinical response in these patients.

Premedication with corticosteroids does not impact the pharmacokinetics of infliximab in inflammatory bowel disease irrespective of azathioprine cotreatment.

Loss of infliximab (IFX) effect is a clinical challenge in the management of patients with Crohn's disease (CD), but this can potentially be reduced with azathioprine (AZA) or with corticosteroids (CS). We aimed to study whether CS premedication with or without cotreatment with AZA could reduce antibody formation and affect the IFX elimination rate. A cross-sectional observational study was conducted at two centers with CD patients receiving maintenance IFX therapy for 12-18 months. In addition to IFX, patients received either CS premedication or not, with or without concominant AZA. Fifty-seven patients were included in the study. Thirty-one patients received premedication with CSs, and 11 (35.5%) of these also received AZA, whereas this was the case for 22 of 26 (84.6%) patients in the non-CS group. No difference in IFX trough level (P=0.10) or halftime elimination (P=0.31) was observed with or without CS premedication. Concomitant AZA was associated with significantly longer mean half-life of IFX (P=0.04). Total IFX antibody concentrations were 15.8 and 12.9 with and without CS, respectively, in those not receiving AZA versus 4.3 and 6.1 AU/ml with and without CS, respectively, in those receiving AZA (P=0.004). Premedication with CS did not have any effect on the frequency of antibody formation (P=0.28). In patients with CD and in maintenance IFX therapy, premedication with CS did not influence antibody formation, IFX trough levels or IFX halftime elimination, irrespective of concomitant AZA use. However, the use of AZA was associated with higher IFX trough levels and lower total IFX antibody concentrations.

P669 Transmural healing is associated with higher infliximab trough levels in Crohn’s disease

P669 Transmural healing is associated with higher infliximab trough levels in Crohn’s disease

Higher Infliximab Trough Levels Are Associated With Better Outcome in Paediatric Patients With Inflammatory Bowel Disease.

The role of therapeutic drug monitoring for infliximab [IFX] therapy in children with inflammatory bowel disease [IBD] is poorly investigated. We determined if IFX exposure correlates with long-term remission in children. In this retrospective study, all children with Crohn's disease [CD] and ulcerative colitis [UC], receiving maintenance IFX at our centre, were included. Serum trough levels and cumulative drug exposure were correlated with clinical, biological, and endoscopic remission. All children received proactive drug monitoring and dose adaptation aiming to target a therapeutic window of 3-7 µg/mL. All data are presented as median [interquartile range]. A total of 686 serum levels during IFX maintenance in 52 paediatric patients [33 CD and 19 UC] were included (median 9 [4-18] per patient). With a median of 17 [8-36] months under IFX therapy, 39/52 [75%] patients were in clinical remission and 29/40 [73%] patients were in endoscopic remission. Median IFX trough levels were significantly higher when children achieved clinical remission (5.4 [3.8-8.0] µg/mL versus 4.2 [2.6-6.7] µg/mL), biological remission (5.2 [3.7-7.7] µg/mL versus 4.2 [2.6-6.5] µg/mL), combined clinical and biological remission (5.7 [4.0-8.2] µg/mL versus 4.4 [2.7-6.8] µg/mL) and endoscopic remission (6.5 [4.2-9.5] µg/mL versus 3.2 [2.3-5.6] µg/mL) compared with not meeting these criteria [all p ≤ 0.001]. In this large paediatric cohort, children with clinical and/or endoscopic remission had significantly higher IFX exposure during maintenance therapy. We showed excellent outcome data using serial and systematic measurements of drug levels. This could provide a rationale for the use of proactive drug monitoring in children in order to improve long-term outcomes.

Success and safety of high infliximab trough levels in inflammatory bowel disease

Objective: A prospective trial suggests target infliximab trough levels of 3–7 μg/mL, yet data on additional therapeutic benefits and safety of higher trough levels are scarce.Aim: To explore whether high infliximab trough levels (≥7 μg/mL) are more effective and still safe.Material and methods: In this cohort study of 183 patients (109 Crohn’s disease and 74 ulcerative colitis) on infliximab maintenance treatment at a tertiary referral center we correlated fecal calprotectin and C-reactive protein to trough levels (426 samples) at different time points during treatment. Rates of infections were compared in quadrimesters (four-month periods) with high trough levels to quadrimesters with trough levels <7 μg/mL during 420 patient-years.Results: Fecal calprotectin and C-reactive protein (median [interquartile range]) were lower in patients with high trough levels (fecal calprotectin 66 mg/kg [30–257]; C-reactive protein 3 mg/L [3–3]) compared to trough levels below 7 μg/mL (fecal calprotectin 155 mg/kg [72–474]; C-reactive protein 3 mg/L [3–14.5]) (p < .001). High trough levels were superior also after excluding samples with trough levels <3 μg/mL from analysis. No differences in rates of infections were observed in quadrimesters with high trough levels (16/129 [12.4%]) compared to quadrimesters with trough levels <7 μg/mL (32/344 [9.3%]) (p = .32). Maintaining high trough levels resulted in 32% (interquartile range: 2–54%) increase of infliximab consumption.Conclusion: High infliximab trough levels provide better control of inflammation in inflammatory bowel disease without increasing the risk of infection.

Body mass index influences infliximab post-infusion levels and correlates with prospective loss of response to the drug in a cohort of inflammatory bowel disease patients under maintenance therapy with Infliximab.

IntroductionInfliximab is an effective treatment for inflammatory bowel disease (IBD). Studies differ regarding the influence of body mass index (BMI) on the response to infliximab, with the majority of studies indicating that increased BMI may be associated with a poorer response to Infliximab. However, the pharmacokinetic mechanisms causing this have not yet been reported.AimsExamine the correlation between BMI/immunosuppressant use with clinical response, trough and post-infusion levels of infliximab, tumour necrosis factor-α(TNF-α) and anti-drug antibodies(ATI), and determine if these factors can predict future response.MethodsWe collected serum from 24 patients receiving Infliximab before and 30 minutes following infusion. Clinical parameters were collected retrospectively and prospectively. ELISA measurements of infliximab, TNF-α and ATI were performed.ResultsWe confirmed that patients with higher infliximab trough levels have a better response rate and that patients with an elevated BMI display a higher rate of loss of response (20%). Patients with a higher BMI had elevated post-infusion levels of infliximab. Additionally, the ratio of IFX/TNF-α trough levels correlated with clinical response to the following infusion.ConclusionThis study confirms that an elevated BMI is associated with a poorer response to infliximab. For the first time, we describe that a higher BMI correlates with higher post-infusion levels, however this does not correlate with a higher rate of response to the drug, suggesting that circulating drug levels do not correlate with tissue levels. Furthermore, in our small cohort of patients, we identified a possible predictive marker of future response to treatment which may be used to guide dose escalation and predict non-response to infliximab.

Higher infliximab trough levels are associated with perianal fistula healing in patients with Crohn's disease.

Infliximab has been found to be efficacious in the treatment of fistulas in the setting of Crohn's disease, even though some patients do not benefit from therapy. To assess the correlation between perianal fistula healing and trough levels of infliximab. In this cross-sectional study, we identified patients with Crohn's disease who had perianal fistulas and were treated with infliximab for at least 24weeks. We excluded patients who underwent a faecal diversion procedure or proctectomy. Predictive variables included demographics, disease phenotype, disease activity, infliximab levels, anti-infliximab antibodies. The primary outcome was fistula healing defined as the absence of drainage. The secondary outcome was complete fistula closure and mucosal healing. 117 patients were included. Patients with fistula healing had significantly higher median serum infliximab levels when compared to those with active fistulas [15.8 vs. 4.4μg/mL, respectively (P<0.0001)]. There was an incremental gain in fistula healing with higher infliximab levels. The AUC for the association between fistula healing and infliximab levels was 0.82 (P<0.0001), while the AUC for the association of infliximab levels and fistula closure was 0.69 (P=0.014). Patients with anti-infliximab antibodies had a lower chance of achieving fistula healing (OR: 0.04 [95%CI: 0.005-0.3], P<0.001). There is a significant association between serum infliximab levels and rates of fistula healing. Achieving infliximab levels ≥10.1mcg/mL in patients with Crohn's disease and perianal fistulas may improve outcomes as part of a treat-to-target strategy.

P309. High infliximab trough levels are associated with better control of inflammation in inflammatory bowel disease

P309. High infliximab trough levels are associated with better control of inflammation in inflammatory bowel disease

Higher Trough Concentrations of Infliximab are Associated with Clinical Remission and Mucosal Healing in Patients with Inflammatory Bowel Disease

Objective: Few studies have correlated the infliximab (IFX) trough concentration, clinical remission (CM) and mucosal healing (MH). The purpose of the study was to determine if higher IFX trough levels are associated with MH and CR, in a group of Brazilian inflammatory bowel disease patients. Methods: Cross-sectional study of 51 IBD patients in IFX maintenance therapy, at a medical center, in Brazil. IFX serum levels were obtained from blood samples collected immediately before drug infusion. The IFX trough levels were correlated with clinical and endoscopic scores and a univariate analysis was conducted to identify factors associated with CR and MH. Results: IFX trough concentration ≥ 2 μg/mL was associated with higher CR (84.2% vs. 28.1%; P<0.001) and MH (83.3% vs. 25.0%; P=0.001). Trough levels of 2.0 μg/mL were 89% specific for CR (sensibility=66%; P<0.001) and 89% specific for MH (sensibility =64%; P<0.001). On univariate analysis, IFX trough concentration was the only variable associated with CR and MH. Conclusion: The study found a significant association between IFX trough level ≥ 2 μg/mL, CR and MH. Therapeutic drug monitoring is an important tool in IBD patients and should routinely be performed to optimize treatment.

A study investigating the association of dermatological and infusion reactions to infliximab and infliximab trough levels.

Although infliximab is an effective therapy for inflammatory bowel disease (IBD), it is associated with dermatological events and infusion reactions. It is not known whether a relationship between these adverse events (AEs) and infliximab trough levels (ITLs) exists. To report the prevalence of infliximab-associated AEs in IBD patients receiving stable maintenance infliximab therapy, and to correlate ITLs with dermatological and infusion reactions to infliximab. Adult IBD patients receiving stable maintenance infliximab therapy were recruited from the University of Alberta Infusion Clinic (Edmonton, Alberta). ITLs were measured in blood samples collected before infusion, and the patients' records were reviewed for dermatological and infusion reactions to infliximab. One-quarter (18 of 71 [25.4%]) of patients experienced dermatological or infusion reactions to infliximab: nine (12.7%) dermatological events and nine (12.7%) infusion reactions. The median ITL was similar among patients with and without these AEs (7.2 μg⁄mL [interquartile range (IQR) 2.0 μg⁄mL to 13.3 μg⁄mL] versus 6.6 μg⁄mL [IQR 3.2 μg⁄mL to 12.7 μg⁄mL]; P=0.648). The median ITL of patients who experienced infusion reactions (2.0 μg⁄mL [IQR 0.1 μg⁄mL to 5.7 μg⁄mL]) was lower than that of patients who experienced no such AEs (6.6 μg⁄mL [IQR 3.2 μg⁄mL to 12.7 μg⁄mL]; P=0.008]) and lower than that of patients who experienced dermatological AEs (13.3 μg⁄mL [IQR 8.8 μg⁄mL to 17.4 μg⁄mL]; P<0.001). One-quarter of IBD outpatients receiving stable maintenance infliximab therapy experienced dermatological and infusion reactions. Low ITLs were correlated with infusion reactions, and normal or high ITLs with dermatological events.